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Preeclampsia (PE) is characterized by de novo hypertension (HTN) and is often associated with intrauterine growth restriction (IUGR). Hallmarks of PE are placental ischemia, decreased nitric oxide (NO) bioavailability, oxidative stress (OS), and organ damage in the kidneys and brain. This study aims to characterize a new model of PE using pregnant IUGR rats from hypertensive placental ischemic dams. It is hypothesized that pregnant IUGR rats from hypertensive placental ischemic dams will have elevated blood pressure (BP), OS, and organ damage. In this study, pregnant rats are divided into two groups: normal pregnant (NP) and hypertensive placental ischemic dams (RUPP). Offspring from NP and RUPP dams were mated at 10 weeks of age to generate pregnant IUGR (IUGR Preg) and pregnant control (CON Preg) rats. BP and other markers of PE were evaluated during late gestation. Pregnant IUGR rats had elevated BP and systemic OS. The maternal body weight of pregnant IUGR rats and their pups' weights were decreased, while the brains were enlarged with elevated OS. In summary, pregnant IUGR rats, born from hypertensive placental ischemic dams, have HTN and increased systemic and brain OS, with larger brain sizes and smaller pups. Furthermore, this study shows that pregnant IUGR rats exhibit a preeclamptic-like phenotype, suggesting a new epigenetic model of PE., (© 2024 The Author(s). Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

The ability to correctly identify Potential Key Fish Habitats (PKFH) before undertaking development assessments or stream restoration projects is a critical step for determining appropriate management interventions and offset strategies to minimize damage to all life stages of fish. However, there are no rapid, low-cost tools that can be universally utilised to identify PKFH in perennial streams and ephemeral streams in particular. We propose a conceptual framework for developing a rapid field appraisal based on a range of physical fish habitat-supporting features. Four steps are involved in developing the framework: 1) understand fish habitat features using published literature and sub-set model selection using actual data, 2) collect field data, 3) develop the conceptual framework, and 4) classify sites. We tested eight fish habitat-supporting features in the assessment and proposed a decision tree that guided the rapid appraisals at 104 ephemeral sites in southeast Australia. Out of 104 sites, 86% were identified as PKFH, 10% as likely key fish habitats and 4% as unlikely key fish habitats. The rapid field appraisal is cost-effective, simple to implement and does not require expert knowledge of fish habitats. Despite some limitations in the conceptual framework, this appraisal has great potential as a screening technique for PKFH in freshwater streams, particularly ephemeral streams in Australia and other overseas jurisdictions., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Introduction: The 2024 Voice AI Symposium, presented by the Bridge2AI-Voice Consortium, featured deep-dive educational workshops conducted by experts from diverse fields to explore the latest advancements in voice biomarkers and artificial intelligence (AI) applications in healthcare. Through five workshops, attendees learned about topics including international standardization of vocal biomarker data, real-world deployment of AI solutions, assistive technologies for voice disorders, best practices for voice data collection, and deep learning applications in voice analysis. These workshops aimed to foster collaboration between academia, industry, and healthcare to advance the development and implementation of voice-based AI tools., Methods: Each workshop featured a combination of lectures, case studies, and interactive discussions. Transcripts of audio recordings were generated using Whisper (Version 7.13.1) and summarized by ChatGPT (Version 4.0), then reviewed by the authors. The workshops covered various methodologies, from signal processing and machine learning operations (MLOps) to ethical concerns surrounding AI-powered voice data collection. Practical demonstrations of AI-driven tools for voice disorder management and technical discussions on implementing voice AI models in clinical and non-clinical settings provided attendees with hands-on experience., Results: Key outcomes included the discussion of international standards to unify stakeholders in vocal biomarker research, practical challenges in deploying AI solutions outside the laboratory, review of Bridge2AI-Voice data collection processes, and the potential of AI to empower individuals with voice disorders. Additionally, presenters shared innovations in ethical AI practices, scalable machine learning frameworks, and advanced data collection techniques using diverse voice datasets. The symposium highlighted the successful integration of AI in detecting and analyzing voice signals for various health applications, with significant advancements in standardization, privacy, and clinical validation processes., Discussion: The symposium underscored the importance of interdisciplinary collaboration to address the technical, ethical, and clinical challenges in the field of voice biomarkers. While AI models have shown promise in analyzing voice data, challenges such as data variability, security, and scalability remain. Future efforts must focus on refining data collection standards, advancing ethical AI practices, and ensuring diverse dataset inclusion to improve model robustness. By fostering collaboration among researchers, clinicians, and technologists, the symposium laid a foundation for future innovations in AI-driven voice analysis for healthcare diagnostics and treatment., Competing Interests: Several educational workshops were conducted by event sponsors. Sponsored workshops were reviewed by the Symposium Planning Committee prior to acceptance to ensure content met high educational and scientific standards. The following authors were representing their institutions and companies as event sponsors: Nate Blaylock for Canary Speech, Joris Castermans and Akash Raj Komarlu for Whispp, Keith Comito and Greg Hale for ASTM and Walt Disney World Parks and Resorts, and Kimberly Kuman and Charlie Reavis for Dysphonia International. Bridge2AI-Voice is the Precision Public Health Grand Challenge of the Bridge2AI Program, funded by the NIH Common Fund, grant number OT2OD032720-01. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Bahr, Anibal, Bedrick, Bélisle-Pipon, Bensoussan, Blaylock, Castermans, Comito, Dorr, Hale, Jackson, Krussel, Kuman, Komarlu, Lerner-Ellis, Powell, Ravitsky, Rameau, Reavis, Sigaras, Cruz, Vojtech, Urbano, Watts, Zhao, Toghranegar and the Bridge2AI-Voice Consortium.)

Background: Advance care planning (ACP) was encouraged by policymakers throughout the COVID-19 pandemic. Little is known about use of ACP during this time., Aim: To compare use of ACP before and during the COVID-19 pandemic., Design & Setting: Retrospective, observational cohort study comparing the creation, use, and content of Electronic Palliative Care Coordination System (EPaCCS) records in London. Individuals aged ≥18 years with a Coordinate My Care record, created and published in the pre-pandemic period (1 January 2018-31 December 2019), wave 1 (W1; 20 March 2020-4 July 2020), interwave (IW; 5 July 2020-30 September 2020), and wave 2 (W2; 1 October 2020-5 March 2021)., Method: Patient demographics and components of ACP were compared using descriptive and comparative statistics., Results: In total, 73 675 records were included; 35 108 pre-pandemic, 21 235 W1, 6323 IW, and 9925 W2 ( n = 1084 records not stratified as created and published in different periods). Most records were created in primary care (55.6% pre-pandemic, 75.5% W1, and 47.7% W2). Compared with the pre-pandemic period, the average weekly number of records created increased by 296.9% W1 ( P <0.005), 35.1% IW, and 29.1% W2 ( P <0.005). Patients with records created during the pandemic were younger (60.8% aged ≥80 years W1, 57.5% IW, 59.3% W2, 64.9% pre-pandemic [ P <0.005]). Patients with records created in W1 had longer estimated prognoses at record creation (73.3% had an estimated prognosis of ≥1 year W1 versus 53.3% pre-pandemic [ P <0.005]) and were more likely to be 'for resuscitation' (38.2% W1 versus 29.8% pre-pandemic [ P <0.005])., Conclusion: During the COVID-19 pandemic increased ACP activity was observed, especially in primary care, for younger people and those not imminently dying. Further research is needed to identify training and planning requirements as well as organisational and system changes to support sustained high-quality ACP within primary care., (Copyright © 2024, The Authors.)

Purpose: Recent success of human epidermal growth factor receptor 2 (HER2)-targeted antibody-drug-conjugate trastuzumab-deruxtecan in HER2-low and HER2-positive tumors has sparked interest in examining the HER2 status of tumors not traditionally associated with HER2 amplification. Despite the increasing number of systemic treatment options, patients with advanced endometrial cancer (EC) still face a poor prognosis. This study evaluates HER2-low status in over 800 EC, correlating HER2 with both molecular and clinical features., Methods: HER2 status was determined by immunohistochemistry (IHC) and dual in situ hybridization (DISH) on four studies of previously classified high-risk EC (PORTEC-3 and Medical Spectrum Twente cohort), recurrent or metastatic EC (DOMEC), and a primary stage IV cohort. EC was classified as HER2-negative (IHC 0), HER2-low (IHC 1+/2+ without amplification), or HER2-positive (IHC 3+ or DISH-confirmed amplification). Survival analysis was performed using the Kaplan-Meier method. Cox proportional hazards models assessed the independence of any prognostic impact of HER2 status., Results: HER2 status was determined in 806 EC: 74.8% were HER2-negative, 17.2% HER2-low, and 7.9% HER2-positive. HER2-low was found across all molecular classes and histotypes. The highest rates of HER2-low and HER2-positive tumors were in recurrent or metastatic EC (35.6% and 15.6%), followed by primary stage IV EC (29.9% and 12.4%) and high-risk EC (14.2% and 6.8%). HER2 status had no independent prognostic value., Conclusion: A quarter of high-risk, metastatic, or recurrent EC exhibited HER2 overexpression. The presence of HER2 overexpression in all clinical and molecular categories highlights the need for broad testing and offers treatment options for a wide range of patients.

Purpose: We assessed the efficacy of cediranib, olaparib, and cediranib/olaparib compared with standard-of-care chemotherapy (SOC) in platinum-resistant or platinum-refractory epithelial ovarian cancer (PROC)., Patients and Methods: NRG-GY005 is an open-label, four-arm, phase II/III superiority trial enrolling patients with high-grade serous/endometrioid PROC and one to three previous therapies. Key exclusion criteria included previous receipt of poly(ADP-ribose) polymerase inhibitor or receipt of antiangiogenic therapy in the recurrent setting. Treatment arms (SOC [once weekly paclitaxel, topotecan, or pegylated liposomal doxorubicin], cediranib, olaparib, or cediranib/olaparib) were equally randomized. A preplanned interim futility analysis on the basis of progression-free survival (PFS) selected treatment arms to advance to phase III. PFS and overall survival (OS) were phase III coprimary end points, with hierarchical testing of PFS followed by OS to preserve type 1 error control, designed to have 90% power for a 0.625 PFS hazard ratio (HR). OS was tested after PFS in the multiple hierarchical testing procedure. Secondary end points included objective response rate (ORR) and patient-reported outcomes., Results: Five hundred sixty-two eligible patients were enrolled for phase II/III. Three arms met PFS criteria to carry forward to phase III (SOC, cediranib/olaparib, and cediranib). Median PFS was 3.4, 5.2, and 4 months with SOC, cediranib/olaparib, and cediranib, respectively, with a median follow-up duration of 42.2 months. PFS HR estimates for cediranib/olaparib and cediranib ( v SOC) were 0.796 (98.3% CI, 0.597 to 1.060) and 0.972 (98.3% CI, 0.726 to 1.300), respectively. Median OS was 13.6, 12.8, and 10.5 months, and of 443 patients with measurable disease, ORR was 8.6%, 24.7%, and 13.1% for SOC, cediranib/olaparib, and cediranib, respectively. No new safety signals were identified. In patients receiving cediranib/olaparib, no statistically significant difference was observed on the NFOSI-DRS-P subscale compared with SOC (98.3% CI, -1.3 to 1.5, P = .8725)., Conclusion: The cediranib-containing arms demonstrated clinical activity on the basis of PFS but were not superior compared with SOC.

Background: Cellular senescence has been associated with cancer as either a barrier mechanism restricting autonomous cell proliferation or a tumour-promoting microenvironmental mechanism that secretes proinflammatory paracrine factors. With most work done in non-human models and the heterogeneous nature of senescence, the precise role of senescent cells in the development of cancer in humans is not well understood. Furthermore, more than 1 million non-malignant breast biopsies are taken every year that could be a major resource for risk stratification. We aimed to explore the clinical relevance for breast cancer development of markers of senescence in mammary tissue from healthy female donors., Methods: In this retrospective cohort study, we applied single-cell deep learning senescence predictors, based on nuclear morphology, to histological images of haematoxylin and eosin-stained breast biopsy samples from healthy female donors at the Komen Tissue Bank (KTB) at the Indiana University Simon Cancer Center (Indianapolis, IN, USA). All KTB participants (aged ≥18 years) who underwent core biopsies for research purposes between 2009 and 2019 were eligible for the study. Senescence was predicted in the epithelial (terminal duct lobular units [TDLUs] and non-TDLU epithelium), stromal, and adipose tissue compartments using validated models, previously trained on cells induced to senescence by ionising radiation (IR), replicative exhaustion (or replicative senescence; RS), or antimycin A, atazanavir-ritonavir, and doxorubicin (AAD) exposures. To benchmark our senescence-based cancer prediction results, we generated 5-year Gail scores-the current clinical gold standard for breast cancer risk prediction-for participants aged 35 years and older on the basis of characteristics at the time of tissue donation. The primary outcome was estimated odds of breast cancer via logistic modelling for each tissue compartment based on predicted senescence scores in cases (participants who had been diagnosed with breast cancer as of data cutoff, July 31, 2022) and controls (those who had not been diagnosed with breast cancer)., Findings: 4382 female donors (median age at donation 45 years [IQR 34-57]) were eligible for the study. As of data cutoff (median follow-up of 10 years [7-11]), 86 (2·0%) had developed breast cancer a mean of 4·8 years (SD 2·84) after date of donation and 4296 (98·0%) had not received a breast cancer diagnosis. Among the 86 cases, we found significant differences in adipose-specific IR and AAD senescence prediction scores compared with controls. Risk analysis showed that individuals in the upper half (above the median) of scores for the adipose tissue IR model had higher odds of developing breast cancer (odds ratio [OR] 1·71 [95% CI 1·10-2·68]; p=0·019), whereas the adipose AAD model revealed a reduced odds of developing breast cancer (OR 0·57 [0·36-0·88]; p=0·013). For the other tissue compartments and the RS model, no significant associations were found (except for stromal tissue via the IR model, had higher odds of developing breast cancer [OR 1·59, 1·03-2·49]). Individuals with both of the adipose risk factors had an OR of 3·32 (1·68-7·03; p=0·0009). Participants with 5-year Gail scores above the median had an OR for development of cancer of 2·33 (1·46-3·82; p=0·0012) compared with those with scores below the median. When combining Gail scores with our adipose AAD risk model, we found that individuals with both of these predictors had an OR of 4·70 (2·29-10·90; p<0·0001). When combining the Gail score with our adipose IR model, we found that individuals with both predictors had an OR of 3·45 (1·77-7·24; p=0·0002)., Interpretation: Assessment of senescence-associated nuclear morphologies with deep learning allows prediction of future cancer risk from normal breast biopsy samples. The combination of multiple models improved prediction of future breast cancer compared with the current clinical benchmark, the Gail model. Our results suggest an important role for microscope image-based deep learning models in predicting future cancer development. Such models could be incorporated into current breast cancer risk assessment and screening protocols., Funding: Novo Nordisk Foundation, Danish Cancer Society, and the US National Institutes of Health., Competing Interests: Declaration of interests IH, MP, and MS-K have filed a provisional patent related to risk prediction methods. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Prescribed opioid analgesics are frequently used to manage pain in pregnancy. However, the available literature regarding the teratogenic potential of opioid use during pregnancy has not been systematically summarised. This systematic review and meta-analysis aimed to assess the quality of the evidence on these potential risks and calculate a pooled estimate of risk for any opioid analgesic and individual opioids., Methods: We searched PubMed, Embase and CINAHL for published studies assessing the risk of major congenital malformations in infants following first-trimester exposure to opioid analgesics compared with a reference group, excluding studies examining opioid agonist therapy or illicit opioid use. We assessed the risk of bias using the Risk of Bias in Non-Randomised Studies of Intervention tool. We pooled adjusted risk estimates from studies rated at serious risk of bias or better in a random-effects meta-analysis., Results: Of 12 identified studies, 11 were at high risk of bias (eight serious; three critical). Relative to unexposed infants, those exposed to any opioid use during the first trimester of pregnancy were not at an increased risk of major congenital malformations overall (relative risk 1.04, 95%CI 0.98-1.11); cardiovascular malformations (relative risk 1.07, 95%CI 0.96-1.20); or central nervous system malformations (relative risk 1.06, 95%CI 0.92-1.21). Raised risk estimates were observed for gastrointestinal malformations (relative risk 1.40, 95%CI 0.38-5.16) and cleft palate (relative risk 1.57, 95%CI 0.48-5.13) following any opioid exposure and atrial septal defects (relative risk 1.20, 95%CI 1.05-1.36) following codeine exposure., Conclusions: Although the meta-analysis did not indicate substantial increased risk for most malformations examined, this risk remains uncertain due to the methodological limitations of the included studies. Healthcare professionals and pharmaceutical regulators should be aware of the issues related to the quality of research in this field., (© 2024 The Authors. Anaesthesia published by John Wiley & Sons Ltd on behalf of Association of Anaesthetists.)

Importance: Lesbian, gay, bisexual, transgender, queer, and/or questioning (LGBTQ+) youth face worse mental health outcomes than non-LGBTQ+ peers. Family support may mitigate this, but sparse evidence demonstrates this in clinical settings., Objectives: To compare depression and suicide risk between LGBTQ+ and non-LGBTQ+ youth in primary care settings and to investigate whether family support mitigates these negative mental health outcomes., Design, Setting, and Participants: This cross-sectional study uses data from well care visits completed by adolescents aged 13 to 19 years from February 2022 through May 2023, including the Patient Health Questionnaire-9 Modified for Teens (PHQ-9-M) and the Adolescent Health Questionnaire (AHQ; an electronic screener assessing identity, behaviors, and guardian support), at 32 urban or suburban care clinics in Pennsylvania and New Jersey., Exposures: The primary exposure was self-reported LGBTQ+ status. Family support moderators included parental discussion of adolescent strengths and listening to feelings. Race and ethnicity (determined via parent or guardian report at visit check-in), sex, payer, language, age, and geography were covariates., Main Outcomes and Measures: PHQ-9-M-derived mental health outcomes, including total score, recent suicidal ideation, and past suicide attempt., Results: The sample included 60 626 adolescents; among them, 9936 (16.4%) were LGBTQ+, 15 387 (25.5%) were Black, and 30 296 (50.0%) were assigned female sex at birth. LGBTQ+ youth, compared with non-LGBTQ+ youth, had significantly higher median (IQR) PHQ-9-M scores (5 [2-9] vs 1 [0-3]; P < .001) and prevalence of suicidal ideation (1568 [15.8%] vs 1723 [3.4%]; P < .001). Fewer LGBTQ+ youth endorsed parental support than non-LGBTQ+ youth (discussion of strengths, 8535 [85.9%] vs 47 003 [92.7%]; P < .001; and listening to feelings, 7930 [79.8%] vs 47 177 [93.1%]; P < .001). In linear regression adjusted for demographic characteristics and parental discussion of strengths, LGBTQ+ status was associated with a higher PHQ-9-M score (mean difference, 3.3 points; 95% CI, 3.2-3.3 points). In logistic regression, LGBTQ+ youth had increased adjusted odds of suicidal ideation (adjusted odds ratio, 4.3; 95% CI, 4.0-4.7) and prior suicide attempt (adjusted odds ratio, 4.4; 95% CI, 4.0-4.7). Parental support significantly moderated the association of LGBTQ+ status with PHQ-9-M score and suicidal ideation, with greater protection against these outcomes for LGBTQ+ vs non-LGBTQ+ youth., Conclusions and Relevance: Compared with non-LGBTQ+ youth, LGBTQ+ youth at primary care visits had more depressive symptoms and higher odds of suicidal ideation and prior suicide attempt. Youth-reported parental support was protective against these outcomes, suggesting potential benefits of family support-focused interventions to mitigate mental health inequities for LGBTQ+ youth.

Broadening gene therapy applications requires manufacturable vectors that efficiently transduce target cells in humans and preclinical models. Conventional selections of adeno-associated virus (AAV) capsid libraries are inefficient at searching the vast sequence space for the small fraction of vectors possessing multiple traits essential for clinical translation. Here, we present Fit4Function, a generalizable machine learning (ML) approach for systematically engineering multi-trait AAV capsids. By leveraging a capsid library that uniformly samples the manufacturable sequence space, reproducible screening data are generated to train accurate sequence-to-function models. Combining six models, we designed a multi-trait (liver-targeted, manufacturable) capsid library and validated 88% of library variants on all six predetermined criteria. Furthermore, the models, trained only on mouse in vivo and human in vitro Fit4Function data, accurately predicted AAV capsid variant biodistribution in macaque. Top candidates exhibited production yields comparable to AAV9, efficient murine liver transduction, up to 1000-fold greater human hepatocyte transduction, and increased enrichment relative to AAV9 in a screen for liver transduction in macaques. The Fit4Function strategy ultimately makes it possible to predict cross-species traits of peptide-modified AAV capsids and is a critical step toward assembling an ML atlas that predicts AAV capsid performance across dozens of traits., (© 2024. The Author(s).)

Background Ambulance callouts and conveyances continue to increase disproportionately to population growth. This is largely driven by low- and medium-acuity patients who do not require ambulance management. We aimed to estimate the proportion of patients paramedics have conveyed to an emergency department (ED) via ambulance whom they considered suitable for primary care, and understand the barriers that contributed to these decisions. Methods A cross-sectional survey of registered paramedics in Victoria, Australia, was undertaken using an online questionnaire during 2022. Responses are presented using descriptive statistics, and logistic regression was used to identify associations between paramedic characteristics and barriers influencing primary care pathway referral. Results A total of 367 responses were received. Of these, 70% of paramedics reported that at least half of the patients they conveyed to an ED were suitable for a primary care pathway. Paramedics reported high levels of confidence and support for primary care pathways in lieu of transport, however this had no correlation with their self-reported practice. The most common barrier to primary care pathway referral was limited access to a suitable primary care pathway (68%) followed by fear of an internal complaint, litigation or organisational pressure to convey patients to an ED (66%). Paramedics regarded themselves as more supportive of primary care pathway referral than those around them, including their peers, mentors, employers and university. They also reported that the COVID-19 pandemic had increased their personal support for primary care pathways, as well as organisational support from their employer, without corresponding increase in the broader medical and public communities. In fact, paramedics reported the COVID-19 pandemic had decreased support from the public and patients to refer patients to primary care pathways, and 57% of paramedics reported conveying a patient that had declined their primary care referral in the past week. Conclusions Paramedics frequently convey to an ED patients who they believe are appropriate for a primary care pathway. Paramedics face practical barriers such as a lack of available primary care providers and perceived lack of cultural support that contribute to this practice.

Objective: The vocal biomarkers market was worth $1.9B in 2021 and is projected to exceed $5.1B by 2028, for a compound annual growth rate of 15.15%. The investment growth demonstrates a blossoming interest in voice and artificial intelligence (AI) as it relates to human health. The objective of this study was to map the current landscape of start-ups utilizing voice as a biomarker in health-tech., Data Sources: A comprehensive search for start-ups was conducted using Google, LinkedIn, Twitter, and Facebook. A review of the research was performed using company website, PubMed, and Google Scholar., Review Methods: A 3-pronged approach was taken to thoroughly map the landscape. First, an internet search was conducted to identify current start-ups focusing on products relating to voice as a biomarker of health. Second, Crunchbase was utilized to collect financial and organizational information. Third, a review of the literature was conducted to analyze publications associated with the identified start-ups., Results: A total of 27 start-up start-ups with a focus in the utilization of AI for developing biomarkers of health from the human voice were identified. Twenty-four of these start-ups garnered $178,808,039 in investments. The 27 start-ups published 194 publications combined, 128 (66%) of which were peer reviewed., Conclusion: There is growing enthusiasm surrounding voice as a biomarker in health-tech. Academic drive may complement commercialization to best achieve progress in this arena. More research is needed to accurately capture the entirety of the field, including larger industry players, academic institutions, and non-English content., (© 2024 American Academy of Otolaryngology–Head and Neck Surgery Foundation.)

Background: Part 1 of the RUBY trial (NCT03981796) evaluated dostarlimab plus carboplatin-paclitaxel compared with placebo plus carboplatin-paclitaxel in patients with primary advanced or recurrent endometrial cancer (EC). At the first interim analysis, the trial met one of its dual primary endpoints with statistically significant progression-free survival benefits in the mismatch repair-deficient/microsatellite instability-high (dMMR/MSI-H) and overall populations. Overall survival (OS) results are reported from the second interim analysis., Patients and Methods: RUBY is a phase III, global, double-blind, randomized, placebo-controlled trial. Part 1 of RUBY enrolled eligible patients with primary advanced stage III or IV or first recurrent EC who were randomly assigned (1 : 1) to receive either dostarlimab (500 mg) or placebo, plus carboplatin-paclitaxel every 3 weeks for 6 cycles followed by dostarlimab (1000 mg) or placebo every 6 weeks for up to 3 years. OS was a dual primary endpoint., Results: A total of 494 patients were randomized (245 in the dostarlimab arm; 249 in the placebo arm). In the overall population, with 51% maturity, RUBY met the dual primary endpoint for OS at this second interim analysis, with a statistically significant reduction in the risk of death [hazard ratio (HR) = 0.69, 95% confidence interval (CI) 0.54-0.89, P = 0.0020] in patients treated with dostarlimab plus carboplatin-paclitaxel versus carboplatin-paclitaxel alone. The risk of death was lower in the dMMR/MSI-H population (HR = 0.32, 95% CI 0.17-0.63, nominal P = 0.0002) and a trend in favor of dostarlimab was seen in the mismatch repair-proficient/microsatellite stable population (HR = 0.79, 95% CI 0.60-1.04, nominal P = 0.0493). The safety profile for dostarlimab plus carboplatin-paclitaxel was consistent with the first interim analysis., Conclusions: Dostarlimab in combination with carboplatin-paclitaxel demonstrated a statistically significant and clinically meaningful OS benefit in the overall population of patients with primary advanced or recurrent EC while demonstrating an acceptable safety profile., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: Voice as a health biomarker using artificial intelligence (AI) is gaining momentum in research. The noninvasiveness of voice data collection through accessible technology (such as smartphones, telehealth, and ambient recordings) or within clinical contexts means voice AI may help address health disparities and promote the inclusion of marginalized communities. However, the development of AI-ready voice datasets free from bias and discrimination is a complex task. The objective of this study is to better understand the perspectives of engaged and interested stakeholders regarding ethical and trustworthy voice AI, to inform both further ethical inquiry and technology innovation., Methods: A questionnaire was administered to voice AI experts, clinicians, scholars, patients, trainees, and policy-makers who participated at the 2023 Voice AI Symposium organized by the Bridge2AI-Voice AI Consortium. The survey used a mix of Likert scale, ranking and open-ended questions. A total of 27 stakeholders participated in the study., Results: The main results of the study are the identification of priorities in terms of ethical issues, an initial definition of ethically sourced data for voice AI, insights into the use of synthetic voice data, and proposals for acting on the trustworthiness of voice AI. The study shows a diversity of perspectives and adds nuance to the planning and development of ethical and trustworthy voice AI., Conclusions: This study represents the first stakeholder survey related to voice as a biomarker of health published to date. This study sheds light on the critical importance of ethics and trustworthiness in the development of voice AI technologies for health applications., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2024.)

Background: Surface contamination with antineoplastic drugs (ADs) is persistent. The use of personal protective equipment (PPE) is recommended to reduce exposure to ADs., Objectives: This study explored the impact of the COVID-19 pandemic on nurses' PPE use and surface contamination with ADs., Methods: Demographic characteristics, PPE use, and associated factors were assessed on two inpatient oncology units where etoposide and cyclophosphamide were administered before (N = 26) and during the COVID-19 pandemic (N = 31)., Findings: PPE use when handling contaminated excreta was significantly higher during the pandemic. Perceived risk of chemotherapy exposure was significantly associated with greater PPE use when handling AD-contaminated excreta, and conflict of interest was related to less PPE use during AD administration and handling of AD-contaminated excreta. During the pandemic, surface contamination with etoposide increased in shared areas and decreased in patient rooms.

Endometrial cancer continues to be the only gynecologic malignancy with a rising incidence and mortality, with both regional and global implications. Combination carboplatin and paclitaxel has been the recognized chemotherapy backbone for the treatment of advanced-stage or recurrent disease, with modest clinical outcomes. Over the last year, significant advances were achieved in improving oncologic outcomes by capitalizing on the molecular characterization of this heterogenous disease. These advances include incorporation of immunotherapy, identification of effective hormonal approaches, the evolution of antibody drug conjugates, and utilization of alternate targeted therapies. PLAIN LANGUAGE SUMMARY: The molecular characterization of endometrial cancer has been critical in informing novel treatment strategies. Over the past year, significant gains have been made via the incorporation of immunotherapy, hormonal combinations as well as antibody drug conjugates., (© 2024 American Cancer Society.)

Purpose: Pelvic recurrence is a frequent pattern of relapse for women with endometrial cancer. A randomized trial compared progression-free survival (PFS) after treatment with radiation therapy alone as compared with concurrent chemotherapy., Materials and Methods: Between February 2008 and August 2020, 165 patients were randomly assigned 1:1 to receive either radiation treatment alone or a combination of chemotherapy and radiation treatment. The primary objective of this study was to determine whether chemoradiation therapy was more effective than radiation therapy alone at improving PFS., Results: The majority of patients had low-grade (1 or 2) endometrioid histology (82%) and recurrences confined to the vagina (86%). External beam with either the three-dimensional or intensity modulated radiation treatment technique was followed by a boost delivered with brachytherapy or external beam. Patients randomly assigned to receive chemotherapy were treated with once weekly cisplatin (40 mg/m 2 ). Rates of acute toxicity were higher in patients treated with chemoradiation as compared with radiation treatment alone. Median PFS was longer for patients treated with radiation therapy alone as compared with chemotherapy and radiation (median PFS was not reached for RT v 73 months for chemoradiation, hazard ratio of 1.25 (95% CI, 0.75 to 2.07). At 3 years, 73% of patients treated definitively with radiation and 62% of patients treated with chemoradiation were alive and free of disease progression., Conclusion: Excellent outcomes can be achieved for women with localized recurrences of endometrial cancer when treated with radiation therapy. The addition of chemotherapy does not improve PFS for patients treated with definitive radiation therapy for recurrent endometrial cancer and increases acute toxicity. Patients with low-grade and vaginal recurrences who constituted the majority of those enrolled are best treated with radiation therapy alone.

Background and Objectives: Adolescent strengths and risks are not routinely captured in systematized and actionable ways in pediatric primary care. To address this problem, we developed a comprehensive adolescent health questionnaire (AHQ) integrated within the electronic health record and evaluated the AHQ's impact on collection of information on prioritized health-related domains., Methods: We developed and pilot tested the AHQ. We then scaled and assessed the AHQ's impact on data collection. AHQ development used innovation methods and measured feasibility and acceptability outcomes. Scaling and postscaling outcomes included Reach, Effectiveness, Adoption, Implementation, Maintenance and Sustainability measures: Reach (total questionnaires completed), Effectiveness (capture of key information across health domains pre- vs post-AHQ scaling), Adoption (proportion of practices that adopted the AHQ), Implementation (proportion of eligible adolescents who completed the AHQ), and Maintenance (monthly completion rates)., Results: AHQ development led to a tool that was feasible and acceptable for use. During scaling (October 2020-December 2021), 22 147 questionnaires were completed by 20 749 unique adolescents aged 13 to 21 years at their preventive visit. Comparing pre- versus post-AHQ scaling data, use of the AHQ increased collection of information across domains, especially for strengths, gun safety, substance use, sexual activity, sexual orientation, and gender identity, from ranges of 0%-25% to 92%-95%. All 31 practices adopted the AHQ with completion at 88.7% of visits (n = 24 968). Two years postscaling, completion rates were >91% per month., Conclusions: We successfully developed, scaled, and maintained an AHQ in a widely-used electronic health record system, a model for improving adolescent care and foundation for developing future interventions., (Copyright © 2024 by the American Academy of Pediatrics.)

Circadian gene expression is fundamental to the establishment and functions of the circadian clock, a cell-autonomous and evolutionary-conserved timing system. Yet, how it is affected by environmental-circadian disruption (ECD) such as shiftwork and jetlag are ill-defined. Here, we provided a comprehensive and comparative description of male liver circadian gene expression, encompassing transcriptomes, whole-cell proteomes and nuclear proteomes, under normal and after ECD conditions. Under both conditions, post-translation, rather than transcription, is the dominant contributor to circadian functional outputs. After ECD, post-transcriptional and post-translational processes are the major contributors to whole-cell or nuclear circadian proteome, respectively. Furthermore, ECD re-writes the rhythmicity of 64% transcriptome, 98% whole-cell proteome and 95% nuclear proteome. The re-writing, which is associated with changes of circadian regulatory cis-elements, RNA-processing and protein localization, diminishes circadian regulation of fat and carbohydrate metabolism and persists after one week of ECD-recovery., (© 2024. The Author(s).)

The COVID-19 pandemic has been associated with increases in pediatric obesity and widening pre-existing disparities. To better understand the pandemic's long-term impacts, we evaluated trends in obesity across different demographic groups during the pandemic through December 2022. Using a retrospective cohort design, we analyzed electronic health record data from a large pediatric primary care network. Logistic regression models fit using generalized estimating equations estimated odds ratios (ORs) for changes in the level and trajectory of obesity across 2-year month-matched periods: prepandemic (June 2017 to December 2019) and pandemic (June 2020 to December 2022). Among a cohort of 153,667 patients with visits in each period, there was a significant increase in the level of obesity at the pandemic onset [OR: 1.229, 95% confidence interval (CI): 1.211-1.247] followed by a significant decrease in the trend for obesity (OR: 0.993, 95% CI: 0.992-0.993). By December 2022, obesity had returned to prepandemic levels. However, persistent sociodemographic disparities remain.

Purpose: This paper compares how the two interacting themes of "Whistleblowing" or "Speaking Up" and the duty of candour (DoC), which are both concerned with safety and quality improvement in health care, got onto the agenda of the British National Health Service (NHS)., Design/methodology/approach: It uses the approach of multiple streams and the methodology of interpretive content analysis in a deductive approach that focusses on both manifest and latent content. It examines official documents that discuss the DoC or whistleblowing or cognate terms in connection with the British NHS from 1999 to 2019., Findings: The main conceptual finding, which mirrors many previous studies, is that it seems difficult to operationalise many of the sub-components of the multiple streams approach. The main empirical finding points to the "focusing event" of the Francis Report into the Mid Staffordshire Trust of 2013 and the importance of its Chair, Sir Robert Francis, as a policy entrepreneur., Originality/value: This is one of the first studies to focus on both issues of whistleblowing and the DoC and the first to compare them through the lens of the multiple streams approach. It has two main conceptual advantages over most previous studies in the field: it compares whistleblowing and the duty of candour rather than the dominant approach of a single case study and explores the different outcomes of failed as well as successful couplings of the streams., (© Emerald Publishing Limited.)

Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationship that could be construed as a potential conflict of interest.

Developing vehicles that efficiently deliver genes throughout the human central nervous system (CNS) will broaden the range of treatable genetic diseases. We engineered an adeno-associated virus (AAV) capsid, BI-hTFR1, that binds human transferrin receptor (TfR1), a protein expressed on the blood-brain barrier. BI-hTFR1 was actively transported across human brain endothelial cells and, relative to AAV9, provided 40 to 50 times greater reporter expression in the CNS of human TFRC knockin mice. The enhanced tropism was CNS-specific and absent in wild-type mice. When used to deliver GBA1 , mutations of which cause Gaucher disease and are linked to Parkinson's disease, BI-hTFR1 substantially increased brain and cerebrospinal fluid glucocerebrosidase activity compared with AAV9. These findings establish BI-hTFR1 as a potential vector for human CNS gene therapy.

Background: Social media use has potential to facilitate the rapid dissemination of research evidence to busy health and social care practitioners., Objective: This study aims to quantitatively synthesize evidence of the between- and within-group effectiveness of social media for dissemination of research evidence to health and social care practitioners. It also compared effectiveness between different social media platforms, formats, and strategies., Methods: We searched electronic databases for articles in English that were published between January 1, 2010, and January 10, 2023, and that evaluated social media interventions for disseminating research evidence to qualified, postregistration health and social care practitioners in measures of reach, engagement, direct dissemination, or impact. Screening, data extraction, and risk of bias assessments were carried out by at least 2 independent reviewers. Meta-analyses of standardized pooled effects were carried out for between- and within-group effectiveness of social media and comparisons between platforms, formats, and strategies. Certainty of evidence for outcomes was assessed using the GRADE (Grading of Recommendations, Assessment, Development, and Evaluations) framework., Results: In total, 50 mixed-quality articles that were heterogeneous in design and outcome were included (n=9, 18% were randomized controlled trials [RCTs]). Reach (measured in number of practitioners, impressions, or post views) was reported in 26 studies. Engagement (measured in likes or post interactions) was evaluated in 21 studies. Direct dissemination (measured in link clicks, article views, downloads, or altmetric attention score) was analyzed in 23 studies (8 RCTs). Impact (measured in citations or measures of thinking and practice) was reported in 13 studies. Included studies almost universally indicated effects in favor of social media interventions, although effect sizes varied. Cumulative evidence indicated moderate certainty of large and moderate between-group effects of social media interventions on direct dissemination (standardized mean difference [SMD] 0.88; P=.02) and impact (SMD 0.76; P<.001). After social media interventions, cumulative evidence showed moderate certainty of large within-group effects on reach (SMD 1.99; P<.001), engagement (SMD 3.74; P<.001), and direct dissemination (SMD 0.82; P=.004) and low certainty of a small within-group effect on impacting thinking or practice (SMD 0.45; P=.02). There was also evidence for the effectiveness of using multiple social media platforms (including Twitter, subsequently rebranded X; and Facebook), images (particularly infographics), and intensive social media strategies with frequent, daily posts and involving influential others. No included studies tested the dissemination of research evidence to social care practitioners., Conclusions: Social media was effective for disseminating research evidence to health care practitioners. More intense social media campaigns using specific platforms, formats, and strategies may be more effective than less intense interventions. Implications include recommendations for effective dissemination of research evidence to health care practitioners and further RCTs in this field, particularly investigating the dissemination of social care research., Trial Registration: PROSPERO International Prospective Register of Systematic Reviews CRD42022378793; https://www.crd.york.ac.uk/prospero/display&#95;record.php?RecordID=378793., International Registered Report Identifier (irrid): RR2-10.2196/45684., (©Sarah Roberts-Lewis, Helen Baxter, Gill Mein, Sophia Quirke-McFarlane, Fiona J Leggat, Hannah Garner, Martha Powell, Sarah White, Lindsay Bearne. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 05.06.2024.)

Patients with autoimmune diseases are at higher risk for severe infection due to their underlying disease and immunosuppressive treatments. In this real-world observational study of 463 patients with autoimmune diseases, we examined risk factors for poor B and T cell responses to SARS-CoV-2 vaccination. We show a high frequency of inadequate anti-spike IgG responses to vaccination and boosting in the autoimmune population but minimal suppression of T cell responses. Low IgG responses in B cell-depleted patients with multiple sclerosis (MS) were associated with higher CD8 T cell responses. By contrast, patients taking mycophenolate mofetil (MMF) exhibited concordant suppression of B and T cell responses. Treatments with highest risk for low anti-spike IgG response included B cell depletion within the last year, fingolimod, and combination treatment with MMF and belimumab. Our data show that the mRNA-1273 (Moderna) vaccine is the most effective vaccine in the autoimmune population. There was minimal induction of either disease flares or autoantibodies by vaccination and no significant effect of preexisting anti-type I IFN antibodies on either vaccine response or breakthrough infections. The low frequency of breakthrough infections and lack of SARS-CoV-2-related deaths suggest that T cell immunity contributes to protection in autoimmune disease.

Background: There is growing awareness that a proportion of children in orphanages have been recruited or transferred into the facility for a purpose of exploitation and/or profit. These children are often falsely presented as orphans to evoke sympathy and solicit funding. This process is known as orphanage trafficking. Although orphanage trafficking can be prosecuted under legal frameworks in some jurisdictions, including Cambodia, there have been limited prosecutions to date. One factor that likely contributes to a lack of prosecution is poor detection, yet the indicators of orphanage trafficking have not been considered by extant research., Objective: The current study was conducted as a first step towards providing evidence-based indicators of orphanage trafficking., Participants and Setting: Professionals who had identified or responded to cases of orphanage-based exploitation in Cambodia were interviewed. Participants included criminal justice professionals, investigators from civil society organisations, and child protection social workers., Methods: Professionals' perspectives on how to identify orphanage trafficking were explored via in-depth interviews, and the data were analysed via thematic analysis., Results: The analysis revealed a distinct set of indicators that may be used to detect orphanage trafficking, including the operation of an unauthorised facility, orphanage tourism and volunteering, and an overt focus on fundraising., Conclusion: The indicators revealed in this study point to the need for an effective and thorough monitoring system for orphanages, as well as adequate education and training of relevant personnel to aid in the detection of orphanage trafficking., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Group B streptococcus (GBS) remains a leading cause of infant sepsis, meningitis and death despite intrapartum antibiotic prophylaxis. A vaccine is urgently required, and two candidates are in advanced clinical trials. For successful GBS vaccine implementation, especially if a vaccine is licensed based on an immunological threshold, there must be cross-sector engagement, effective advocacy, robust plans for phase IV studies and equitable access., Meeting: A round-table discussion, held at St George's University of London, reviewed the current position of GBS vaccines in the UK context, focusing on phase IV plans, convening a diverse group of stakeholders from across the UK, with a role in GBS vaccine licensure, advocacy, implementation or effectiveness evaluation.Presentations outlined the latest UK epidemiology, noting the rising infant invasive GBS (iGBS) infection rates from 1996 to 2021 for both early and late onset disease, with the highest disease rates in Black infants (1.1/1000 livebirths vs white infants (0.81/1000 livebirths). Potential coverage of the candidate vaccines was high (>95%). Regulatory input suggested that EU regulators would consider waiving the need for a pre-licensure efficacy study if a putative correlate of protection could be adequately justified. Phase IV study methodologies for a GBS vaccine were considered, largely based on previous UK maternal vaccine assessments, such as a nationwide cohort study design using a vaccine register and a maternal services dataset. Other strategies were also discussed such as a cluster or stepped-wedge randomised trial to evaluate implementation outcomes. Opportunities for advocacy, education and engagement with additional key partners were discussed and identified., Conclusions: With an approved GBS vaccine a near possibility, planning of phase IV studies and identification of critical barriers to implementation are urgently needed. Cross-sector engagement is essential and will facilitate a successful pathway., Competing Interests: No competing interests were disclosed., (Copyright: © 2024 Thorn N et al.)

Background: Immunotherapy has transformed the endometrial cancer treatment landscape, particularly for those exhibiting mismatch repair deficiency [MMRd/microsatellite instability-hypermutated (MSI-H)]. A growing body of evidence supports the integration of immunotherapy with chemotherapy as a first-line treatment strategy. Recently, findings from ongoing trials such as RUBY (NCT03981796), NRG-GY018 (NCT03914612), AtTEnd (NCT03603184), and DUO-E (NCT04269200) have been disclosed., Materials and Methods: This paper constitutes a review and meta-analysis of phase III trials investigating the role of immunotherapy in the first-line setting for advanced or recurrent endometrial cancer., Results: The pooled data from 2320 patients across these trials substantiate the adoption of chemotherapy alongside immunotherapy, revealing a significant improvement in progression-free survival compared to chemotherapy alone [hazard ratio (HR) 0.70, 95% confidence interval (CI) 0.62-0.79] across all patient groups. Progression-free survival benefits are more pronounced in MMRd/MSI-H tumors (n = 563; HR 0.33, 95% CI 0.23-0.43). This benefit, albeit less robust, persists in the MMR-proficient/microsatellite stable group (n = 1757; HR 0.74, 95% CI 0.60-0.91). Pooled data further indicate that chemotherapy plus immunotherapy enhances overall survival compared to chemotherapy alone in all patients (HR 0.75, 95% CI 0.63-0.89). However, overall survival data maturity remains low., Conclusions: The incorporation of immunotherapy into the initial treatment for advanced and metastatic endometrial cancer brings about a substantial improvement in oncologic outcomes, especially within the MMRd/MSI-H subset. This specific subgroup is currently a focal point of investigation for evaluating the potential of chemotherapy-free regimens. Ongoing exploratory analyses aim to identify non-responding patients eligible for inclusion in clinical trials., (Copyright © 2024 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)

Issues: Although maternal substance use is a known risk factor for child maltreatment, evidence on the scale of substance use is needed to inform prevention responses. This systematic review synthesised prevalence estimates of maternal substance use during pregnancy and early life among children at risk of maltreatment. Ovid, Pubmed, CINAHL, PsychInfo and ProQuest databases were searched. We included observational studies that sampled children at risk of maltreatment in high-income countries and reported information on maternal substance use during pregnancy and/or the child's first year of life. We extracted study characteristics and data to calculate prevalence, assessed risk of bias and conducted a narrative synthesis; there were insufficient comparable populations or outcomes to quantitatively synthesise results., Key Findings: Thirty five of 14,084 titles were included. Fifteen studies had adequately sized and representative samples to estimate prevalence. Maternal substance use prevalence ranged from 2.4% to 40.6%. Maternal substance use was highest among infants referred to child protection at birth (40.6%) and children in out-of-home care (10.4% to 37.2%). Prevalence was higher when studies defined substance use more broadly and when maternal substance use was ascertained from both child and mother records., Implications: Supportive, coordinated responses to maternal substance use are needed from health and child protection services, spanning alcohol and other drug treatment, antenatal and postnatal care., Conclusions: Prenatal and early life maternal substance use is common among child maltreatment populations, particularly among younger children and those with more serious maltreatment., (© 2024 The Authors. Drug and Alcohol Review published by John Wiley & Sons Australia, Ltd on behalf of Australasian Professional Society on Alcohol and other Drugs.)

Objectives: Interprofessional education is recognized for its potential for collaboration and teamwork, reflecting clinical practice; however, existing literature for simulation-based interprofessional education does not include Physician Associate (PA) students. This initiative aimed to explore the students' perception of interprofessional clinical simulation for PA students and allied health professional (AHP) students as part of our program development., Methods: A high-fidelity simulation session was designed and conducted for volunteering students from the PA, paramedic science, and physiotherapy courses. We used a mixed-method electronic questionnaire consisting of 15 statements rated on a numerical rating scale (0-5) and four open-ended questions with unlimited free-text responses to explore student perceptions. Inductive thematic analysis was used for qualitative analysis. The session design was underpinned by Allport's (intergroup) contact hypothesis with an emphasis on mutual intergroup differentiation., Results: Forty-six students participated in the simulation teaching, with 48% (n = 22) providing feedback. Overall student perception was mainly positive toward the interprofessional simulation; however, some barriers to learning were recognized. Based on the evaluation of our initiative and existing literature, we propose 5 top tips to promote an effective learning experience for students. (1) Understand the importance of interprofessional collaboration. (2) Establish clear roles. (3) Plan the scenarios in advance. (4) Maintain equal status between groups. (5) Provide clear instructions and expectations., Conclusion: To our knowledge, this is the first study of high-fidelity interprofessional simulation involving PA and AHP students. We successfully explored student perception which highlighted aspects that can impact learning. This pilot study demonstrated that interprofessional simulation is a feasible and acceptable form of learning for our students and highlighted how to improve future interprofessional simulation teaching sessions., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2024.)

Objectives: Universal opt-out antenatal screening for Hepatitis C virus (HCV) is not currently recommened and it is recommended that maternity services offer risk-based testing. We aimed to investigate antenatal HCV testing and adherence to testing guidance., Methods: A cross-sectional survey was circulated to maternity service providers between November-December 2020 which included testing policy, training for healthcare staff, and management of women found to be HCV positive. Descriptive data are presented., Results: A total of 75 questionnaires were returned, representing 48 % of English maternity service providers. 87 % of providers reported offering antenatal HCV risk-based testing. Risk factors used to identify pregnant women for testing varied. Less than 15 % of respondents considered women that were ever homeless or with history of incarceraton or from higher HCV prevalence areas as high risk., Conclusions: Current antenatal HCV testing practices are inadequate and HCV infection likely goes undiagnosed in pregnancy, especially among vulnerable population groups. In the absence of universal antenatal screening, re-framing antenatal HCV risk-based testing and management as a quality improvement initiative and developing HCV specific pathway guidance for maternity units is required., (© 2024 Walter de Gruyter GmbH, Berlin/Boston.)

Purpose: This paper reports the efficacy of the poly (ADP-ribose) polymerase inhibitor olaparib alone and in combination with the antiangiogenesis agent cediranib compared with cediranib alone in patients with advanced endometrial cancer., Methods: This was open-label, randomized, phase 2 trial (NCT03660826). Eligible patients had recurrent endometrial cancer, received at least one (<3) prior lines of chemotherapy, and were Eastern Cooperative Oncology Group performance status 0 to 2. Patients were randomly assigned (1:1:1), stratified by histology (serous vs. other) to receive cediranib alone (reference arm), olaparib, or olaparib and cediranib for 28-day cycles until progression or unacceptable toxicity. The primary end point was progression-free survival in the intention-to-treat population. Homologous repair deficiency was explored using the BROCA-GO sequencing panel., Results: A total of 120 patients were enrolled and all were included in the intention-to-treat analysis. Median age was 66 (range, 41-86) years and 47 (39.2%) had serous histology. Median progression-free survival for cediranib was 3.8 months compared with 2.0 months for olaparib (hazard ratio, 1.45 [95% CI, 0.91-2.3] p = .935) and 5.5 months for olaparib/cediranib (hazard ratio, 0.7 [95% CI, 0.43-1.14] p = .064). Four patients receiving the combination had a durable response lasting more than 20 months. The most common grade 3/4 toxicities were hypertension in the cediranib (36%) and olaparib/cediranib (33%) arms, fatigue (20.5% olaparib/cediranib), and diarrhea (17.9% cediranib). The BROCA-GO panel results were not associated with response., Conclusion: The combination of cediranib and olaparib demonstrated modest clinical efficacy; however, the primary end point of the study was not met. The combination was safe without unexpected toxicity., (© 2023 American Cancer Society.)

Objective: This qualitative study aimed to identify categories within therapeutic self-compassion letters written by healthcare workers. Resulting categories were assessed for their relevance to the construct of self-compassion., Design: This was a qualitative descriptive study that used summative content analysis and inductive coding., Setting: A US-based academic healthcare system., Participants: Healthcare workers who attended a self-compassion webinar were recruited., Intervention: The online self-compassion tool asked participants to write a letter to themselves from the perspective of a friend providing support and encouragement., Results: 116 letters were analysed. Five major categories emerged: Looking Forward, Reaffirming Self, Reaffirming Reminders, Hardships and Self-Disparagement. Respondents' letters were mostly positively framed and forward thinking, including their hopes of improving themselves and their lives in the future. Negative content generally described hardships and often served to provide self-validation or perspective on obstacles that had been overcome., Conclusion: The writing prompt elicited content from the writers that reflected the core elements of self-compassion (ie, self-kindness, common humanity, mindfulness). Continued research to further understand, refine and improve the impact of therapeutic letter writing to enhance well-being is warranted to reduce burnout and promote quality patient care., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Doxycycline postexposure prophylaxis (doxy-PEP) reduces sexually transmitted infections (STIs) in men who have sex with men (MSM) and transgender women (TGW). In a clinical trial of doxy-PEP, we sought to assess acceptability, impact, and meaning of doxy-PEP use among MSM/TGW. We conducted semistructured, in-depth 1:1 interviews with MSM and TGW enrolled in the intervention arm of the Doxy-PEP study. We queried motivations for and meaning of use, attitudes, beliefs, adherence, effect on sexual behaviors, and partner, community, and structural factors related to use. We coded interview transcripts into content areas, followed by thematic analysis. We interviewed 44 participants (median age 38), 2% were TGW, 17% Black, 61% White, 30% Hispanic, and 45% persons with HIV. We identified three overarching themes. First, participants found doxy-PEP acceptable, and believed it was effective based on their history of STIs, easy to adhere to, and acceptable to sex partners. Second, doxy-PEP benefited their quality of life and mental health, offering "peace of mind" by reducing their anxiety about acquisition or unwitting transmission of STIs. Participants reported feeling more "in control" of preventing STIs, and positive about supporting their personal, partner, and community health. Third, impact on sexual behavior was variable, with most reporting no change or a brief initial change. Participants in a multi-site clinical trial of doxycycline for STI prevention perceived it to be efficacious, and that it provided quality-of-life benefits, including reduced anxiety and sense of control over sexual health. Doxy-PEP had limited impact on sexual behavior. Clinicaltrials.gov: NCT03980223.

Background: In recent years, stimulant use has increased among persons who use opioids in the rural U.S., leading to high rates of overdose and death. We sought to understand motivations and contexts for stimulant use among persons who use opioids in a large, geographically diverse sample of persons who use drugs (PWUD) in the rural settings., Methods: We conducted semi-structured individual interviews with PWUD at 8 U.S. sites spanning 10 states and 65 counties. Content areas included general substance use, injection drug use, changes in drug use, and harm reduction practices. We used an iterative open-coding process to comprehensively itemize and categorize content shared by participants related to concurrent use., Results: We interviewed 349 PWUD (64% male, mean age 36). Of those discussing current use of stimulants in the context of opioid use (n = 137, 39%), the stimulant most used was methamphetamine (78%) followed by cocaine/crack (26%). Motivations for co-use included: 1) change in drug markets and cost considerations; 2) recreational goals, e.g., seeking stronger effects after heightened opioid tolerance; 3) practical goals, such as a desire to balance or alleviate the effects of the other drug, including the use of stimulants to avoid/reverse opioid overdose, and/or control symptoms of opioid withdrawal; and 4) functional goals, such as being simultaneously energized and pain-free in order to remain productive for employment., Conclusion: In a rural U.S. cohort of PWUD, use of both stimulants and opioids was highly prevalent. Reasons for dual use found in the rural context compared to urban studies included changes in drug availability, functional/productivity goals, and the use of methamphetamine to offset opioid overdose. Education efforts and harm reduction services and treatment, such as access to naloxone, fentanyl test strips, and accessible drug treatment for combined opioid and stimulant use, are urgently needed in the rural U.S. to reduce overdose and other adverse outcomes., (© 2024. The Author(s).)

This paper explores the keywords of 'National', 'Health' and Service' in the road to the NHS in 1948. It uses a form of Qualitative Content Analysis to analyse key documents in the period leading to the 'Appointed Day' when the NHS was created in 1948. In terms of 'national', most documents favoured Local Authorities, with 'National' coming rather late in the day. For 'health', most of the documents 'talk' of a broad or 'positive' health, but they lack any specific details, and seem to focus on a narrower curative medical service. Finally, most proposals relating to 'service' are based on insurance and a '90% service', with the free and universal (100%) service arriving rather late in the period. Clearly, the three keywords could be combined in many ways, resulting in many possible types of NHS. However, bringing them together suggests that it was probably only with Beveridge onwards that the three keywords of national, health and service (citizenship) combined to form Bevan's NHS.

Introduction: Accuracy and validity of voice AI algorithms rely on substantial quality voice data. Although commensurable amounts of voice data are captured daily in voice centers across North America, there is no standardized protocol for acoustic data management, which limits the usability of these datasets for voice artificial intelligence (AI) research., Objective: The aim was to capture current practices of voice data collection, storage, analysis, and perceived limitations to collaborative voice research., Methods: A 30-question online survey was developed with expert guidance from the voicecollab.ai members, an international collaborative of voice AI researchers. The survey was disseminated via REDCap to an estimated 200 practitioners at North American voice centers. Survey questions assessed respondents' current practices in terms of acoustic data collection, storage, and retrieval as well as limitations to collaborative voice research., Results: Seventy-two respondents completed the survey of which 81.7% were laryngologists and 18.3% were speech language pathologists (SLPs). Eighteen percent of respondents reported seeing 40%-60% and 55% reported seeing >60 patients with voice disorders weekly (conservative estimate of over 4000 patients/week). Only 28% of respondents reported utilizing standardized protocols for collection and storage of acoustic data. Although, 87% of respondents conduct voice research, only 38% of respondents report doing so on a multi-institutional level. Perceived limitations to conducting collaborative voice research include lack of standardized methodology for collection (30%) and lack of human resources to prepare and label voice data adequately (55%)., Conclusion: To conduct large-scale multi-institutional voice research with AI, there is a pertinent need for standardization of acoustic data management, as well as an infrastructure for secure and efficient data sharing., Level of Evidence: 5 Laryngoscope, 134:1333-1339, 2024., (© 2023 The American Laryngological, Rhinological and Otological Society, Inc.)

Inequities in preventive cancer screening, diagnosis, treatment, and inferior cancer outcomes continue to pose challenges across the cancer continuum. While the exact reasons for these inferior outcomes are unknown, multiple barriers to various domains of social determinants of health (SDOH) play a vital role, leading to inequities in cancer care. These include barriers to transportation, housing, and food insecurities, contributing to delays in preventive screening and treatment. Furthermore, aggressive biologies also exist across various racial profiles with accompanying germline mutations. For example, African Americans (AAs) have a higher incidence of triple-negative breast cancer subtype and a high prevalence of BRCA1/2 gene mutations, increasing the risk of multiple cancers, warranting high-risk screening for these populations. Unfortunately, other barriers, such as financial insecurities, low health literacy rates, and lack of awareness, lead to delays in cancer screening and genetic testing, even with available high-risk screening and risk reduction procedures. In addition, physicians receive minimal interdisciplinary training to address genetic assessment, interpretation of the results, and almost no additional training in addressing the unique needs of racial minorities, leading to suboptimal delivery of genetic assessment provision resources among AAs. In this review, we discuss the confluence of factors and barriers limiting genetic testing among AAs and highlight the prevalence of germline mutations associated with increased risk of breast cancer among AAs, reflecting the need for multi-panel germline testing as well as education regarding hereditary cancer risks in underserved minorities., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Background: Gepotidacin is a novel, bactericidal, first-in-class triazaacenaphthylene antibiotic that inhibits bacterial DNA replication by a distinct mechanism of action and a unique binding site, providing well balanced inhibition of two type II topoisomerase enzymes. Oral gepotidacin is under investigation to treat uncomplicated urinary tract infections. We aimed to compare the efficacy and safety of oral gepotidacin with that of nitrofurantoin in adolescent and adult female individuals with uncomplicated urinary tract infections., Methods: EAGLE-2 and EAGLE-3 were phase 3, randomised, multicentre, double-blind, double-dummy, non-inferiority (10% margin) trials, in which patients were enrolled at 219 centres worldwide. Patients assigned female at birth, non-pregnant, aged 12 years or older, weighing 40 kg or more, with two or more symptoms of dysuria, frequency, urgency, or lower abdominal pain, and with evidence of urinary nitrite, pyuria, or both were eligible for inclusion. Patients were randomly assigned (1:1) centrally by interactive response technology to receive oral gepotidacin (1500 mg twice daily for 5 days) or oral nitrofurantoin (100 mg twice daily for 5 days), with randomisation stratified by age category and history of recurrent uncomplicated urinary tract infections. Patients, investigators, and the sponsor study team were masked to treatment assignment. The primary endpoint, therapeutic response (success or failure) at test-of-cure (ie, day 10-13), was evaluated in randomly assigned patients with nitrofurantoin-susceptible qualifying uropathogens (≥10 5 colony-forming units [CFU] per mL) and who received at least one dose of study treatment. Conforming to regulatory guidance, therapeutic success was defined as combined clinical success (ie, complete symptom resolution) and microbiological success (ie, reduction of qualifying uropathogens to <10 3 CFU/mL) without other systemic antimicrobial use. Safety analyses included patients who were randomly assigned and who received at least one dose of study treatment. The trials are registered with ClinicalTrials.gov, NCT04020341 (EAGLE-2) and NCT04187144 (EAGLE-3), and are completed., Findings: Studies were undertaken from Oct 17, 2019, to Nov 30, 2022 (EAGLE-2), and from April 23, 2020, to Dec 1, 2022 (EAGLE-3). 1680 patients in EAGLE-2 and 1731 patients in EAGLE-3 were screened for eligibility, of whom 1531 and 1605 were randomly assigned, respectively (767 in the gepotidacin group and 764 in the nitrofurantoin group in EAGLE-2, and 805 in the gepotidacin group and 800 in the nitrofurantoin group in EAGLE-3). After an interim analysis, which was prospectively agreed as a protocol amendment, both studies were stopped for efficacy. Thus, the primary analysis population included only patients who, at the time of the interim analysis data cutoff, had the opportunity to reach the test-of-cure visit or were known to not have attained therapeutic success before the test-of-cure visit. In EAGLE-2, 162 (50·6%) of 320 patients assigned gepotidacin and 135 (47·0%) of 287 patients assigned nitrofurantoin had therapeutic success (adjusted difference 4·3%, 95% CI -3·6 to 12·1). In EAGLE-3, 162 (58·5%) of 277 patients assigned gepotidacin and 115 (43·6%) of 264 patients assigned nitrofurantoin had therapeutic success (adjusted difference 14·6%, 95% CI 6·4 to 22·8). Gepotidacin was non-inferior to nitrofurantoin in both studies and superior to nitrofurantoin in EAGLE-3. The most common adverse event with gepotidacin was diarrhoea (observed in 111 [14%] of 766 patients in EAGLE-2 and in 147 [18%] of 804 patients in EAGLE-3), whereas the most common adverse event with nitrofurantoin was nausea (in 29 [4%] of 760 patients in EAGLE-2 and in 35 [4%] of 798 patients in EAGLE-3). Cases were mostly mild or moderate. No life-threatening or fatal events occurred., Interpretation: Gepotidacin is an efficacious oral antibiotic with acceptable safety and tolerability profiles. As a first-in-class investigational oral antibiotic with activity against common uropathogens, including clinically important drug-resistant phenotypes, gepotidacin has the potential to offer substantial benefit to patients., Funding: GSK and the US Office of the Assistant Secretary for Preparedness and Response, Biomedical Advanced Research and Development Authority., Competing Interests: Declaration of interests FW is an adviser to GSK and a principal investigator in a GSK-sponsored study; is a speaker of the DFG (German Research Foundation) funded research group BARICADE (FOR5427/1-466687329); and a member of the DZIF (German Center for Infection Research; site: Giessen–Marburg–Langen). CRP, NES-O, HM, MP, EJ, JD, AS, DB, JB, and SJ are employees of, and shareholders in, GSK. TMH is an adviser to GSK., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: We aimed to determine if salivary cadmium (Cd) levels had any association with breast density, hoping to establish a less invasive cost-effective method of stratifying Cd burden as an environmental breast cancer risk factor., Methods: Salivary Cd levels were quantified from the Marin Women's Study, a Marin County, California population composite. Volumetric compositional breast density (BD sxa ) data were measured by single x-ray absorptiometry techniques. Digital screening mammography was performed by the San Francisco Mammography Registry. Radiologists reviewed mammograms and assigned a Breast Imaging-Reporting and Data System score. Early morning salivary Cd samples were assayed. Association analyses were then performed., Results: Cd was quantifiable in over 90% of saliva samples (mean = 55.7 pg/L, SD = 29). Women with higher saliva Cd levels had a non-significant odds ratio of 1.34 with BI-RAD scores (3 or 4) (95% CI 0.75-2.39, p = 0.329). Cd levels were higher in current smokers (mean = 61.4 pg/L, SD = 34.8) than former smokers or non-smokers. These results were non-significant. Pilot data revealed that higher age and higher BMI were associated with higher BI-RAD scores (p < 0.001)., Conclusion: Salivary Cd is a viable quantification source in large epidemiologic studies. Association analyses between Cd levels and breast density may provide additional information for breast cancer risk assessment, risk reduction plans, and future research directions. Further work is needed to demonstrate a more robust testing protocol before the extent of its usefulness can be established., (© 2024 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Arctic Grayling Thymallus arcticus are Holarctically distributed, with a single native population in the conterminous United States occurring in the Big Hole River, Montana, where water temperatures can fluctuate throughout the year from 8 to 18 °C. A gradual increase in mean water temperature has been reported in this river over the past 20 years due to riparian habitat changes and climate change effects. We hypothesized that exposing Arctic Grayling to higher temperatures would result in lower survival, decreased growth, and increased stress responses. Over a 144-day trial, Arctic Grayling juveniles were subjected to water temperatures ranging from 8-26 °C to measure the effects on growth, survival, gene expression and antioxidant enzyme activity. Fish growth increased with increasing water temperature up to 18 °C, beyond which survival was reduced. Fish did not survive at temperatures above 22 °C. In response to temperatures above 16 °C, a 3-fold and 1.5-fold increase in gene expression was observed for superoxide dismutase ( SOD ) and glutathione peroxidase ( GPx ), respectively, but no changes were seen in the ratio of Heat Shock Protein 70 ( HSP70 ) and heat shock protein 90 ( HSP90 ) expression. Enzyme activities of SOD and GPx also rose at temperatures above 16 °C, indicating heightened oxidative stress. Catalase (CAT) gene expression and enzyme activity decreased with rising temperatures, suggesting a preference for the GPx pathway, as GPx could also be providing help with lipid peroxidation. An increase of Thiobarbituric acid reactive substances (TBARS) was also recorded, which corresponded with rising temperatures. Our findings thus underscore the vulnerability of Arctic Grayling to minor changes in water temperature. Further increases in mean water temperature could significantly compromise survival of Arctic Grayling in the Big Hole River.