Surgical menopause impact on vaginal mechanical properties.

Increasing contextualization of care rates through clinician prompting interventions.

Mitiperstat is a novel myeloperoxidase inhibitor being investigated for the treatment of heart failure, metabolic dysfunction-associated steatohepatitis, and chronic obstructive pulmonary disease. Pharmacokinetic data from five clinical trials were used to develop a mitiperstat population pharmacokinetics (popPK) model. In total, 2856 plasma samples from 128 mitiperstat-treated participants were collected during the first-in-human single-ascending dose (SAD) study; multiple-ascending dose studies (MAD) in healthy volunteers, including healthy Japanese and Chinese volunteers (JCMAD); the phase 2a SATELLITE study in patients with heart failure with preserved/mildly reduced ejection fraction (HFpEF/HFmrEF); and from a study in patients with severe renal impairment. The mitiperstat concentration-time data were pooled and analyzed with the software NONMEM. The covariates considered in this analysis were baseline estimated glomerular filtration rate (eGFR), baseline body weight, baseline body mass index, sex, race (Asian or non-Asian), age, disease status (healthy volunteers or patients with HFpEF/HFmrEF), and formulation (oral suspension or tablet). The final popPK model is a two-compartment model with first-order absorption and linear elimination. Baseline body weight, disease status, Asian race, and eGFR were identified as significant covariates for apparent clearance, and age was identified as a significant covariate for apparent central volume of distribution. The final model predicts that severe renal impairment and lower body weight have the largest impact on exposure. Exposure to mitiperstat increased as eGFR declined. This popPK model constitutes an important step toward optimizing doses for efficacy and safety in the different mitiperstat development programs. Trial Registration: ClinicalTrials.gov: NCT02712372.

Metformin and exercise are often co-prescribed in adults with prediabetes and type 2 diabetes mellitus (T2DM). However, metformin may alter metabolic responses to exercise. This systematic review and meta-analysis evaluated the impact of metformin on exercise metabolism including lactate, glucose, insulin, and free fatty acids (FFA), along with exercise capacity. Electronic databases (Web of Science, PubMed/Medline, Embase, and SPORTDiscus) were searched through January 2025. Twenty-one studies that involved acute (single dose), non-acute (multiple doses), and habitual metformin (prescribed) intake were included in the systematic review. Study quality and risk of bias were assessed using the Cochrane RoB 2 tool. Random-effects meta-analyses conducted on lactate, glucose, insulin, and exercise capacity during acute and non-acute studies and effects are reported as standardized mean differences (SMD) with 95% confidence intervals. Across 325 participants (female n=125), metformin doses ranged from 500 to 3,000 mg/day and interventions ranged from 1 dose to 12 weeks. Acute studies were primarily in young, healthy males, while habitual studies involved older adults (predominantly female) on long-term metformin treatment. Metformin was associated with greater lactate concentrations during exercise (SMD=0.98, 95% CI: 0.36, 1.60, p=0.002). Metformin modulates exercise metabolism, with the largest impact being on lactate accumulation during exercise. The direction of these interactions may depend on dose, duration, and participant characteristics. This review provides the first critical synthesis of available literature combining metformin and exercise metabolism, capacity, and training adaptations, offering insights to clinicians and exercise practitioners on potential implications of co-prescribing metformin and exercise.

The NHS Breast Screening Programme invites eligible women using either a timed appointment letter (option to change), or an open invitation to make an appointment. Non-attenders receive a 'Timed' or 'Open' second invitation. NHS England commissioned a service evaluation to determine the effect of different combinations of timed and open invitations. Seven services, selected to ensure adequate representation of diverse socio-economic, ethnic, urban/rural, and current uptake groups, participated. Women were individually quasi-randomised to four combinations of Open/Timed invitations. The primary outcome was 90-day attendance. 17,965 women (mean age 58 years, IQR: 47-69) invited from April-October 2023 were included. Attendance overall increased from 49.1% (95%CI 47.7-50.6%) for Open/Open to 67.9% (66.5-69.2%) for Timed/Timed. Attendance following Open/Timed or Timed/Open invitations was 60.0% (58.6-61.4%) and 64.7% (63.3-66.1%) respectively. The same pattern was observed across all deprivation quintiles. Attendance amongst the most deprived increased from 41.1% (38.2-44.1%; Open/Open) to 63.3% (60.6-66.2%; Timed/Timed), compared with 61.4% (57.6-65.2%) to 78.0% (74.5-81.4%) for the least deprived quintile. Sending timed appointment invitations increases attendance at breast screening. This might have a larger impact in the most deprived areas. Findings informed NHS England on the most effective invitation methodologies from April 2025.

Apical periodontitis (AP) diagnosis primarily relies on periapical radiographs (PRs) and the Periapical Index (PAI) scoring system. However, existing automated approaches often simplify PAI into binary categories or ignore essential clinical metadata, limiting diagnostic performance and applicability. Such limitations hinder timely and accurate diagnosis of AP, which may complicate treatment planning by creating uncertainty about the appropriate timing and type of intervention, and ultimately challenge clinicians' ability to make consistent and informed decisions. This study aimed to develop and validate a novel Mamba-based classification model that integrates PR with structured clinical metadata to predict detailed PAI scores across the full 5-class. In this retrospective diagnostic accuracy study, PRs and corresponding metadata-including patient age, tooth location, tooth number and arch type-were collected from a single institution. Two expert endodontists independently assigned PAI scores (1-5) based on Ørstavik's criteria, with the final reference standard set by consensus. The proposed artificial intelligence (AI) model utilized a Mamba-based state-space architecture to capture spatial dependencies and incorporate structured clinical metadata features. Training and evaluation were conducted using stratified 5-fold cross-validation. The model achieved 54.72% accuracy and a quadratic-weighted kappa (QWK) of 0.713 in 5-class classification, outperforming the latest models based on convolutional neural networks (CNNs) and object detection networks. Ablation analysis further supported the value of integrating patient information, showing that age was the largest impact on model performance. Gradient-weighted Class Activation Mapping (Grad-CAM) analysis for model explainability demonstrated that the model's highlighted areas were aligned with clinically meaningful periapical regions. The proposed model addresses limitations of prior methods by leveraging the full range of the PAI scores and incorporating structured clinical information. It has the potential to support more consistent radiographic interpretation, reduce inter-examiner variability and serve as an interpretable tool in educational and clinical decision-support.

Whose wine is it anyway? Examining private label cask wine ownership among Australian alcohol retailers.

The construction industry is a major contributor to global carbon emissions; therefore, finding a way to reduce emissions to meet climate-mitigation goals is vital. The challenges that impede emissions reductions are numerous and reliant on implemented policies. This study proposes an explainable machine learning framework to predict and interpret carbon emission reduction performance in building projects by integrating project characteristics, policy intervention indicators, certification levels, lifecycle information, and emission-related variables. Three machine learning models were created-Ridge Regression, Random Forest, and Gradient Boosting-and tested on a split of the data to assess their performance. To explain emissions reductions, the models were evaluated for predictive performance using a set of statistical measures and the explainable machine learning metric, Shapley Additive Explanations (SHAP). The models demonstrated robust predictive performance, with a coefficient of determination of over 0.81 for each model, and all models had similar performance despite using different statistical techniques. Shapley values attributed most of the focus to high-level green certifications and policy measures, whereas project size had little influence on reducing emissions. The results reinforce the idea that policies have the largest impact on emissions reductions in the building sector. The suggested explainable framework provides clarity and relevant insights into policies that aid evidence-based decision-making and strategic planning for decarbonising the building sector.

A 7-year, American Paint maiden mare, was presented 2 days after foaling following manual removal of retained fetal membranes. Fetid vaginal discharge was noticed and subinvoluted uterus was palpated transrectally. Endometrial cytology had Gram-positive cocci, Gram-negative and positive rods, and clostridial organisms with spores. Small fragment of fetal membranes was retrieved during uterine lavage. Mare developed signs of gastrointestinal disease with a large colon impaction and had refractory pain (response to multimodal analgesia). Despite intensive therapy, mare’s condition deteriorated. Abdominocentesis revealed turbid fluid with increased protein and lactate consistent with elevated inflammatory cells and peritonitis. Necropsy confirmed necrotizing metritis with vascular thrombosis, localized fibrinous peritonitis, and focal adhesion between uterus and pelvic flexure of the large intestine. This case illustrated the rapid progression from retained fetal membranes to systemic illness and highlighted the diagnostic value of cytology to select antimicrobial agents in advance of culture and sensitivity results.

Abstract Assisted gene flow is used to increase the resilience of populations to climate change. Although the selection of genotypes used to reinforce populations is expected to have a significant impact on climate change vulnerability of target populations, the potential of nearby genotypes to increase climate resilience remains unexplored. With a common understory species, Primula elatior , we combined common garden experiments with conservation genomics to compare population reinforcement for climate adaptation with genotypes from southern France (southern) versus Belgium (regional) as sources for assisted gene flow. We used population genomic approaches to identify genetic markers associated with adaptation and investigated how these genomic signatures of adaptation changed from parents to offspring depending on the origin of the parents. Southern genotypes had the largest impact on the distribution of climate‐associated genetic markers, but regional genotypes also increased adaptive potential, most likely due to microclimate differences between source and target populations. We argue that the importance of microscale environmental variation in boosting resilience to climate change deserves to be considered more frequently as a climate‐oriented conservation strategy that has much less risk of outbreeding depression.

Childhood maltreatment (CM), particularly emotional neglect and abuse, has been associated with an increased risk of anxiety and less favorable psychotherapy outcomes in adulthood. Impairments in personality functioning are a significant mechanism mediating this relation. This naturalistic cross-sectional study examined the mediating role of personality functioning in the relation between CM and anxiety symptoms in a clinical adult sample. A total of 335 adult patients starting individual psychotherapy completed intake self-report questionnaires about CM experiences, personality functioning, and anxiety symptoms. We assessed the two dimensions of personality functioning described in Section III of the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), specifically, self-functioning and interpersonal functioning. Bootstrapped mediation analyses were conducted to evaluate the mediating role of personality functioning in the association between each CM type and anxiety symptoms. 64.2% of the sample reported at least one type of CM. Personality functioning explained 73% of the total effect of CM on anxiety symptoms. Only emotional abuse and emotional neglect showed significant total effects. Emotional abuse retained a direct effect, while emotional neglect was fully mediated by personality functioning. Both personality functioning dimensions were significant mediators, yet self-functioning had a larger impact. Psychotherapeutic interventions targeting impairments in personality functioning are essential for treating anxiety symptoms in adults with CM. Findings emphasize the importance of trauma-informed, personalized interventions, and CM prevention strategies.

Previous population-based studies on ovarian cancer survival have evaluated less granular disease staging categories and histologic sub-types than are in current use, and there is a need to assess survival in the context of more contemporary treatment practices and histotype classifications. Using flexible parametric models, we assessed the 1-, 3-, 5-, and 10-year net survival and excess mortality hazards of 54,267 incident invasive ovarian cancer cases by stage and histology and 9478 borderline cases diagnosed between January 1, 2010 and December 31, 2021 recorded in Germany. Net survival differed markedly by stage, with consistently favorable long-term survival for early-stage (I to II) and poor outcomes for advanced-stage (III to IV) disease across histotypes. Although most stage I tumors showed high 10-year net survival (≥ 77%), carcinosarcomas represented a notable exception. Net survival declined with advancing stage, with 10-year estimates ranging from 46% to 76% for stage II, 18% to 55% for stage III, and poor 5-year survival for stage IV tumors (15% to 41%). Considering patterns by time since diagnosis, the excess mortality hazard was the highest across all histotype-stage groups during the first 3 years with variability suggestive of histotype-specific treatment resistance and disease recurrence. The influence of stage decreased over the follow-up, with the largest impact mostly observed during the first year after diagnosis. Net survival for borderline tumors was high (10-year survival = 92.9%). Net survival was favorable for patients with early-stage disease. Variability was observed across histotypes by stage. The early post-diagnosis period is a critical window for excess mortality, and the development of histotype-specific treatments is needed.

The purpose of this study was to assess the environmental impacts of ultrasound modality operations within the larger radiology department to find areas in which sustainability efforts may have the largest impact. Life cycle assessment of the ultrasound section of a large academic hospital serving adult inpatient, outpatient, and emergency department patients was performed. In addition to assessing the energy use of ultrasound units themselves, this study included assessment of the carbon footprint and environmental impact of ultrasound unit production and disposal, ultrasound examination supplies like ultrasound gel and linens, and the data storage and imaging interpretation equipment. Unlike other imaging modalities, linens (35%; 5.5/17.0 metric tons CO2e) and disposable supplies (34%; 5.5 out of 17.0 t CO2e) accounted for the majority of greenhouse gas emissions, while production (7%; 1.1 out of 17.0 metric tons CO2e) and energy use (3%; 0.5 out of 17.0 metric tons CO2e) of the ultrasound machine were minor contributions to the carbon footprint of ultrasound. Gloves and ultrasound gel were the largest contributors to the carbon footprint among the single-use supplies. Ultrasound is a unique imaging modality in that the major environmental impacts come not from the modality use and production itself, but rather from the use of supplies needed to perform the examination. Giving the increasing use of ultrasound worldwide, focus on minimizing and optimizing the use of linens, gel, and other supplies can have a significant impact on the global carbon footprint of radiology departments. Strategies to reduce and optimize the use of supplies, in accordance with the principles of circularity, should be explored in future research.

BackgroundVancomycin has a narrow therapeutic window and is primarily renally excreted. This study explored whether varied estimated glomerular filtration rate (eGFR) equations lead to differences in chronic kidney disease (CKD) staging and vancomycin dosage, and their impact on treatment outcomes.MethodsThis cross-sectional study retrospectively included adult patients receiving vancomycin for therapeutic purposes (empirical or targeted therapy) at Nanjing Drum Tower Hospital (2019–2023). Consistency of each of the metrics (eGFR values, CKD staging, dose staging, and staging recommendations) derived from different equations was compared. Incidences of distinct clinical outcomes were compared among patients receiving doses recommended by different eGFR equations. Logistic regression analyzed associations between inconsistent status and patient characteristics as well as clinical outcomes.ResultsA total of 832 patients were identified. The Chinese population-adjusted creatinine (Cr)-based European Kidney Function Consortium equation (EKFC-eGFRCr[CN]) had the smallest impact on dosing adjustments (3.4%), whereas the cystatin(Cys)-based Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation (CKD-EPI-eGFRCys) had the largest impact (16.0%) and exhibited favorable performance in target vancomycin trough concentration (Cmin) attainment and other clinical outcomes (except for target 24 h area under the concentration-time curve [AUC0~24]). Only staging discordance between the Xiangya equation and EKFC-eGFRCr+Cys was associated with a reduced Cmin attainment rate. When dosing recommendations disagreed with those from the Cockcroft-Gault equation, all eGFR equations except the Xiangya equation were associated with higher Cmin attainment rates.ConclusionOur study found that the CKD-EPI-eGFRCys equation required the most dosing adjustments, while the EKFC-eGFRCr(CN) equation required the fewest. Preferentially using the CKD-EPI-eGFRCys equation was optimal for target attainment of key clinical outcomes.

In multicellular organisms, development entails the progression of diverse cellular processes that need to be temporally coordinated. During C. elegans postembryonic development, the events of molting and cell divisions progress in parallel during four larval stages and are modulated by external cues such as temperature and nutrient availability. While seam cell divisions occur predominantly before ecdysis of the cuticle, the order of the events can change, suggesting that they are controlled by independent mechanisms. Here, we have analyzed the impact of reduced insulin signaling in molting and in stage-specific cell divisions. We find that reduced insulin signaling in the daf-2(e1370) allele delays both of these events but has a larger impact on the timing of cell divisions, thus increasing the desynchrony between the events. The relative delay in seam cell divisions leads to a delay in the initiation of the subsequent stage of the molting program, providing a mechanism for resynchronization of developmental processes to the beginning of the larval stages.

Metal(IV) phosphonates are a type of organic-inorganic coordination polymer material with promise for a variety of applications including catalysis, sorption, separations, proton exchange and energy storage. The extent of phosphonate coordination to the metal(IV) can vary in these materials, which has substantial implications on their functionality. This study demonstrates how the choice of tetravalent metal, the type of metal(IV) precursor, synthesis duration and synthesis temperature can all be used to control phosphonate availability, which was characterised via solid-state NMR of eight different amorphous metal(IV) phosphonate sorbents. It was found that Zr chloride (compared to Zr propoxide and Zr tert-butoxide) was the most effective Zr precursor for inducing a greater extent of phosphonate coordination. Increasing reaction time also increased phosphonate coordination, but increasing synthesis temperature had the largest impact. Changing the metal(IV) from Zr to Ti resulted in a substantially reduced reactivity with the phosphonate group. Sorbents prepared with Ti resulted in lower ligand content, a high proportion of free phosphonate environments, formation of anatase and even crystallisation of unreacted 2,6-bis(1,2,3-triazol1-ethanephosphonate)pyridine ligand, for which a novel crystal structure was identified. This work also reveals a novel means of assessing phosphonate availability using x-ray absorption spectroscopy (XAS), which opens new avenues for studying metal phosphonate materials given XAS is not restricted to the rigid measurement conditions of solid-state NMR. • Metal(IV) phosphonate synthesis conditions control phosphonate availability. • Low temperature, alkoxide precursors & short synthesis increase free phosphonate. • Zr(IV) reacts more effectively with phosphonate than Ti(IV). • Novel phosphonate crystal structure identified. • New XAS method to assess phosphonate availability developed.

Gender affirming mastectomy surgery, also known as top surgery, is known to improve psychological health and quality of life for transgender and gender diverse patients, but little is known about effects on physical health. 1 This study examines how baseline demographics and gender affirming mastectomy surgery impact longer-term lifestyle behaviours. Gender affirming mastectomy patients, aged 18+, were recruited from Women's College Hospital and McLean Clinic. A survey was administered preoperatively (T1), 4 months postoperatively (T2), and 1 year postoperatively (T3). The survey consisted of the Short Multidimensional Inventory Lifestyle Evaluation, a self-assessment tool. Data was analyzed with ANOVA, Kruskal Wallis, and Wilcoxon signed rank tests using RStudio. 288 patients were eligible and 234 patients consented. 166 completed the survey at T1 (71%). Patients with higher household incomes and education scored better (p=0.003; p=0.0003). Household income had the largest impact on social supports (p=0.03); higher education was associated with better diet and stress management (p=0.001; p=0.0004). 109 patients completed the survey at T2 (66%). The total score was equivalent (p=0.19). At T3, 103 patients completed the survey (62%). Between T1 and T3, the total score increased from 75.66 to 78.06 (p=0.003). The scores improved in nutrition (p=0.01), physical activity (p=0.03), stress management (p=0.001), restorative sleep (p=0.01), and environmental exposures (p=<0.01). Social determinants of health can play a significant role in lifestyle behaviours in TGD patients. This study found long-term improvements between pre- and postoperative lifestyle behaviours and across several domains. Further research should examine effects of gender affirming surgery across a longer timeframe.

In an era of endemic SARS-CoV-2 transmission, countries are continuing to evaluate how best to schedule ongoing COVID-19 booster vaccinations. Mathematical modelling provides a useful tool to predict the benefit of future vaccination strategies, incorporating the loss of protection due to waning immunity and strain mutation. We adapted a combined immunological-population transmission model for SARS-CoV-2, to better capture contemporary understanding of exposure- and vaccine-derived immunity, to simulate ongoing endemic transmission of SARS-CoV-2 in a highly exposed high-income setting. We used this model to estimate the impact of targeted booster dose strategies in the older population, both in the context of continued circulation of the current dominant viral strain, and in the presence of a new antigenically distinct variant. We found that at the population level, an annual COVID-19 vaccine booster dose to the 65+ years population at 60% coverage could avert 8–16% of hospitalisations over a single wave, depending on how well-matched the vaccine is to the circulating SARS-CoV-2 strain. With lower coverage of 40%, estimated median impact was between 6% and 11%. A second booster dose to the 75+ population after 6 months was particularly beneficial if a new distinct variant strain increases the magnitude of the wave. Of the vaccine scenarios explored, we found that increasing uptake of the annual booster dose in the 65+ population is likely to have a larger impact on hospitalisations than optimising dose timing. This adapted model captures endemic viral transmission and could readily be used to explore vaccine impact across other settings.

Building transit-oriented developments presents a chance to address the impacts of transport poverty by providing affordable housing in highly accessible locations. We implement transport poverty indices on a series of scenarios for underdeveloped station areas in five mid-sized Canadian cities. TODs are not only an effective strategy for addressing transport poverty but a necessary one, with affordable housing provision as a core condition for impact. The largest impact is achieved by TODs with high access and many opportunity sites, but even TODs in peripheral areas can achieve significant results if the design and scale of development compensate for the lower accessibility.

Gonorrhoea treatment in sub-Saharan Africa relies on syndromic management, which has poor diagnostic performance and misses asymptomatic infections. Point-of-care tests (POCTs) could address these limitations, but anticipated supply constraints necessitate strategic allocation to maximise impact. We developed a deterministic compartmental model of gonorrhoea transmission in Kenya to evaluate allocating POCTs for diagnostic confirmation of symptomatic care attendees versus screening of routine healthcare service attendees across five priority populations: female sex workers (FSW), their male clients (CFSW), pregnant women, adolescent girls and young women, or total population men. We modelled constrained and unrestricted POCT availability during 2025-2030, and estimated infections averted relative to baseline syndromic management. Quality-adjusted life years (QALYs) gained were quantified using probability tree models. At baseline, incidence was highest among FSW (11.9 [UI:5.7-18.6] per 100 per year) and CFSW (13.1 [6.9-24.8]), while most QALY losses (80.6% [76.1-83.8%]) were among pregnant women and their infants. With constrained POCTs (sufficient to test 0.1% of adults annually), diagnostic confirmation averted the most transmission when among symptomatic FSW (2.1% [0.6-5.6%] of infections) or CFSW (2.2% [0.8-5.3%]), and the most morbidity when among symptomatic pregnant women (3.5% [1.8-7.2%] of QALY losses). Screening averted <1% of infections or QALY losses across populations. With unrestricted POCTs, screening had larger absolute impacts but lower per-test efficiency than diagnostic confirmation. Our modelling supports prioritising diagnostic confirmation over screening, consistent with WHO guidance to strengthen aetiologic diagnosis within syndromic care. Diagnostic testing among symptomatic pregnant women had the largest impact on mitigating gonorrhoea-related morbidity.