Current professional guidelines recommend discontinuing Papanicolaou (Pap) test screening in women aged 65 years and older who have had adequate prior negative testing. However, limited data exist on Pap test performance and histologic outcomes in this population.

Searches were performed for all Pap tests from women aged 65 years and older accessioned at a women's hospital between January 2023 and December 2024. Pap tests were performed using the liquid-based cytology ThinPrep test, and high-risk HPV testing was performed using Aptima high-risk human papillomavirus (HPV) assays. Surgical pathology follow-up within 6 months was recorded. A Pearson χ² test was performed to compare HPV positivity among patients who had abnormal Pap tests.

In total, 1536 women aged 65 years and older underwent Pap testing during the study period. The overall HPV-positivity rate was 24.2%. Abnormal Pap results (atypical squamous cells of undetermined significance or worse) comprised 939 of 1536 cases (61.1%). Histologic follow-up was available for 402 cases. Lesions categorized as cervical intraepithelial neoplasia grade 2 (CIN2) or more severe disease were identified in 94 cases (23.3%), including 11 squamous cell carcinomas, three endocervical carcinomas, 40 CIN2/3 lesions, and 40 endometrial carcinomas. Notably, three of 11 squamous cell carcinomas (27.3%) and 12 of 40 CIN2/3 lesions (30%) were HPV-negative.

The abnormal Pap rate in women aged 65 years and older was high (61.1%), whereas HPV positivity remained low. CIN2 or more severe disease and endometrial lesions after negative HPV testing occurred at a substantial rate (33.8%). The rate for detecting atypical glandular cells was also elevated (3.0%), correlating with a significant number of endometrial carcinoma diagnoses. These findings underscore the need for additional research and suggest that continued screening with Pap and HPV cotesting may benefit older women.

To reduce worldwide inequalities, WHO made a call for action to eliminate cervical cancer by vaccinating 90% of girls, screening 70% of women, and treating 90% of pre-cancers and cancers. Low-income countries and lower-middle-income countries (LMICs) are far from reaching the WHO elimination targets compared with high-income countries (HICs). Using mathematical modelling, we aimed to examine the following questions: (1) Are we on the path to cervical cancer elimination in LMICs and HICs? (2) What is the potential evolution of inequalities in cervical cancer between LMICs and HICs under current screening and vaccination coverage? And (3) what would be the potential impact of enhanced prevention strategies (ie, human papillomavirus [HPV] vaccination and screening) on inequalities and cervical cancer elimination?

We used the HPV-ADVISE model to project the age-standardised cervical cancer incidence in 67 LMICs and 42 HICs for different HPV vaccination and screening scenarios. For the status quo scenario (of HPV vaccination and screening), we modelled the vaccine used, the start year of vaccination, vaccination coverage, and the target population for each country, and current screening coverage in LMICs and HICs. We examined five enhanced prevention strategies for LMICs: (1) status quo for all countries using the nine-valent vaccine; (2) reaching 90% vaccination coverage for girls-only routine vaccination; (3) reaching the WHO vaccination, screening, and treatment elimination targets; (4) adding routine vaccination for boys with 90% coverage (ie, universal routine vaccination) and multi-age-cohort vaccination; and (5) reaching the WHO elimination targets combined with universal routine and multi-age-cohort vaccination. Inequalities were measured as the age-standardised cervical cancer incidence (ASR) ratio between LMICs and HICs (RR_LMIC/HIC=ASR_LMICs/ASR_HICs).

Under the status quo, the model projected that cervical cancer incidence in LMICs would decrease by only 23% while HICs would reach elimination by 2048 (age-standardised cervical cancer incidence <four cases per 100 000 women-years), leading to substantial increases in inequalities (RR_LMIC/HIC=3 in 2022 and 12 in 2105). Reaching 90% vaccination coverage among girls in LMICs would reduce these inequalities (RR_LMIC/HIC=2 in 2105) and lead to elimination in LMICs outside sub-Saharan Africa. To reach equality between LMICs and HICs and elimination in all LMIC regions, LMICs would need to reach the WHO elimination targets and introduce universal vaccination and multi-age-cohort vaccination.

Worldwide inequalities in cervical cancer have been projected to increase dramatically without enhanced HPV prevention strategies. Reaching WHO vaccination and screening elimination targets or introducing universal vaccination with high coverage is necessary to eliminate cervical cancer in LMICs, which would substantially attenuate worldwide inequalities.

Canada Research Chairs Program, Canadian Institute of Health Research, and Fonds de recherche du Québec through the research centre grant for the CHU de Québec-Université Laval Research Center.

For premenopausal women with oestrogen receptor (ER)-positive early breast cancer, the additional protective effect of ovarian function suppression (OFS, by ablation or drugs) may depend on menopausal status after any chemotherapy, and tamoxifen usage. We assess the effects of OFS on breast cancer outcomes among premenopausal women and how they vary by patient or tumour characteristics and receipt of other treatments.

We conducted a meta-analysis of individual participant data from the randomised trials comparing OFS versus no OFS, in women with ER-positive or ER-unknown early breast cancer who were premenopausal at randomisation and younger than 55 years. Trials were categorised by whether premenopausal status was or was not confirmed after chemotherapy (if given), and by allocation to tamoxifen. Primary outcomes were invasive breast cancer recurrence, breast cancer mortality, other mortality, and all-cause mortality. ER-weighted log-rank methods estimated event rate ratios (RRs) for ER-positive disease.

Datasets were provided for 23 of 25 identified eligible trials, comprising 18 851 (98·9%) of 19 053 randomly assigned women. Among 15 075 premenopausal women with ER-positive or ER-unknown tumours, allocation to OFS significantly reduced recurrence rates (RR 0·82, 95% CI 0·77-0·87; p<0·00001), with larger reductions in women who were confirmed premenopausal after chemotherapy (or who did not receive chemotherapy) than in those with unconfirmed premenopausal status after chemotherapy; heterogeneity p=0·0004. Among confirmed premenopausal women, recurrence reductions were larger in older trials without tamoxifen (RR 0·61, 0·52-0·71; p<0·0001) than in more recent trials of OFS plus tamoxifen versus tamoxifen (RR 0·79, 0·70-0·91; p=0·0008). In these more recent trials, the additional recurrence reduction with OFS appeared larger in women younger than 45 years than in women aged 45-54 years (RR 0·73, 0·63-0·86 vs RR 0·95, 0·75-1·21; p=0·072); in those younger than 45 years, breast cancer mortality was similarly improved (RR 0·74, 0·58-0·94; p=0·012). There was no increase in deaths without recurrence. Findings did not differ significantly by OFS method or other recorded patient or tumour characteristics.

For premenopausal women with ER-positive early breast cancer, even if chemotherapy or tamoxifen are given, OFS significantly reduces the 15-year risk of recurrence and death.

Nuffield Department of Population Health, University of Oxford; Cancer Research UK; the Breast Cancer Research Foundation; and the UK Medical Research Council.

The long noncoding RNA LINC01012 is known to play critical roles in tumorigenesis. However, its underlying regulatory mechanisms remain largely unclear in hepatitis B (HBV)-related hepatocellular carcinoma (HCC). This study aimed to identify the potential protein targets of LINC01012 and to elucidate the molecular mechanisms by which LINC01012 promotes HBV-HCC progression. Bioinformatics analysis was employed to investigate whether LINC01012 expression is abnormal in HCC and whether such abnormalities hold clinical significance. HBV-HCC cases were collected to validate LINC01012 expression levels and clinical value in HBV-HCC. The effects of LINC01012 knockdown on cell proliferation, migration, and invasion were studied using HBV-HCC cell lines (HepAD38 and HepG2.2.15). Bioinformatics predictions combined with RIP and RNA pulldown experiments were employed to predict and validate RBPs interacting with LINC01012 and its downstream target genes. The results showed that LINC01012 was significantly upregulated in HBV-HCC tissues and serum and correlated with advanced T stage, TNM stage, vascular invasion, and poor survival. Multivariate Cox analysis confirmed high LINC01012 expression as an independent prognostic factor (HR = 2.52, 95%CI: 1.21-5.24). Functional studies demonstrated that LINC01012 knockdown suppressed proliferation, migration, invasion, and expression of α-SMA. Mechanistically, LINC01012 directly interacted with HNRNPL, which in turn promoted the stability of the oncogenic splice variant SLK-S. Silencing LINC01012 reduced both HNRNPL and SLK-S expression. In conclusion, LINC01012 may act as an oncogenic lncRNA in HBV-HCC by stabilizing SLK-S via interaction with HNRNPL, promoting malignant phenotypes, and predicting poor prognosis. These findings highlight its potential as a therapeutic target and prognostic biomarker in HBV-driven HCC.

Bacterial extracellular vesicles (bEVs) are increasingly recognized as critical mediators of gut-host interactions; however, their specific role in the aging process remains obscured by fragmented data and disease-specific silos. Current understanding lacks a cohesive mechanism that explains how age-related physiological changes transform bEVs from commensal signals into systemic drivers of pathology. This review synthesizes disparate findings to elucidate a synergistic mechanism: aging compromises intestinal barrier integrity, facilitating bEV translocation, while simultaneously impairing immune clearance capabilities (e.g. loss of Vsig4+ Kupffer cells), leading to their toxic accumulation. We resolve conflicting reports on bEV functionality-such as the paradoxical pro-calcific effects of Lactobacillus rhamnosus GG-derived vesicles in chronic kidney disease-by contextualizing them within the host's aging microenvironment. Beyond mapping these interactions across the gut-brain, metabolic, cardiovascular, and bone axes, we identify specific cargo molecules, such as lipopolysaccharide (LPS), curli, and bacterial DNA, that fuel inflammaging. However, translating these insights into therapeutic applications faces significant challenges, including methodological heterogeneity in isolation protocols and unresolved immunogenicity risks. By outlining a strategic roadmap for standardization and rigorous clinical validation, this study redefines bEVs not merely as biomarkers but as actionable targets for delaying aging and mitigating age-related diseases.

Patients with heavily calcified coronary arteries represent a challenge in percutaneous coronary intervention (PCI), as severe calcification impairs device delivery and limits optimal stent expansion, leading to higher risks of stent thrombosis, restenosis, and adverse clinical outcomes. Approximately 20% of patients undergoing PCI exhibit severe coronary calcification, which independently predicts incomplete revascularization, increased mortality, and higher rates of major adverse cardiovascular events over mid-term follow-up. Recent advances have focused on improving the assessment and management of calcified lesions. Intracoronary imaging modalities, including intravascular ultrasound and optical coherence tomography, allow precise detection and characterization of calcium burden, overcoming the limitations of angiography. These tools play a pivotal role in guiding procedural strategy, enabling tailored selection of calcium-modifying techniques based on lesion morphology, and optimizing stent deployment. Technological innovations have significantly expanded therapeutic options. While non-compliant balloon angioplasty alone is often insufficient, adjunctive devices such as cutting and scoring balloons improve plaque modification in focal disease. Atherectomy techniques, including rotational and orbital systems, are effective for more complex lesions but require technical expertise and carry procedural risks. Intravascular lithotripsy has emerged as a promising, less aggressive modality capable of fracturing deep calcium, while excimer laser atherectomy offers an alternative for resistant lesions. Despite these advances, current evidence supporting calcium-modifying strategies is largely based on procedural outcomes rather than definitive improvements in long-term clinical endpoints. Meta-analyses and randomized trials have not demonstrated clear superiority of any single technique, and most studies remain underpowered. Intriguingly, recent data suggest that outcomes in treated calcified lesions may approximate those of non-calcified disease, raising the hypothesis that these technologies could mitigate the adverse impact of calcification. However, this remains unproven, highlighting the urgent need for adequately powered randomized trials to determine their true clinical benefit.

Alcohol use disorder accounts for 5% of deaths worldwide annually, and there is an urgent need for new therapeutic interventions. Preclinical and initial human studies indicate that the GLP-1 receptor agonist semaglutide might reduce alcohol drinking. This study evaluated the efficacy of semaglutide once-weekly in treatment-seeking patients with alcohol use disorder and comorbid obesity.

In a 26-week, single-centre, randomised, double-blinded, placebo-controlled trial, treatment-seeking participants with moderate to severe alcohol use disorder and comorbid obesity were assigned (1:1) to receive once-weekly semaglutide (2·4 mg subcutaneously) or placebo (saline subcutaneously), in addition to standard cognitive behavioural therapy. The primary endpoint was a reduction in the number of heavy drinking days assessed after 26 weeks of intervention, analysed with an ANCOVA model. Analysis adhered to the intention-to-treat principle, and missing outcome data were addressed using multiple imputations. Safety was assessed in all treated patients. The trial is registered at ClinicalTrials.govNCT05895643, and is complete.

From June 10, 2023, to Feb 4, 2025, 108 participants (53 women and 55 men) were enrolled, with 54 participants in each of the semaglutide and placebo treatment groups, and all were included in the data analysis. Overall, 88 participants (81%) completed the full intervention. Semaglutide was associated with a reduction in heavy drinking days (-41·1 percentage points from baseline, 95% CI -48·7 to -33·5) compared with placebo (-26·4, -34·1 to -18·6; estimated treatment difference -13·7 percentage points, -22·0 to -5·4; p=0·0015), and had substantial effects on multiple secondary alcohol-related and somatic outcomes. Adverse events were transient, generally mild to moderate gastrointestinal effects, and occurred more frequently in the semaglutide group.

Semaglutide showed robust therapeutic effects in treatment-seeking participants with obesity and alcohol use disorder and this trial supports previous preclinical and clinical findings suggesting GLP-1 receptor agonists as a potential novel treatment target for alcohol use disorder.

The Research Foundation, Mental Health Services (Capital Region of Denmark), the Novo Nordisk Foundation, the Novavi Foundation, the Hartmann Foundation, and the Augustinus Foundation.

The present study provides a comprehensive introduction to the features of histone tails, including their length, subtypes, nomenclature, biological functions, and regulation, and systematically reviews their roles in psychiatric disorders. A literature search was conducted, covering over 200 common histone modifications and the top 20 common psychiatric disorders. The results indicate that 26 histone tail modifications are positively associated with ten psychiatric disorders, with most located at H3 and H4 tails, and only one at the H2AX tail. All modifications occur at lysines (K), except for two at arginine (R) or serine (S). The top five modifications associated with psychiatric disorders are H3K9ac, H3K4me3, H3K27ac, H3K9me2, and γH2AX. The majority of the studies (92%) report substance use disorders, Alzheimer's disease, major depressive disorder, schizophrenia, and autism spectrum disorders as the top five psychiatric disorders associated with histone tail modifications. In conclusion, histone tail modifications play crucial roles in various psychiatric disorders, and targeting them and associated epigenetic regulators may offer potential therapeutic strategies for treating psychiatric disorders by providing new insights into the molecular mechanisms underlying abnormal gene expression.

Meeting the needs of autistic children requires the effective implementation of evidence-based interventions (EBIs). The TEAMS project tested the effectiveness of leader-level and provider-level implementation strategies to support the implementation of two autism-focused EBIs. The leader-level strategy was found effective in improving observed provider fidelity and standardized caregiver-reported child outcomes. This study extends the primary trial findings by assessing individualized child outcomes.

The current study examines the individual and combined effects of the TEAMS implementation strategies - TEAMS Leadership Institute (TLI) and TEAMS Individualized Provider Strategy (TIPS) - on caregiver-identified Top Problems.

Data were extracted from the TEAMS project, a hybrid type 3 implementation-effectiveness trial testing the effects of implementation strategies when paired with AIM HI (An Individualized Mental Health Intervention for Autism) in mental health programs (Study 1) and CPRT (Classroom Pivotal Response Teaching) in classrooms (Study 2). Programs/districts were randomized to TLI and/or TIPS. Data from 353 caregivers of autistic children (M _age = 7.89 years, SD = 2.92, 80.1% male, 44.2% Latinx) were analyzed. Clinical outcomes were measured using the Top Problems Assessment at intake and after 6 months.

Controlling for study intervention (AIM HI or CPRT), a significant TLI x Time interaction (B = -0.95, p = .021) indicated greater reductions in Top Problem intensity in the TLI (vs. no-TLI) condition. No significant effects were found for TIPS or TIPSxTLI.

Findings support the effectiveness of leader-focused implementation strategies in improving the outcomes valued most by families.

Depression is a common illness that affects people within every society around the world. It afflicts the young and the old and everyone in between, and as such poses an immense global burden. New interventions and a deeper understanding of this illness are emerging, but improving the use of existing treatments is equally important and might be a more efficient and effective strategy to addressing depression. Therefore, it is imperative that we improve the diagnosis of depression and its clinical management.