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PubMed2026

A profile of firearm-related fatalities admitted to the Diepkloof Forensic Pathology Service Soweto medico-legal mortuary during the COVID-19 and post COVID-19 periods.

This retrospective descriptive study examined firearm-related fatalities during (April-December 2020; n = 241) and after (April-December 2023; n = 299) COVID-19 lockdowns using 540 cases from the Diepkloof Forensic Pathology Service, Soweto, South Africa. Data was obtained from autopsy reports, forensic records, police statements, and death scene documentation. Firearm violence affected young adult Black males (22-43 years), with only minor demographic shifts post-pandemic. The overall burden and core patterns of violence remained stable, with criminal activity - primarily robbery and interpersonal violence - persisting as the leading contexts, and homicide the dominant manner of death. Post-COVID-19 findings demonstrated contextual shifts, including increased incidents in public and social environments, reflecting greater mobility and resumption of social activity. A significant rise in mean blood alcohol concentration (0.09 g/100 mL vs 0.14 g/100 mL; p < 0.0001) suggests increased alcohol involvement following easing of restrictions. Unfortunately, persistent information gaps, noted particularly in circumstantial history, incident location, firearm type, highlighting the need for improved data provision and capture systems. While the epidemiology of firearm-related fatalities remained unchanged, the post-COVID-19 period was characterised by increased alcohol involvement, shifts toward public-space violence, and fewer gunshot wounds per victim, suggesting changes in situational and behavioural dynamics rather than underlying drivers of violence.

Humans↗

PubMed2026

Power as equal ability, knowledge and resistance: Systematic review of experiences of adults with noncommunicable diseases.

PURPOSE: To analyse subjective experiences of power of adults with noncommunicable diseases in relationships with healthcare practitioners as well as underlying facilitators and barriers of these experiences. METHODS: Systematic review (4 databases) of experiences using reflexive thematic analysis underpinned by critical realist approach. The analysis was conducted with an abductive reasoning using previous theories on social power as well as retroduction. RESULTS: Based on 24 studies, we formed three themes, which depict experiences of power as 1) the position, equal ability and freedom to make one's own choices and (re)negotiate within shared dialogue, 2) the ability to use knowledge to claim one's rights, 3) resistance. Facilitators were connected to acknowledgement as an equally valuable individual, positive healthcare practitioner attitudes and actions towards patient activity and views, safety in the relationship as well as to sufficient, clear and varied information. Main barriers were experiences of dehumanisation, negative healthcare practitioner attitudes and actions, perceived or assumed practitioner domination in interactions, lack of or incomprehensible knowledge and testimonial smothering. CONCLUSION: Results suggest that adults with noncommunicable diseases may experience power primarily as a positive power: being acknowledged as having legitimate position to make decisions and being in possession of varied knowledge through which they can gain agency to protect and claim their rights, by resisting, if necessary. Healthcare practitioners are in key position to support these experiences through positive transforming actions, while knowledge asymmetries, persistent inequality and paternalistic structures continue to hinder it.

Humans↗

PubMed2026

Genome-wide association study of estimated glomerular filtration rate using repeated measurements in the Taiwan Biobank.

BACKGROUND: Chronic kidney disease (CKD) is a major global public health issue, with genetic factors playing a significant role in kidney function. Although genome-wide association studies (GWAS) have identified numerous loci associated with estimated glomerular filtration rate (eGFR), most studies relied on a single time-point measurement, which limits the capacity to account for within-individual measurement variability. METHODS: We performed a repeated-measurement GWAS in the prospective Taiwan Biobank (Taiwanese ancestry; n = 25,004) using two repeated creatinine-based eGFR measurements. Repeated eGFR values were analyzed using a linear mixed-effects model with a subject-specific random intercept and time-varying covariates, providing a more precise estimate of eGFR level. Identified loci underwent functional annotation (expression quantitative trait locus, deleteriousness prediction, and epigenetic markers) and were compared with results from a single-measurement GWAS. RESULTS: Six loci associated with eGFR were identified, including four previously reported regions (1q22, 4q21.1, 11p14.1, and 17q21.2) and two additional loci (6p21.32 and 15q24.2). Functional annotation implicated several candidate genes-such as MUC1/EFNA1, SHROOM3, HLA-DQB1, MPPED2, NRG4, and PGAP3/FBXL20-in the regulation of kidney function. CONCLUSION: Incorporating repeated eGFR measurements into GWAS may improve phenotypic precision for identifying genetic associations with kidney function. This study identified eGFR-associated loci and biologically plausible candidate genes in a Taiwanese population, which require further replication and functional validation.

Chronic kidney disease↗

PubMed2026

Epigenetics and In Silico Transcriptome Analysis of Pediatric Acute Myeloid Leukemia.

Pediatric acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy that accounts for about 15%-20% of childhood leukemias. Despite therapeutic advances, relapses remain common, and survival for high-risk patients is below 60%. Unlike adult AML, pediatric AML displays distinct genetic mutations, including FLT3-ITD, NPM1, KMT2A rearrangements, and core-binding factors (CBF) fusions, as well as extensive epigenetic dysregulation. Aberrant DNA methylation, histone modifications, and altered non-coding RNA expressions disrupt hematopoietic differentiation and activate oncogenic transcriptional networks. Recent advances in silico transcriptomic analysis have transformed the study of pediatric AML by integrating gene expression and epigenetic data to identify molecular drivers and regulatory networks. Computational RNA-seq pipelines and pathway analyses have highlighted key epigenetic regulators, including DNMT3A, TET2, and HDACs, as potential therapeutic targets. Multi-omics approaches combining transcriptomic, methylomic, and chromatin accessibility data are increasingly used to define biomarkers for diagnosis, prognosis, and therapeutic response. This review provides a comprehensive overview of the molecular and epigenetic landscape of pediatric AML, emphasizing the power of in silico transcriptome analysis to uncover disease mechanisms, refine patient stratification, and guide the development of precision-based epigenetic therapies aimed at improving long-term outcomes in children with AML.

Humans↗

PubMed2026

Venomous Lepidoptera: defensive toxin systems, venom composition, and clinical significance.

Venomous Lepidoptera constitute an underrecognized yet medically significant group of toxin-producing arthropods that employ contact-mediated defensive envenomation through specialized integumentary structures such as setae, spines, and scoli. Unlike actively stinging arthropods, these insects deliver venom passively upon contact, eliciting a diverse spectrum of clinical manifestations collectively termed lepidopterism. Clinical outcomes range from localized pain and dermatitis to severe systemic effects, including hemorrhagic syndromes, complement activation, and chronic inflammatory disorders. Recent advances in proteomic and transcriptomic technologies have transformed our understanding of lepidopteran venoms, revealing unexpectedly complex toxin repertoires comprising serine proteases, phospholipases, pore-forming proteins, disulfide-rich peptides, neuroactive RF-amide peptides, and immune-modulating components. These findings have provided new insights into the molecular basis of toxicity, host-pathogen interactions, and the evolutionary diversification of venom systems within Lepidoptera. This review synthesizes current knowledge on the morphology of venom-delivery structures, venom composition, mechanisms of action, and associated clinical manifestations, while highlighting medically important taxa, particularly species of the genus Lonomia. The successful development of antivenom against Lonomia envenomation underscores the translational relevance of lepidopteran toxin research and its potential for therapeutic innovation. By integrating molecular, clinical, and evolutionary perspectives, this review repositions venomous Lepidoptera as a legitimate and important component of arthropod toxinology. Furthermore, it identifies critical methodological limitations and key knowledge gaps, providing a framework for future investigations aimed at advancing our understanding of toxin biology, immunopathology, and the development of novel biomedical applications.

Animals↗

PubMed2026

Duration and characteristics of hypoglycemia with once-weekly insulin efsitora alfa versus once-daily basal insulins in adults with type 2 diabetes: Exploratory safety analysis of QWINT 2-4.

AIMS: Efsitora is a novel once-weekly basal insulin. Efsitora demonstrated similar efficacy and safety compared with once-daily basal insulin comparators across four phase 3 clinical trials for type 2 diabetes. This exploratory safety analysis further characterizes hypoglycemia events in the efsitora and once-daily treatment groups in three of these trials (QWINT-2, -3, and -4). METHODS: Median duration of hypoglycemia events was assessed with masked continuous glucose monitoring. Incidence of persistent-recurrent (PR) hypoglycemia was assessed by investigators and by a pre-specified algorithm using SMBG e-diary data. Factors contributing to hypoglycemia, characteristics of hypoglycemia, and treatment methods were reported by participants and assessed across groups. RESULTS: Across the three trials, durations of hypoglycemic events for efsitora vs once-daily basal insulin comparators were: Level 1 and 2 [<70 mg/dL]: 40-42.5 vs 40 min; Level 2 [<54 mg/dL]: 35-39.9 vs 35 min. Few incidences of PR hypoglycemia were reported for efsitora or once-daily comparators. No major descriptive differences were observed between hypoglycemia contributing factors, characteristics, or treatment methods in efsitora and once-daily treatment groups. CONCLUSIONS: No clinically relevant differences were observed between the duration or characteristics of hypoglycemic events in efsitora and once-daily treatment groups in the QWINT-2, -3, and -4 trials.

Adult↗

PubMed2026

Screening for neurofibromatosis type 1-related optic pathway gliomas: a systematic review.

BACKGROUND: Neurofibromatosis-type 1 (NF1) is a genetic disorder characterized by developing optic pathway gliomas (OPGs) in 15%-20% of patients with higher estimates where consanguinity is prevalent. Clinically, NF1-OPG might be unpredictable with the risk of OPG progression and visual impairment. The optimal time for screening is controversial. We aim to identify the mean/median age at diagnosis of NF1-OPG and its clinical spectrum. METHODS: A systematic review of PubMed, Web of Science, and Embase databases was conducted for English-language publications from January 1993 to October 2025, exploring the visual screening of OPGs in NF1 patients, following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and registered in the Prospective Register of Systematic Reviews (PROSPERO ID: CRD420251036244). Inclusion criteria focused on studies reporting the age at OPG diagnosis and visual manifestations in NF1 patients. Data were extracted on demographics, age at NF1 and OPG diagnosis, tumour location (using the Dodge classification), and presenting symptoms. Sixteen studies met the inclusion criteria. RESULTS: Among 4 739 NF1 patients, 818 had OPGs, with prevalence ranging from 4.2% to 46.7%. The age at NF1 diagnosis ranged from 0 to 132 months (mean: 18-38 months), and at OPG diagnosis from 0-240 months (median: 29-58 months). Approximately 58.4% of OPGs were asymptomatic, and 25% were above the age of 5 years. Among symptomatic patients, the most frequent presentations included decreased visual acuity (62%), abnormal optic disc (45%), proptosis (20%), strabismus (12%), and visual field defects (7%). CONCLUSIONS: NF1-related OPGs typically present early within 6 years of age. Early ophthalmologic and/or radiologic screening at the time of NF1 diagnosis enhances the detection of silent OPGs.

Humans↗

PubMed2026

Normoalbuminuric and albuminuric diabetic kidney disease exhibit divergent renal proteomic characteristics: implications for management.

BACKGROUND: The pathogenesis of diabetic kidney disease (DKD) is complex. Normoalbuminuric diabetic kidney disease (NADKD) is a special subtype of DKD that often progresses insidiously without detectable albuminuria, posing diagnostic and therapeutic challenges. Its pathogenesis remains unclear. Proteomic analysis of renal tissues may offer insights into its pathogenesis and identify biomarkers. METHODS: Clinicopathological data from 295 biopsy-proven DKD patients were collected and classified into normoalbuminuric (UACR < 30 mg/g, n = 25), microalbuminuric (UACR 30-300 mg/g, n = 26), and macroalbuminuric (UACR > 300 mg/g, n = 244) groups. Laser microdissection combined with mass spectrometry (LMD/MS) was used to analyze glomerular and proximal tubule proteomics in 5 patients per DKD subgroup and 5 control subjects. Associations with clinical features were examined. RESULTS: Glomerular proteomic analysis revealed that oxidative stress and metabolic pathways (UQCRC1) were upregulated in NADKD group, whereas the complement and coagulation cascades (C3, C5, C6, C9, CFH, CFHR1) were significantly upregulated in the microalbuminuric and macroalbuminuric DKD groups. The proximal tubule proteomics analysis showed that oxidative phosphorylation-related proteins (SDHA, CYCS, UQCRQ) were upregulated in NADKD, and collagen I related proteins (COL1A1, COL1A2) were significantly upregulated. CONCLUSION: Oxidative stress and mitochondrial dysfunction are involved in the progression of NADKD, lesions predominantly located in the tubulointerstitium. The complement pathway participates in the pathogenesis and progression of albuminuric DKD (ADKD). These divergent molecular profiles suggest that NADKD and ADKD may reflect different pathophysiological mechanisms and have important implications for therapeutic strategies in diabetes management.

Humans↗

PubMed2026

Reinforcement learning-based dynamic ensemble for missense variant effect prediction and tiered prioritization of VUS.

BACKGROUND: Accurate classification of missense variants remains a challenging task despite major advances in genomics. Numerous computational models have been developed to assist in variant classification, but often require repeated integration and benchmarking efforts. Ensemble methods have been proposed to overcome the limitations of single predictors, but mostly rely on fixed, predefined weights that constrain their ability to capture interactions among predictive signals. METHODS: We present GenixRL, a dynamic ensemble framework that reformulates model fusion as a reinforcement learning optimization problem. GenixRL uses a Q-learning agent to learn a policy that dynamically weights the probabilistic outputs of complementary predictors, including BayesDel (addAF and noAF), ClinPred, and MetaRNN. Replacing static weighting with policy learning allows GenixRL to adaptively identify optimal weightings and substantially improve classification accuracy. RESULTS: In benchmark evaluation against 25 state-of-the-art predictors, GenixRL achieved an AUROC of 0.9644 on an independent ClinVar dataset. On saturation genome editing assays for BRCA1 and BRCA2, GenixRL achieved the best performance and ranked highest on 14 of 17 clinically significant genes in a zero-shot evaluation. Applied to uncertain and conflicting ClinVar variants, GenixRL enabled tiered, evidence-based prioritization of hundreds of thousands of variants as likely pathogenic or pathogenic with high confidence, supported by orthogonal population evidence from gnomAD. CONCLUSION: GenixRL advances pathogenicity prediction for missense variants and provides an adaptive ensemble that sorts variants of uncertain significance into tiered candidates for expert curation and functional validation.

Mutation, Missense↗

PubMed2026

Glycemic and safety outcomes of the insulin-only bionic pancreas in older adults and individuals with impaired awareness of Hypoglycemia: a post hoc analysis of a randomized pivotal trial.

AIMS: Evaluate the efficacy and safety of iLet Bionic Pancreas (BP) in older adults and individuals with impaired awareness of hypoglycemia (IAH). METHODS: This post hoc analysis used individual participant-level data from the Insulin-Only Bionic Pancreas Pivotal Trial (n = 440; NCT04200313). Eligible participants (n = 96) with type 1 diabetes, aged ≥ 60 years and/or had IAH (Clarke score ≥ 4), were randomized to BP with aspart/lispro (BP-Asp/Lis; n = 45), BP with fast-acting aspart configuration (BP-Fiasp; n = 31), or standard care (SC; n = 20) for 13 weeks. RESULTS: Compared with SC, time-in-range (70-180 mg/dL) significantly increased by 7.49 % (95 % CI: 2.61 to 12.38; ∼1.8 h/day) with BP-Asp/Lis and by 8.28 % (95 % CI: 3.15 to 13.41; ∼2.0 h/day) with BP-Fiasp, driven by reduced hyperglycemia. No significant differences were observed in hypoglycemia exposure. Severe hypoglycemia occurred in four participants (four events) on BP-Asp/Lis and one participant (two events) on SC. One diabetic ketoacidosis event occurred on BP-Fiasp due to an infusion set failure. CONCLUSIONS: In high-risk, clinically vulnerable populations, the BP system significantly improved glycemic control while maintaining safety parity with respect to hypoglycemia risk, providing a resilient therapeutic alternative for vulnerable cohorts.

Humans↗

PubMed2026

Ultrastructural Insights Into the Reproductive Anatomy and Eggs of Cotton Pink Bollworm, Pectinophora gossypiella Saunders (Lepidoptera: Gelechiidae).

The pink bollworm, Pectinophora gossypiella Saunders is a major pest of cotton, notorious for its high reproductive potential and rapid evolution of resistance to Bacillus thuringiensis (Bt) toxins. Despite its economic significance, detailed knowledge of its reproductive anatomy and egg ultrastructure has remained limited, constraining the development of advanced molecular control strategies such as CRISPR/Cas9-based genome editing. The present study provides the first comprehensive characterization of the reproductive system and egg surface morphology of P. gossypiella using stereomicroscopy and scanning electron microscopy (SEM) techniques. The male reproductive system consists of fused, bean-shaped testes, seminal vesicles, duplex and simplex ejaculatory ducts, and paired accessory glands. The female reproductive system comprises paired ovaries with four polytrophic ovarioles per ovary, lateral and common oviducts, accessory glands, corpus bursae, and spermathecal glands. Eggs are oval, dorsoventrally flattened, exhibit a reticulated chorion with distinct micropylar and aeropylar regions. SEM images revealed 6-9 rosette cells encircling a circular micropylar plate, 14-19 first order and 17-23 s order ribs, and 250-291 polygonal surface cells. The structural features of P. gossypiella eggs reveal key sites for sperm entry, aeropylar respiration, and candidate zones for microinjection in gene editing applications. These findings establish a morphological baseline critical for optimizing embryo manipulation and ribonucleoprotein (RNP) delivery in lepidopteran genome editing. This study represents a pioneering effort to integrate classical egg morphology with molecular entomology, thereby advancing precision genetic interventions aimed at resistance management and population suppression in P. gossypiella.

Animals↗

PubMed2026

A streamlined workflow for high throughput metaproteomic analysis of the rumen microbiome.

Metaproteomics can provide direct functional insights into complex microbial communities, yet its application in rumen research remains limited due to labor-intensive and low-throughput sample preparation workflows before the MS analysis. This work aimed to develop and characterize a streamlined, high throughput metaproteomic workflow optimized for rumen samples. Key steps, including microbial cell extraction, cell lysis, protein digestion, and LC-MS/MS acquisition, were systematically assessed and optimized to reduce hands-on time while maintaining deep proteome coverage. The optimized workflow integrates a minimized cell extraction protocol using 0.5 g starting material and in-solution tryptic digestion. Application of the final workflow to 72 samples from in vitro fermentation revealed that biological variability between inocula dominated technical variability, which remained moderate (median CV of 21-24% across batches). Overall, the optimized workflow supports robust taxonomic and functional characterization of the rumen microbiome with improved scalability. These advances provide a foundation for applying metaproteomics to larger experimental designs, including nutritional trials and cohort studies, thereby enabling broader functional interrogation of rumen microbial ecosystems. SIGNIFICANCE: This study addresses current limitations in the application of metaproteomics to rumen microbiome research by developing a streamlined and scalable sample preparation workflow. By optimizing key steps and reducing sample input while maintaining reproducibility and proteome coverage, this work enables more efficient processing of larger sample sets. These advances support the broader use of metaproteomics in rumen studies and facilitate functional investigations relevant to animal nutrition and sustainable livestock production.

Animals↗

PubMed2026

Parents' Awareness of Their Adolescents' Sexual Behaviors and Experiences: A Concordance Analysis.

PURPOSE: Adolescence is a developmental period during which sexual exploration is normative. Parental awareness of adolescents' sexual behaviors can be protective during this stage; however, research suggests both parents and adolescents tend to avoid open conversations about these sensitive issues. This study aimed to examine concordance between parent proxy-reports and adolescent self-reports across three domains of adolescents' sexual behaviors and experiences. METHODS: Data were collected from a national sample of 522 parent-adolescent dyads (aged 15-17 years) from the AmeriSpeak panel (data collected May-September 2022). Prevalence-adjusted bias-adjusted kappa (PABAK) statistics were calculated to evaluate agreement. RESULTS: Findings revealed weak-to-moderate concordance regarding adolescents sending and receiving sexual photos (PABAKs = 0.54-0.79), whereas stronger concordance was observed for experiences related to nonconsensual sharing of sexual photos (PABAKs = 0.92-0.94), with high agreement largely driven by low reported prevalence of these experiences. Strong concordance regarding whether adolescents had ever had sex (PABAK = 0.80) was largely driven by both parents and adolescents reporting the adolescent had not had sex. Concordance regarding sexually transmitted infection and pregnancy prevention methods varied, ranging from weak to strong agreement across specific methods (or lack thereof; PABAKs = -0.07-0.79). DISCUSSION: Results highlight significant discrepancies in parents' knowledge about their adolescents' sexual behaviors and experiences. Interventions aimed at enhancing trust and open dialogue between parents and adolescents about sexuality-related topics, as well as ensuring adolescents have a variety of trusted sources to consult for sexual information, can help adolescents make informed sexual health decisions.

Humans↗

PubMed2026

Optimal dose and exercise modality to improve HbA1c in older adults with type 2 diabetes mellitus: a systematic review with pairwise, network, and dose-response meta-analyses.

We aimed to compare exercise modalities and evaluate dose-response relationships with glycemic control including continuous aerobic exercise (CAE), resistance training (RT), combined exercise (CE), mind-body exercise (MBE), and high-intensity interval training (HIIT) in older adults with type 2 diabetes mellitus (T2DM). Three databases were searched for randomized controlled trials of exercise interventions in older adults with T2DM reporting glycated hemoglobin (HbA1c). Pairwise, Bayesian network, and dose-response meta-analyses were conducted. Compared with control, HIIT demonstrated the largest estimated reduction (MD = -0.95%; 95% CrI -1.45, -0.49), followed by CE (MD = -0.59%; 95% CrI -0.93, -0.25), CAE (MD = -0.46%; 95% CrI -0.69, -0.24), MBE (MD = -0.42%; 95% CrI -0.76, -0.10), and RT (MD = -0.29%; 95% CrI -0.51, -0.08). Dose-response network meta-analyses suggested a non-linear association between overall exercise dose and HbA1c reduction, with maximal estimated benefits at approximately 704 METs-min/week with the 95% CrI excluding zero between 241 and 920 METs-min/week. HIIT demonstrated the steepest estimated dose-response relationship, but with wider credible intervals. Other exercise modalities showed more gradual dose-response patterns across their estimated effective ranges. Our findings suggest that exercise prescription for older adults with T2DM should be individualized according to exercise modality, dose, and health status.

Humans↗

PubMed2026

Foot exercise plus education versus brief advice for the treatment of plantar heel pain (FEET Trial): a feasibility randomised controlled trial.

BACKGROUND: Despite foot muscle strengthening being a target of exercise interventions for plantar heel pain (PHP) no study has measured foot muscle outcomes, and existing research is limited by a lack of control (no treatment) comparisons. OBJECTIVES: To determine the feasibility of conducting a randomised controlled trial and investigate the acceptability and credibility of comprehensive progressive foot exercise and education compared to brief advice for PHP. DESIGN: Randomised parallel group feasibility trial. METHOD: People with PHP were randomised (1:1 concealed allocation) to receive either foot exercise plus education or brief advice for twelve weeks. Primary outcomes included willingness to enrol, recruitment rate, adherence, logbook completion, dropout rate, early withdrawal reasons, adverse events, additional treatments sought, and credibility/expectancy. RESULTS: Twenty people with PHP (16 women; age 50 ± 9 years; body mass index = 30.7 ± 4.6 kg/m2) were recruited over 15 weeks (1.3 participants per week). Primary outcomes were willingness to enrol (80%), adherence (physiotherapy sessions attended: foot exercise plus education 85%, brief advice 100%; home exercise program: 62% daily sessions completed, 72% thrice weekly sessions completed), logbook completion (foot exercise plus education 75%, brief advice 90%), dropout rate (15%), and additional treatments sought (69%). There were no intervention-related adverse events, and credibility scores were higher for foot exercise plus education. CONCLUSIONS: This study confirms feasibility and acceptability of a protocol comparing foot exercise plus education with brief advice in individuals with PHP, generating key insights to inform future trial design.

Humans↗

PubMed2026

Molecular targeted therapy in combination with chemotherapy for the treatment of platinum-resistant/refractory ovarian cancer (PROC): a systematic review and network meta-analysis.

BACKGROUND: Although single-agent chemotherapy is the most common approach for treating platinum-resistant or refractory ovarian cancer (PROC), there is growing evidence that combining molecular targeted agents with chemotherapy is beneficial, especially for certain patient groups. However, the most effective combination regimen remains elusive. OBJECTIVES: This Bayesian network meta-analysis (NMA) aims to identify the best combination therapy for PROC. METHODS: Relevant studies were searched in PubMed, EMBASE, Web of Science and the Cochrane Central Register of Controlled Trials from their inception until October 2024. The primary outcomes were overall survival (OS), progression-free survival (PFS) and adverse events (AEs). Statistical analyses were performed using the GEMTC package (1.0-2) and R 4.2.0. This review was registered in PROSPERO (CRD42023428414). RESULTS: Our analysis of 22 randomized controlled trials (RCTs) (n = 3408) demonstrated that chemotherapy combinations with bevacizumab (hazard ratio (HR) = 0.52-0.65), sorafenib (HR = 0.65, 95% confidence interval (CI): 0.45-0.93) or adavosertib (HR = 0.56, 95%CI: 0.35-0.90) significantly improved OS and PFS versus chemotherapy alone. Notably, adavosertib + gemcitabine was associated with an increased risk of grade 3-4 AEs (relative risk (RR) = 1.8, 95%CI: 1.3-2.7), but these were generally manageable. CONCLUSIONS: Bevacizumab-based combinations demonstrate consistent benefits across multiple regimens for PROC. Paclitaxel + bevacizumab emerges as the optimal balance of efficacy and safety. Topotecan + sorafenib could be an alternative for patients who are ineligible for anti-angiogenic therapy.

Humans↗

PubMed2026

Long-term hormone therapy for perimenopausal and postmenopausal women.

BACKGROUND: Hormone therapy is widely provided to control menopausal symptoms and has been used for the management and prevention of cardiovascular disease, osteoporosis and dementia in older women. This is an updated version of a Cochrane review first published in 2005. OBJECTIVES: To assess the long-term effects of prolonged use (at least one year) of hormone therapy on mortality, cardiovascular outcomes, cancer, gallbladder disease, fractures and cognition in perimenopausal and postmenopausal women. SEARCH METHODS: We used the Cochrane Gynaecology and Fertility Group Specialised Register, CENTRAL, MEDLINE, three other databases and two trial registers, together with reference checking, citation searching and contact with study authors to identify the studies included in the review. The latest search date was 26 September 2024. SELECTION CRITERIA: We included randomised, double-blind trials in which peri- or postmenopausal women took hormone therapy or placebo for at least one year. We included various oestrogen formulations, with or without progestogens. We focused on studies assessing hormone therapy's effects on long-term clinical outcomes, including death, coronary events and cancer. Hormone therapy's efficacy in managing menopausal symptoms was beyond the scope of this review, and is assessed in other Cochrane reviews. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies, assessed risk of bias and extracted data. We calculated risk ratios (RRs) for dichotomous data and mean differences (MDs) for continuous data, along with 95% confidence intervals (CIs). We assessed the certainty of the evidence using GRADE. MAIN RESULTS: We included 24 studies - with two newly added in this update - involving 45,660 participants. We derived nearly 70% of the data from two well-conducted studies: the Heart and Estrogen/progestin Replacement Study (HERS 1998) and the large, multi-component Women's Health Initiative research programme, which included two hormone therapy arms (WHI 1998). Across all the studies, most participants were postmenopausal American women with one or more comorbidities. The mean participant age in most studies was over 60 years. Only one included study focused on perimenopausal women. We present full results for all included studies with available data in the main review. The results presented below are drawn from WHI 1998, in which the combined hormone therapy arm and the oestrogen-only arm were run concurrently, with women assigned to the appropriate trial based on their uterus status. One study with 16,608 postmenopausal women with an intact uterus compared combined continuous hormone therapy (conjugated equine oestrogen and medroxyprogesterone acetate) to placebo, and measured outcomes at an average of 5.6 years of follow-up. Based on this study, combined continuous hormone therapy probably makes little to no difference to the risk of a coronary event (RR 1.17, 95% CI 0.95 to 1.44; moderate-certainty evidence). It may increase the risk of stroke (RR 1.39, 95% CI 1.09 to 2.09; low-certainty evidence) and venous thromboembolism (RR 2.03, 95% CI 1.55 to 6.64; low-certainty evidence). Compared to placebo, combined continuous hormone therapy probably increases the risk of breast cancer (RR 1.27, 95% CI 1.03 to 1.56; moderate-certainty evidence) and probably makes little to no difference to the risk of lung cancer (RR 1.06, 95% CI 0.77 to 1.46; moderate-certainty evidence). It may increase gallbladder disease requiring surgery (RR 1.64, 95% CI 1.30 to 2.06; 14,203 participants; low-certainty evidence), and probably reduces the risk of all clinical fractures (RR 0.78, 95% CI 0.71 to 0.86; moderate-certainty evidence). One study including 10,739 postmenopausal women who had undergone a hysterectomy compared oestrogen-only (conjugated equine oestrogen) hormone therapy to placebo, and measured outcomes at an average of seven years' follow-up. Based on this study, oestrogen-only hormone therapy probably makes little to no difference to the risk of coronary events (RR 0.94, 95% CI 0.78 to 1.13), venous thromboembolism (RR 1.32, 95% CI 1.00 to 1.74) and breast cancer (RR 0.79, 95% CI 0.61 to 1.01), all with moderate-certainty evidence. It may make little to no difference to the risk of lung cancer (RR 1.04, 95% CI 0.73 to 1.48; low-certainty evidence). Oestrogen-only hormone therapy probably increases the risk of stroke (RR 1.33, 95% CI 1.06 to 1.67) and gallbladder disease requiring surgery (RR 1.78, 95% CI 1.42 to 2.24), and probably reduces the risk of all clinical fractures (RR 0.73, 95% CI 0.65 to 0.80), all with moderate-certainty evidence. We judged most included studies to have a low risk of bias for most domains. The overall certainty of evidence for the main comparisons was moderate. The main limitation was that only about 30% of women were 50 to 59 years old at baseline, the age group most likely to consider hormone therapy for vasomotor symptoms. AUTHORS' CONCLUSIONS: Long-term follow-up of women using hormone therapy suggests that the risk profiles vary between combined hormone therapy and oestrogen-only therapy. Oestrogen-only hormone therapy probably makes little to no difference to coronary events, and probably increases the risk of stroke and gallbladder disease. It probably makes little to no difference in the risk of breast cancer, and probably reduces the risk of all fractures. Combined hormone therapy may increase the risk of thromboembolism and probably increases the risk of breast cancer. These results should be interpreted with caution as they are based on one study using oral hormone therapy, which may not represent the risks of the hormone therapy currently used in clinical practice.

Humans↗

PubMed2025

UV-based homogeneous disinfection process for removal of antibiotic resistance genes: Efficiency, mechanisms and influencing factors.

The proliferation and dissemination of antibiotic resistance genes (ARGs) in aquatic environments pose a serious threat to global public health. Ultraviolet-driven homogeneous advanced oxidation processes (UV-AOPs) represent a prospective suite of technologies for the efficient removal of ARGs. This review critically assesses recent advances in the application of UV-AOPs, specifically UV/hydrogen peroxide (UV/H2O2), UV/peracetic acid (UV/PAA), UV/persulfate (UV/PS), and UV/chlorine (UV/Cl), for the elimination of extracellular ARGs and intracellular ARGs. The underlying mechanisms involve direct ultraviolet-induced DNA damage, including pyrimidine dimer formation and strand breakage, as well as oxidation mediated by radicals such as hydroxyl radicals, sulfate radicals, carbon-centered radicals, and reactive chlorine species. The relative contribution of radical and non-radical pathways is strongly influenced by water chemistry and process conditions. We further expound on the critical operational and environmental factors governing ARG removal kinetics, including UV wavelength and fluence, oxidant type and dosage, ARG sequence characteristics, pH, ubiquitous anions, and dissolved organic matter, which collectively affect radical generation, quenching, and reaction microenvironments. Notably, for i-ARGs, UV-AOPs facilitate degradation not only through direct radical attack but also by disrupting cellular integrity and permeabilizing membranes, thereby enhancing the exposure of genetic materials to oxidative and photolytic damage. This review synthesizes current understanding to provide a mechanistic basis for the design and optimization of UV-AOP systems, highlighting their potential as effective barriers against the dissemination of antibiotic resistance in water reuse and purification scenarios.

Disinfection↗