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Up to 80% of diffuse midline gliomas (DMGs) are characterized by a lysine to methionine driver mutation (K27M) in the tail of histone variant H3.3, pointing to likely roles for epigenetic mechanisms in K27M-driven tumorigenesis. Understanding the effects of mutant histone H3.3 on the complex patterns of histone modifications and interactions with chromatin structure and modifying enzymes is essential to developing effective combination treatment therapies for K27M DMG such as targeting multiple epigenetic enzymes at once. Here, using a genomics approach, we identified combinatorial patterns of epigenetic modifications that are affected by mutant H3.3 in DMG. We also characterized a strong association between H3.3 and the structural chromatin regulator CTCF, finding that mutant H3.3 leads to ectopic binding of CTCF at many additional sites across the genome in DMG. Notably, a number of these ectopic CTCF binding events occur within the HOX gene loci and are associated with an increase in H3K27me3 levels at bivalent domains and a decrease in HOX gene expression. We also find an association of H3.3 and CTCF at genomic sites adjacent to regions with active or repressive modifications, suggesting a potential role for these two factors in segmenting the chromatin and regulating, perhaps insulating, different types of domains. Together our data suggest that H3.3 K27M both affects epigenetic marks and chromatin organization in part through interaction with CTCF and point to a potentially novel contributory role for CTCF in promoting oncogenesis in DMG. These findings could have potential implications for designing therapy regimens to more effectively target the chromatin changes and genomic instability observed in H3.3K27M glioma cells.

Health-related quality of life (HRQoL) is a vital indicator of evaluating care outcomes and prognosis, yet little is understood about its developmental trajectories in older patients with chronic pain. This study aimed to identify latent HRQoL trajectories and their predictors, and to develop explainable machine learning models for predicting HRQoL deterioration. This prospective cohort study assessed 608 older patients with chronic pain at admission and at 1, 3, and 6 months post-admission, collecting data on HRQoL, general characteristics, pain level, activities of daily living (ADL), depression, and perceived social support. Growth mixture modeling was applied to identify trajectories of physical and mental HRQoL. Predictors were selected using LASSO regression and SVM-RFE. Nine explainable machine learning models were developed for both components, and SHAP interpreted the outputs. An HRQoL decision-support dashboard was developed to facilitate potential clinical application. Three physical HRQoL trajectories were identified: Stable High, Decline and Low Stability, alongside two mental HRQoL trajectories: Improvement and Decline. Key predictors included education level, pain duration, pain level, ADL, depression, and perceived social support, with ADL and pain level being the most influential for physical and mental HRQoL, respectively. This dual-trajectory study identified five distinct HRQoL patterns in older patients with chronic pain, elucidating key predictors via explainable machine learning. The proposed HRQoL decision-support dashboard may provide an interpretable tool to support understanding of predictive relationships and assist healthcare professionals in HRQoL assessment. Not applicable.

Cold preservation is a critical logistical step in liver transplantation but induces ischemia-reperfusion injury (IRI), a key driver of early graft dysfunction. While bulk tissue assays capture global damage, they obscure the cell-type-specific transcriptional programs engaged during hypothermic storage. We utilized a multicellular human liver-on-chip model comprising Patient-Derived Organoids (PDOs), hepatic stellate cells (HSCs), liver sinusoidal endothelial cells (LSECs), and macrophages. Chips were exposed to 24-h static cold storage using either the clinical standard University of Wisconsin (UW) solution or a hyperbranched polyglycerol (HPG)-based formulation, followed by normothermic reperfusion. Single-cell RNA sequencing (scRNA-seq) was performed to map transcriptional trajectories across the preservation-reperfusion axis. We identified candidate solution-dependent transcriptional differences across cell types. PDOs from UW-preserved chips showed comparatively higher mean expression of inflammatory and oxidative stress-associated transcripts (IFI27, SAA1, HMOX1) and mitochondrially-encoded genes (MT-ND5) relative to HPG-preserved samples, which retained comparatively higher expression of homeostatic epithelial markers (EPCAM, KRT18). HSCs and LSECs in the UW group showed comparatively elevated expression of fibrosis-associated (COL1A1, TAGLN) and endothelial adhesion (ICAM1) transcripts. Ligand-receptor interaction modelling identified candidate inflammatory communication axes, including chemokine signaling interactions (CXCL1, CCL20) between macrophages and epithelial compartments, with higher predicted activity under UW preservation. This study provides an exploratory, high-resolution map of cell-type-specific transcriptional patterns associated with hypothermic preservation in a liver-on-chip model. Our findings suggest that preservation solution chemistry is associated with distinct transcriptional signatures spanning stress response, mitochondrial, and intercellular signaling pathways. Transcriptional patterns in HPG-preserved cells were consistent with comparatively attenuated injury responses; however, these observations are hypothesis-generating and require independent biological replication and functional validation, including metabolic flux assays and ROS production measurements before conclusions regarding mitochondrial protection or clinical preservation efficacy can be drawn.

Representatives of the phylum Methanobacteriota occur in various anoxic environments, but only members of the genera Methanosphaera and Methanobrevibacter exclusively colonize the digestive tract of animals. Recent phylogenomic analyses revealed that the genus Methanobrevibacter, which harbors the majority of the intestinal species, is severely underclassified and represents a family-level taxon, "Methanobrevibacteraceae", that evolved entirely in the digestive tract of animals. Comparative genome analysis of 158 species of Methanobacteriota, including uncultured representatives in the Genome Taxonomy Database (GTDB), demonstrated that the intestinal lineages are clearly separated from the remaining members of the phylum. They differ from the non-intestinal lineages in genome size, GC content, coding density, an increased number of pseudogenes and adhesin-like proteins, and show numerous adaptations to the copiotrophic gut environment. A decreased biosynthetic potential led to a dependence on other community members and limits the dispersal of intestinal species into other habitats, which is reflected in coevolutionary patterns with their major host groups among arthropods, ungulates, and primates. Certain lineages even engaged in symbiotic associations with intestinal protists, presumably benefiting from the H2 produced by the hydrogenosomes of their anaerobic hosts. Our results reveal that the transition of free-living Methanobacteriota to a host-associated lifestyle involves the same genomic changes that were previously recognized in gut bacteria and bacterial endosymbionts of protists, reflecting resemblances between the two prokaryotic domains that are caused by evolutionary convergence in similar environments.

Healthcare-seeking behavior is a key factor in how well a health system performs and how fair it is. In Saudi Arabia, public healthcare services are free, yet many people still choose private healthcare, especially in cities like Riyadh. It is important to understand why people seek care from private clinics to help shape health policies, distribute resources better, and improve services across the healthcare system. This study aimed to examine the frequency of private healthcare use, defined as the reported usual or concurrent use of private healthcare services, and to identify sociodemographic, behavioral, and health-related factors associated with this choice among adults in Riyadh, Saudi Arabia. A cross-sectional study was carried out in Riyadh from March to July 2023 using a multistage cluster sampling method. We randomly selected 48 government primary healthcare centers and invited adults aged 18 and older who visited these centers to participate. We collected data electronically with a validated questionnaire that covered sociodemographic details, patterns of healthcare use, reasons for choosing private healthcare, behavioral risk factors, and existing health conditions. We used multivariate logistic regression analysis to find independent predictors of private healthcare use, reporting adjusted odds ratios (AORs) and 95% confidence intervals (CIs). Of 14,239 participants, 72.4% reported using private healthcare services either as a usual source of care or alongside public services. The multivariable analysis revealed several factors to be positively related to private healthcare utilization. Those who were married were more likely to use private healthcare services (AOR 1.23, 95% CI 1.11-1.36). Those with insurance coverage were threefold higher odds of private healthcare use (AOR 3.51, 95% CI 3.13-3.94). Smokers were more likely to seek private healthcare (AOR 1.60, 95% CI 1.45-1.77) than non-smokers, and those who exercised reported increased utilization (AOR 1.83, 95% CI 1.67-2.00). Obesity was also positively related to private healthcare utilization (AOR 1.38, 95% CI 1.12-1.71), and those with heart disease had substantially higher odds of using private healthcare services (AOR 2.09, 95% CI 1.59-2.76). Private healthcare use in Riyadh is common and associated with insurance coverage, marital status, behavioral factors, and certain chronic conditions. These findings provide descriptive insights into factors related to private healthcare utilization among public PHC attendees in Riyadh, without implying causal effects or policy recommendations beyond the scope of the data.

SMARCB1-deficient sinonasal carcinoma (SDSC) is a rare, highly aggressive malignancy with limited therapeutic options and no established preclinical models. Here, single-nucleus RNA sequencing (snRNAseq), spatial transcriptomics, and ex vivo patient-derived tissue slice culture (TSC) were combined to resolve intratumoral heterogeneity, niche organization, and treatment vulnerabilities in an index SDSC. snRNAseq identified three malignant subpopulations, including two specialized states marked by ALDH1A1 and NTN4. Spatial profiling mapped these states to distinct niches. The ALDH1A1+ compartment localized to a basal-associated niche with intermingled p63-positive basal cells adjacent to stroma, showed reduced proliferative activity, and displayed stem-like transcriptional features. Ex vivo drug testing revealed a striking response: the mTOR inhibitor Sapanisertib induced extensive tumor necrosis and was associated with near-complete depletion of ALDH1A1+ and NTN4+ states, accompanied by strong stress/apoptosis signatures and reduced endothelial cells. In an additional retrospective cohort of 12 SDSC, ALDH1A1 was present in all cases with heterogeneous spatial patterns and higher levels in recurrences. Mesothelin was expressed in the index case and a subset of tumors, supporting mesothelin-directed therapeutic strategies.

Cis-regulatory elements (CREs) drive tissue- and cell-specific gene expression and are essential for safe, sustainable genetic control strategies in pest and vector insects, including the engineering of gene drives in the primary human-malaria vector Anopheles gambiae. Yet CREs remain poorly defined in mosquitoes due to limited computational tools and practical methods for identification and validation. We present a systematic in silico approach for CRE discovery, correlating targeted DNA-motif searches with gene expression, followed by frequency and distribution analysis within putative promoter regions. Applied to the A. gambiae germline, this approach identified hundreds of putative CREs significantly correlated with germline expression in one or both sexes, often linked to distinct sperm developmental stages and chromosomal locations, suggesting roles in broader regulatory mechanisms such as dosage compensation and meiotic silencing. When mapped onto pre-characterised germline promoters, CRE distribution aligned with regions associated with experimental expression patterns. Finally, we validated a top-ranked testis-enriched CRE using an in vivo dual-reporter assay, showing that mutation of conserved nucleotides drastically altered male germline expression. To the best of our knowledge this work provides the first nucleotide-resolution regulatory genome annotation of the A. gambiae germline, offering a transferable framework to aid promoter design for genetic control strategies against malaria mosquitoes and other insect pests.

Ureteral stents are routinely used following endourological procedures to ensure adequate drainage and prevent obstruction. However, stent-related morbidity remains common, and optimal stent dwell time and removal methods are not well defined. This systematic review aimed to evaluate clinical and procedural factors influencing ureteral stent dwell time and the methods used for stent removal after endourological interventions. A systematic review was conducted in accordance with PRISMA guidelines and registered on PROSPERO. MEDLINE and Embase were searched from inception to October 2025. Randomized controlled trials and comparative observational studies evaluating ureteral stent dwell time and/or removal methods in adults undergoing endourological procedures were included. Risk of bias was assessed using RoB 2 and ROBINS-I tools. Thirty-two studies encompassing 4,373 patients were included. Reported stent dwell times varied widely, most commonly ranging between 10 and 14 days in uncomplicated cases, with longer durations associated with increased rates of encrustation and removal difficulty. Removal techniques included rigid cystoscopy (48.7%), flexible cystoscopy (19.9%), extraction strings (23.5%), and device-assisted methods (7.9%). Less invasive approaches, particularly flexible cystoscopy and extraction-string removal, were consistently associated with reduced pain scores and improved patient comfort, although extraction strings carried a small risk of premature dislodgement. While practice patterns vary, the evidence suggests that a 10-14 day dwell time might be the optimal window to balance healing with the prevention of encrustation. Less invasive removal approaches, particularly flexible cystoscopy and extraction-string techniques, were generally associated with lower pain scores and high procedural success rates in selected patients. While these methods are safe and better tolerated, extraction strings carried a small, reproducible risk of premature dislodgement. High-quality prospective studies are needed to define determinant-based, individualized stent management strategies.

The main goal of this paper is to examine variations in the political attitudes of elites in Chile concerning two key dimensions: socioeconomic attitudes (concerning redistribution, taxation, and state provision of services) and sociocultural attitudes (concerning immigration, LGBTQ+ rights, gender equality, and democratic values). I propose a framework that underscores the potential impact of the source of elite power-whether economic, political, or cultural-in shaping differences in political attitudes. Additionally, I suggest that patterns of intergenerational persistence and mobility (e.g., being born into an elite family) may contribute to variations in attitudes among elite individuals. To test the study's expectations, I use survey data collected between 2019 and 2020 from a sample of 416 individuals belonging to Chile's economic, political, and cultural elites. Using multiple correspondence analysis (MCA), findings reveal substantial variation in political attitudes among elite individuals, with socioeconomic and sociocultural orientations strongly aligned. Explanatory analyses using multivariate regression models reveal that variations in attitudes among elite individuals are largely shaped by their elite type and social origins, with members of the economic elite and those from elite origins displaying the most conservative and inegalitarian views on both dimensions. Moreover, significant attitudinal tensions are observed between inheritors and newcomers, not only across the elites as a whole but also within the economic, political, and cultural elite groups.

Population-based organized prostate-specific antigen (PSA) screening is implemented in 80% of Japanese municipalities; however, Shiga Prefecture remains a unique exception without such a systematic program. This study characterized the longitudinal clinical features and treatment patterns in this opportunistic testing environment using data from 1716 patients diagnosed via prostate biopsy in 2012, 2017, and 2022. While median PSA levels remained stable (10.40-11.43 ng/mL), median age at diagnosis increased from 72 to 74 years. Over the decade, the incidence of International Society of Urological Pathology Grade Group 1 and cT1c stages decreased significantly (p&#x2009;<&#x2009;0.001), with nearly 90% of cases being cT2 or higher in 2022. Risk classification showed a decrease in low-risk cases and a rise in high-risk cases. Regarding treatment, radical prostatectomy rates remained stable at approximately 25%, whereas the overall use of active surveillance (AS) increased from 1 to 9%. Notably, among low-risk patients, AS adoption rose markedly from 2.3% in 2012 to 68% in 2022. While clinical practices have evolved to successfully minimize unnecessary invasive intervention, these findings suggest that clinical progress alone cannot fully compensate for the lack of organized efforts to improve early detection.

RNA modifications regulate post transcriptional gene expression, yet most computational methods model each modification independently and overlook competition among modification types at a single site. We present EvoRMD, a biologically contextualized and interpretable framework for RNA modification prediction. EvoRMD combines RNA language model embeddings with structured metadata, including species, organ, cell type, and subcellular localization, and uses attention to identify informative sequence positions. A shared multiclass classifier produces context conditioned predictions across 11 modification types. EvoRMD achieves strong performance and provides interpretable insights through attention patterns and motif analyses, supporting biologically grounded prioritization of candidate RNA modifications.

Federated learning (FL) has become a highly promising paradigm for privacy-preserving distributed model training by enabling edge devices to train without sharing raw data. But in practice, edge environments are both non-stationary and asymmetric, with varying data distributions due to shifts in user behaviour, sensing conditions, and overall environmental dynamics. This causes concept drift (sudden, gradual, and recurrent), leading to poor model performance, slower convergence, and predictive bias. Current approaches to FL are not combined to tackle problems of drift adaptation, differential privacy (DP) and resource efficiency (FedAvg, DP-FedAvg). To address these constraints, we present FedDriftGuard. This Federated learning layer unifies client-level drift detection, drift-adaptive aggregation, and adaptable differential privacy into a single, FLE architecture-compatible system. The proposed DP-DriftNet model implements attention-based time encoding to capture changing data patterns and drift-directed feature weighting to allow greater flexibility in the presence of distributional changes. A drift-optimal privacy scheduler allocates noise probabilistically, subject to a limited privacy budget, thereby enforcing an appropriate privacy-utility trade-off without cancelling formal DP guarantees. Also, update sparsification, compression and periodic transmission techniques are used to reduce communication overhead. Decades of experimentation on real-world and synthetic drift datasets have shown that FedDriftGuard outperforms baseline FL techniques, achieving accuracy and F1-score gains of 9-14% and 11-17%, respectively, with adaptation latency 28% shorter and communication cost 20-35% lower. Such findings are statistically significant and confirm the soundness of the suggested method. FedDriftGuard offers effective, scalable privacy-preserving learning in adaptable, edge-drifting environments.

Triple Negative Breast Cancer (TNBC) is one of the most aggressive subtypes of breast cancer (BC), which is associated with a very poor prognosis. It is a broad category of tumors with a variety of biological, clinical, and morphological characteristics. FOXM1 is a pivotal transcription factor that modulates proliferation-associated genes through complex protein-DNA and protein-protein interactions, making it a highly attractive target in cancer therapy. However, existing small-molecule inhibitors often suffer from limited specificity and efficacy. In this study, we designed, synthesized, and evaluated novel series of 2-aminothiazole derivatives (C1-C15) as potential FOXM1 inhibitors. Molecular docking and molecular dynamics (MD) simulations were employed to investigate the binding interactions of these compounds with the FOXM1 DNA-binding domain (FOXM1-DBD). Structural analysis highlighted the importance of crucial residues, including Asn283, His287, and Arg286, in mediating inhibitory activity. Among the synthesized compounds, C11 exhibited remarkable structural alignment and interaction patterns with FOXM1-DBD, comparable to the reference inhibitor FDI-6. In vitro studies using TNBC cell lines (MDA-MB-231, BT-549, and BT-20) demonstrated that compound C11 significantly outperformed FDI-6 in potency. Western blot analysis revealed that C11 effectively suppressed FOXM1 transcriptional activity at concentrations of 10&#x2009;&#xb5;M in BT-549 cells and 20&#x2009;&#xb5;M in MDA-MB-231 cells. These findings underscore the potential of C11 as a potent FOXM1 inhibitor and highlight its promise for further development in TNBC therapy.

Low-grade fibromyxoid sarcoma (LGFMS) is a rare soft tissue malignancy with non-specific imaging features. We present a case of a 57-year-old woman with a right axillary mass to highlight the diagnostic value of advanced ultrasound techniques. Conventional ultrasound showed an irregular, vascularized hypoechoic mass. Contrast-enhanced ultrasound (CEUS) revealed early centripetal hyperenhancement and rapid washout, suggesting malignancy. Super-resolution ultrasound (SR-US) further characterized the lesion's disorganized microvascular architecture, providing insights beyond conventional imaging. The diagnosis was confirmed pathologically. This case underscores how integrating CEUS and SR-US aids preoperative assessment of LGFMS by delineating tumor vascular patterns unavailable through standard imaging.

Executive function assessment is central in clinical practice and research, and the Behavior Rating Inventory of Executive Function-Adult Version (BRIEF-A) is widely used in adults. However, its nine-factor structure has rarely been evaluated with contemporary factor-analytic standards, prompting this study to examine its factorial validity and propose a psychometrically robust alternative. Adult participants completed the French version of the BRIEF-A, including a university student sample (N&#x2009;=&#x2009;775) and a community adult sample (N&#x2009;=&#x2009;1599). Factorial validity was examined using confirmatory and exploratory factor analyses, conducted on manifest items. A split-sample cross-validation procedure was applied to item-level analyses to identify a reduced item configuration reflecting the latent structure. None of the traditional BRIEF-A factor structures reported in the literature demonstrated acceptable model fit, whether analyses were based on individual items or parceled scores. In contrast, a six-factor, 24-item solution emerged, showing strong model fit, accounting for approximately 50% of the variance, and replicating across samples. The 24-item configuration provides a parsimonious representation of response patterns associated with adult executive functioning compared with the original 70-item organization. These findings concern the latent structure of BRIEF-A responses and do not constitute an alternative instrument. Future studies should examine the factorial structure of the BRIEF-A in clinical populations to further assess the robustness and generalizability of these findings.

Neuropathic pain caused by spinal cord injury severely compromises patients' quality of life. The clinical application of ropivacaine is limited by its short duration of action and the significant side effects associated with repeated administration. In this study, we developed a Gelatin methacryloyl/hyaluronic acid-based hydrogel (Ropi-GelMA/HA) to enable localized and controlled delivery of ropivacaine by photo-crosslinking. In a rat model of spinal cord contusion, Ropi-GelMA/HA was associated with lower Nav1.3 and TNF-&#x3b1; expression and higher NGF and BDNF expression, together with improved motor recovery in rats with SCI. In vitro studies further supported the hydrogel's favorable biocompatibility and controlled release behavior during the early phase after administration. Under the tested dosing regimens, Ropi-GelMA/HA was associated with reduced hepatorenal toxicity and more durable analgesic efficacy compared with free ropivacaine, resulting in prolonged analgesic effects and improved functional outcomes under localized controlled delivery conditions. These findings highlight the potential clinical utility of Ropi-GelMA/HA in the treatment of neuropathic pain following spinal cord injury.

Dried blood spot (DBS) biosampling holds promise for expanding routine viral load (VL) monitoring for youth with HIV (YWH), particularly those at highest risk for HIV medication non-adherence. This mixed methods study piloted home-based DBS collection with YWH, aged 15-24 years. We enrolled 34 YWH with suppressed VL from April 22, 2020, to December 15, 2021, a subset of a fully virtual, nationwide decentralized clinical trial (ATN 144 SMART). Participants were mailed a HemaSpot&#x2122;-HF kit and asked to complete a computer-assisted self-interview (CASI) with an instructional DBS video. Surveys and semi-structured interviews provided quantitative and qualitative data to assess feasibility, appropriateness, and acceptability of home-based DBS for VL monitoring. Of 239 total screener attempts, 134 individuals were eligible and 115 provided contact information/completed the screener; 34 enrolled and returned DBS kits. Descriptive analyses showed a positive relationship between perceived suitability, feasibility, and acceptability. Perceived suitability was negatively associated with age, and feasibility differed significantly by health insurance coverage. Qualitative findings identified facilitators such as clinic/provider support, awareness of DBS innovation, insurance coverage, and streamlined mailing processes. Barriers included living environment challenges, cost concerns, and mail delivery issues. This pilot supports a self-management model and provides preliminary evidence that home-based DBS collection is feasible and acceptable among YWH. Scaling up this method through clinic and provider promotion could transform YWH HIV care by enabling remote VL monitoring. Findings also underscore the value of DBS as a practical biospecimen collection strategy for decentralized research models.