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Mexico has experienced escalating dengue transmission driven by the co‑circulation of four antigenically distinct serotypes (DENV‑1 through DENV‑4). Multi‑serotype transmission is epidemiologically relevant, yet its spatiotemporal patterns at sub‑national resolution remain poorly characterized. We analyzed 103,426 PCR‑confirmed, serotyped dengue cases across 1,547 of 2,471 Mexican municipalities from January 2020 to December 2025. Kulldorff's space‑time scan statistic under a discrete Poisson model was applied independently to each serotype and to all serotypes combined. Co‑circulation was defined as the spatiotemporal overlap of significant clusters from at least two serotypes within the same municipality for ≥ 1 epidemiological week. We identified 159 statistically significant clusters across all serotypes combined. DENV‑3 was dominant (64.4% of cases; annual incidence 59.9/100,000), consistent with the reemergence of a long‑absent serotype. The 2024-2025 season produced a nationally synchronized epidemic across geographically distant regions. Co‑circulation of at least two serotypes occurred in 1,545 municipalities; 217 experienced simultaneous clustering of all four serotypes. Active co‑circulation was present in 275 of 311 study weeks. Mean pairwise temporal overlap ranged from 8.0 to 12.0 weeks, with maximum overlaps of 29-30 weeks. Four‑serotype co‑circulation was documented at municipal resolution, concentrated in the Gulf coast, the Yucatán Peninsula, and northeastern Mexico. The 217 municipalities with simultaneous clustering of all four serotypes may represent areas of epidemiological interest for further investigation. This municipality‑level spatiotemporal framework offers operationally relevant resolution for tracking multi‑serotype activity and supporting serotype‑aware dengue monitoring at sub‑national scale.

This study examines the heterogeneity of CEOs' risk attitudes and how fixed versus variable compensation components shape their strategic risk-taking, as part of corporate governance policy. Building on psychological Regulatory Focus Theory (RFT) and established management frameworks, we developed a conceptual model with six hypotheses. We applied a validated Polish Linguistic Inquiry and Word Count (LIWC) dictionary to measure CEOs' promotion and prevention focus through content analysis of their shareholder letters. Our dataset covers 82 companies listed on the Warsaw Stock Exchange (WSE) from 2011 to 2020, analyzed using longitudinal panel data. The results confirmed that a CEO's regulatory focus is a significant motivational factor in strategic risk-taking. Promotion-focused CEOs tend to pursue bolder, riskier decisions, increasing the firm's strategic risk, whereas prevention-focused CEOs are more cautious and inclined to mitigate risk, aligning with prior findings in the literature. Moreover, these relationships are moderated by compensation structure. Higher fixed salaries are associated with reduced strategic risk, reinforcing risk aversion, while larger annual bonuses are associated with greater risk-taking. In particular, fixed compensation strengthened the natural risk-avoidant tendencies of prevention-focused CEOs, suggesting that higher guaranteed income reinforces a cautious strategy. Unexpectedly, large annual bonuses did not temper the risk appetite of promotion-focused CEOs; instead, bonuses amplified their risk-taking, indicating that intrinsic motivation can outweigh extrinsic incentives for risk moderation. These findings underscore the need for tailoring executive compensation policies to individual CEOs' risk preferences. Fixed salaries may temper excessive risk-taking in promotion-focused CEOs, while performance-based bonuses may motivate otherwise cautious, prevention-focused CEOs to undertake strategic risks. Such insights are valuable for refining corporate governance strategies in European public firms, especially in Poland, to better align CEO behavior with shareholder interests.

Seepage-erosion-induced water inrush in karst cavities is a typical form of water-inrush disaster in karst tunnels. It is governed not only by the spatial distribution of karst cavities and hydraulic recharge conditions, but also by the particle-size gradation and composition of the cavity fill. During seepage erosion, fill particles are progressively transported by flowing water, which may trigger a sudden water-inrush catastrophe. To reveal the catastrophe mechanism and establish early-warning indicators, this study employs the Smoothed Particle Hydrodynamics (SPH) method to simulate the evolution of seepage-erosion-induced water inrush under different particle-size gradations, cavity confining stresses, and seepage velocities. The inflection point of the cumulative particle loss rate is used as an indicator of catastrophic transition. The relationships among particle-size gradation, confining stress, seepage velocity, and particle loss rate at the transition point are then analyzed to determine early-warning thresholds. The results show that fill-particle loss is positively correlated with both seepage velocity and confining stress. When the content of fine particles, such as rock cuttings and fine sand, exceeds 60%, the inflection point corresponds to a seepage velocity of 1.6 m/s and a confining stress of 2.6 MPa, with an early-warning particle-loss range of 8%-15%. When the content of coarse particles, such as coarse sand and gravel, exceeds 40%, the inflection point corresponds to a seepage velocity of 3.0 m/s and a confining stress of 4.5 MPa, with an early-warning particle-loss threshold of approximately 45%.

In response to individual and systemic barriers hindering the timely and effective treatment of eating disorders (EDs), the Australia & New Zealand Academy for Eating Disorders (ANZAED) introduced an eating disorder credential for clinicians in June 2022. The Credential aims to enhance treatment access, quality, and outcomes. While the Credential has been well received by stakeholders, its effectiveness from the perspective of those with lived experience of an ED needs to be more fully understood. The current study aims to explore the experiences and perspectives of people living with an ED in relation to their treatment experiences provided by Credentialed Eating Disorder Clinicians (credentialed clinicians) and non-credentialed clinicians. An exploratory mixed-methods cross-sectional study was conducted involving 100 participants with personal lived experience of an ED. Participants were recruited via Australian eating disorder services and organisations, including the ANZAED and National Eating Disorders Collaboration (NEDC) membership databases, with recruitment information distributed through their email and social media platforms. Participants completed a survey with open- and closed-ended questions on their attitudes towards the Credential and experiences of treatment by a credentialed clinician or non-credentialed clinician. Descriptive statistics and Mann-Whitney U tests were used to examine differences in attitudes, treatment experiences, and helpfulness ratings between participants who had seen credentialed and non-credentialed clinicians, alongside inductive thematic analysis of open-ended survey responses. Irrespective of their own clinicians' credentialing status, participants valued the Credential; almost two thirds identified that their most helpful treatment experience was with a credentialed clinician. Three themes were generated from open-ended survey responses that explored the treatment experiences of those with lived experience of an ED: (1) Expertise, Accessibility, and Continuity of Care, (2) A Collaborative Approach, and (3) Personalised and Effective Treatment Delivered with Understanding, Compassion, and Respect. The current study adds to the ED literature by highlighting the perceived value of the ANZAED Eating Disorder Credential by individuals with lived experience. Further, it supports existing research that identifies clinician's expertise, a collaborative approach to treatment, and the provision of individualised treatment as key factors contributing to positive treatment outcomes. However, barriers to accessibility, including the cost of treatment and availability of credentialed clinicians, remain and need to be addressed for individuals to receive the full benefits of the Credential. In June 2022, the Australia & New Zealand Academy for Eating Disorders (ANZAED) introduced the ANZAED Eating Disorder Credential to the public, to improve timely access to eating disorder treatment provided by appropriately trained and experienced clinicians. The current study explores the perspectives of those with a lived experience of an eating disorder towards the Credential and their treatment experiences with credentialed and non-credentialed clinicians. Participants valued the Credential’s existence, regardless of their own clinician’s credentialing status, expressing preference to receive treatment from a credentialed clinician, placing greater trust in their advice and believing the Credential would improve health outcomes and access. Almost two thirds of participants reported that their most helpful treatment experience was with a credentialed clinician and highlighted the importance of expertise, a collaborative approach, and tailoring treatment to the individual. Barriers to accessing care, a lack of interdisciplinary collaboration, and forced or involuntary treatment were found to be key contributors to participants’ least helpful treatment experiences, pointing to a need for ongoing improvements to ensure the Credential delivers its full potential.

High temperature is one of the major environmental stressors that severely affects plant growth. Paris polyphylla var. yunnanensis, a traditional Chinese herbal medicine, is sensitive to high temperature. However, the underlying mechanisms of its response to high temperature remain unclear. In this study, we investigated the physiological and proteomic change of P. polyphylla var. yunnanensis under different treatments (25°C, 30°C, 35°C, 40°C). Our results showed that high temperature directly impaired photosynthesis and disrupted metabolism, evidenced by reduced chlorophyll and photosynthetic rate, as well as accumulated proline and increased conductivity. A total of 893 differentially expressed proteins (DEPs) were identified, with significant changes in the expression levels of enzymes associated with protein processing and synthesis. Additionally, the expression levels of key proteins involved in the circadian pathway and the glutathione pathway were also notably upregulated. Dynamic changes in the endocytosis and autophagy-related proteins ATG3 and ATG8C were also observed, suggesting that these processes may play a significant protective role under high-temperature stress. Overall, this study provides an important starting point for improving the heat tolerance of P.polyphylla var. yunnanensis through genetic engineering.

In scientific studies of human-AI interaction dynamics, researchers often need to present participants with opportunities to interact with live large-language models (LLMs). However, technical and practical challenges (from survey platform limitations and logging chat data to manipulating AI behaviors for experimental designs) often inhibit survey-based deployment of AI stimuli. We developed DiSCoKit-an open-source toolkit for deploying live LLM experiences (e.g., ones based on models delivered through Microsoft Azure portal) through JavaScript-enabled survey platforms (e.g., Qualtrics). We describe the toolkit's scientific motivation, architecture, and operation. We also offer an example of toolkit deployment and customization, along with discussing its possibilities and limitations. Altogether, DiSCoKit gives researchers a flexible, secure, scalable solution for deploying naturalistic LLM stimulus experiences through online surveys.

This study explores the potential of artificial intelligence (AI) using a hybrid deep learning Convolutional Neural Network-Long Short-Term Memory (CNN-LSTM) framework, for EEG-based classification and analysis of Dravet Syndrome (DS). The study cohort comprised nine pediatric patients with DS, confirmed through either a heterozygous pathogenic mutation in the SCN1A gene or a clinical diagnosis consistent with established diagnostic criteria. In addition, EEG recordings from age-matched healthy control subjects and pediatric patients with non-Dravet epilepsy ("abnormal" EEG) were included. Data on demographic information, seizure characteristics, developmental skills, cognitive functions, and genetic results were gathered from patient records. EEG recordings were analyzed using a subject-independent leave-one-subject-out validation strategy, spatial and temporal features by employing this model on preprocessed EEG data, effectively differentiating DS patients from Abnormal cases and healthy controls. Among the evaluated CNN-LSTM models, the pre-trained architecture achieved superior performance with improved stability across most subjects, with an overall accuracy of 85%, balanced accuracy of 85%, a macro-averaged F1-score of 0.85, and a macro-averaged ROC-AUC of 0.87, demonstrating stable performance for multi-class EEG classification of DS, Abnormal, and control subjects. The non-pretrained model showed reduced sensitivity and increased inter-class confusion, particularly for DS and Abnormal classes. This study demonstrates that a pre-trained CNN-LSTM framework can support automated EEG-based classification of DS-related patterns as a proof-of-concept methodological approach, even in the context of limited subject availability. EEG-specific pretraining improves classification consistency and feature separability compared with training from scratch, highlighting the value of representation learning for rare epilepsy syndromes. Larger multi-center datasets and prospective validation will be required to assess robustness, generalizability, and clinical utility.

Primary care physicians (PCPs) are on the front lines of health promotion and disease prevention, yet evidence supports a longstanding gap in physicians' capacity to counsel about diet, a key factor in patient health and chronic disease risk. Momentum to address the nutrition training needs of physicians is growing; however, challenges PCPs experience due to inadequate training are further complicated by clinical practice barriers. This study seeks to better understand the complex problem PCPs face addressing nutrition with patients to inform potential solutions. This qualitative study takes a design thinking approach to understanding the problem by learning from PCPs about their experience, challenges, and priorities addressing nutrition with patients. Findings from semi-structured interviews with 32 PCPs revealed that while they value nutrition and believe they have an important role in addressing diet with patients, their role as a generalist in addressing nutrition lacks clarity. PCPs describe learning their current approach to nutrition primarily outside of formal medical training, resulting in variability and inconsistency in approaches and recommendations and general frustrations about their ability to give actionable guidance. While registered dietitians (RDs) are often viewed as valuable support for patients, PCPs describe multiple challenges to RD utilization and subsequently at times may be the only ones with the opportunity to address diet with patients. Additional system- and societal-level barriers, such as time limitations and the food environment, further complicate PCPs' experiences advising patients about nutrition. Main limitations of this study are limited generalizability from recruiting graduates of a single medical school and PCPs with greater interest in nutrition or more frustration with their current approach to nutrition may have been more likely to participate. Our results support the need to clearly define a realistic role for PCPs as generalists addressing nutrition. Clarified expectations in turn can inform nutrition training of physicians and guiding frameworks and strategies for giving practical, evidence-based nutrition guidance. PCPs also need increased support through access to resources, strategies to improve RD collaboration, and attention to system- and societal-level challenges influencing dietary interventions in primary care.

Although bar charts are widely used in scientific publications, their rasterized format within Portable Document Format (PDF) files complicates automated data extraction, hindering large-scale evidence synthesis and meta-analysis. To address this, we developed and evaluated an automated pipeline for extracting quantitative data from bar charts embedded in the biomedical literature. The four-stage pipeline comprises (1) image extraction and panel segmentation, (2) optical character recognition (OCR)-based text detection, (3) image disassembly to identify chart components, and (4) data reconstruction using numeric parsing and axis-based interpolation. The system combines edge detection, morphological operations, and convolutional neural network (CNN)-based figure classification using a transfer-learned Inception v3 model. Performance was validated on randomized controlled trials in age-related macular degeneration, with manually annotated values from a semi-automated labeling tool as the reference standard, and agreement was assessed using Bland-Altman analysis. Across 28 bar charts from ten publications, the pipeline correctly recognized 92.9% (95% confidence interval [CI], 77.4-98.0) of figure types, 96.0% (95% CI, 94.2-97.3) of text blocks, and 79.1% (95% CI, 74.7-83.0) of bars. For numerical reconstruction, 81.2% (95% CI, 76.3-85.2) of bar values fell within ±5% of the reference standard, 63.0% (95% CI, 57.3-68.3) within ±2%, and 48.6% (95% CI, 43.0-54.3) within ±1%. Bland-Altman analysis showed a small negative bias of -0.18 (95% CI, -0.34 to -0.02), with 94.9% of differences within the limits of agreement. Most outliers arose from OCR digit misclassification or ambiguous bar boundaries. This proof-of-concept study demonstrates the feasibility of automated data extraction from bar charts using a hybrid approach that combines image-processing heuristics with CNN-based classification. Although currently limited to bar charts and a single clinical domain, the pipeline represents a step toward scalable, end-to-end systems for automated evidence extraction to support meta-analyses across the biomedical literature.

Slow, endogenous brain rhythms in the auditory cortex are hypothesized to track acoustic amplitude modulations during speech comprehension. Temporal predictions from the motor system are thought to enhance this tracking. However, direct evidence for the involvement of endogenous auditory and motor brain rhythms is lacking. Combining magnetoencephalographic recordings with behavioral data, we here show that endogenous peak frequencies of individuals' resting-state theta rhythm in superior temporal gyrus predict speech tracking during comprehension. Importantly, endogenous rates of speech motor areas predicted auditory-cortical speech tracking only in individuals with high auditory-motor synchronization profiles. Higher rates in the supplementary motor area and lower rates in inferior frontal gyrus predicted stronger tracking. These findings provide support for oscillatory accounts of auditory-motor interactions during speech perception. Behaviorally, higher auditory-motor synchronization was related to higher comprehension, with effects of the spontaneous speech motor production rate only in high synchronizers. Working memory capacity predicted speech comprehension performance only in individuals with low auditory-motor synchronization profiles. No significant relationship between the neural data and behavioral readouts was observed. The findings highlight differential speech processing preferences across individuals, with an auditory-motor route related to enhanced comprehension performance.

Venom-induced compartment syndrome (VICS) is a rare but severe complication of snakebite which poses unique challenges in diagnosis and treatment. Published literature largely focuses on VICS in the North American context, while information on clinical presentations, diagnostic and treatment approaches, clinical outcomes and associated challenges from the world's most snakebite endemic regions remain fragmented and scarce. A scoping review using PRIMSA-ScR methodology of the global literature on VICS was performed by searching the PubMed, Embase, and Cochrane databases. Literature was divided into 1) Case reports on VICS and 2) General literature. Clinical data from eligible case reports was extracted to describe management of VICS and associated challenges. Available evidence on diagnostic and treatment strategies was extracted from the general literature. Of 115 cases of VICS analyzed, most were from Europe (40%); Only 13% and 6% were reported from South-East Asia and Africa respectively. Viperids caused 73% of bites and upper extremities were most frequently affected (63%). Compartment pressure was measured in 38% of patients. Compartment pressure was more commonly measured in the 12% of non-surgically treated patients, none of whom developed ischaemic contracture or required amputation. Coagulopathy was the most common systemic toxicity, present in 40% of patients at admission. Results from eight animal studies support the use of antivenom for treating VICS. Analysis of 17 human observational studies suggests an overdiagnosis of VICS using clinical symptoms alone, highlighting the need to investigate diagnostic tools, such as ultrasound, for diagnosing compartment swelling. Antivenom as first-line treatment for VICS is supported by animal and human observational studies. However, additional data is needed to inform decision-making on when fasciotomy is indicated as a rescue therapy. Improved evidence generation will depend on the collection of high-quality clinical and diagnostic observational data from patients treated with antivenom in snakebite-endemic regions.

Radiology impressions guide clinical care. Large Language Models (LLMs)-drafted impressions can drift into generic, off-style text. Retrieval-augmented generation (RAG) enables context-aware few-shot prompting during inference. This retrospective IRB-approved study included 11,998 CT pulmonary angiography (CTPA) reports. We built a retrieval bank from 11,399 reports and reserved 599 reports for testing. GPT-4o and LLaMA 3.1-70B generated impressions from the "findings" section using three setups: zero-shot, fixed random few-shot, and dynamic retrieval-selected few-shot (top-k semantic matches; k&#x2009;=&#x2009;3/5/10). We ran temperatures 0, 0.7, 1. We scored outputs against the original impressions with ROUGE and BERTScore F1, report mean scores with 95% confidence intervals, and tested for statistical significance using Wilcoxon signed-rank test. Dynamic retrieval-based few-shot prompting outperformed zero-shot and fixed few-shot prompting across all configurations (all p&#x2009;<&#x2009;0.05). The highest scores were observed at temperature 0 and k&#x2009;=&#x2009;10. ROUGE-1 F1 increased to 0.44-0.47 for GPT-4o and 0.37-0.50 for LLaMA, versus 0.35-0.37 and 0.25-0.37, respectively, in zero-shot prompting. Lower temperature and larger k were associated with higher similarity scores. Dynamic, case-matched retrieval improved alignment of LLM-generated CTPA impressions with reference impressions on automated text-similarity metrics. Scores remained moderate, and radiologists' verification is still required before clinical deployment.

This study investigates how the spatial structure of Metroidvania game worlds relates to the layout of key functional nodes. Using Hollow Knight, Prince of Persia: The Lost Crown, and Blasphemous 2 as case studies, the maps were transformed into graph structures based on spatial data compiled from gameplay observation, in-game maps, community maps, and verification through gameplay videos. On the basis of this graph representation, the study adapts the Nearest Neighbor Index by replacing Euclidean distance with network shortest-path distance in order to evaluate the distribution patterns of save points, teleport points, and boss points. It further employs multi-source k-hop reachability analysis to measure service coverage and redundancy. Finally, closeness centrality and betweenness centrality are calculated on the full network, and Spearman rank correlation is used to test the association between functional areas and centrality. The results reveal clear differences in the structural roles of functional nodes across the three games. In Hollow Knight and The Lost Crown, save points are relatively dispersed, weakly coupled with centrality, and function as a distributed safety net. In Blasphemous 2, save points exhibit higher small-radius coverage and redundancy and are more strongly aligned with central positions, indicating a hub-like stronghold structure. Teleport systems likewise reflect different design strategies, ranging from exploration-oriented sparse layouts to later-stage mobility optimization. Boss points in all three games generally remain structurally isolated, showing low overlap and weak centrality association. These findings suggest that differences in the placement of save points, teleport points, and boss points reflect distinct structural design strategies, and that network analysis can provide a quantitative basis for evaluating and optimizing such layouts in level design.

Typhoid is a significant global health challenge due to its high pathogenicity and antimicrobial resistance. Salmonella typhi (S.typhi)&#xa0;can switch its lifestyles between biofilm and planktonic phase which allows it to evade host defenses and develop resistance to antibiotics. Salmonella sp. harbors multiple genes encoding efflux-pumps systems whose up-regulation contributes to multi-drug resistance (MDR) and extensive drug-resistance (XDR). To overcome the battle against resistant S. typhi strains, novel non-antibiotics inhibitors are required for inhibitory application. This study assesses the inhibitory effect of lignans against drug resistance of S. typhi. Clinical resistant and sensitive strains of S. typhi were obtained and characterized. The inhibitory effect of lignans, specifically Schisandrin A and B, purified from the plant Schisandra chinensis, are found to be effective non-antibiotic inhibitors were evaluated through standard microbiological techniques like growth curve and time-kill assays. Impact on bacterial morphology was analyzed using scanning electron microscopy (SEM). Our study explores two approaches, such as efflux pumps (EPs) inhibition and antibiofilm assays. Using colony-forming unit (CFU) assays, growth curve analysis, and SEM imaging, we observed significant bacteriostatic effects, with Schisandrin B causing notable membrane disruption. Schisandrin B also showed remarkable biofilm inhibition (90.33%) and strong efflux pumps inhibition. This study offers a strong basis for future research on addressing antibiotic resistance in clinically relevant pathogens.

CD4+ T cells that produce IFN-&#x3b3; (T helper 1 [Th1] cells) chiefly mediate vaccine acquired resistance to fungal infections. However, the key regulators of the development of Th1 cells and acquired resistance to fungi are incompletely understood. Here, we report that Natural Killer Cell Granule Protein (NKG7) acts as an unappreciated regulator inducing anti-fungal Th1 cells to produce IFN-&#x3b3; and converting plastic Th17 cells into polyfunctional memory Th1 cells.

Prostate cancer (PCa) is characterized by molecular heterogeneity and metabolic reprogramming, but the relationships among transcriptomic, proteomic, and metabolic signals remain incompletely defined. Here, we present a human-centered, cross-dataset analysis of public RNA, protein, and metabolomics data in PCa. We analyzed RNA and protein profiles from PC3 parental and drug-resistant cells together with an independent human matched tissue metabolomics dataset from Metabolomics Workbench (ST000784). RNA-protein overlap analysis identified seven genes that were significant at both layers, including five concordantly upregulated genes: UPP1, IGF2R, FLNC, DSP, and PLEC. Among these, UPP1 provided the most direct metabolic interpretation because it encodes uridine phosphorylase 1, an enzyme linked to pyrimidine salvage. Independent ST000784 matched prostate tissue metabolomics supported broader nucleotide metabolism remodeling, including significant changes in N-carbamoyl-L-aspartate, guanosine monophosphate, and adenosine 3,5-cyclic monophosphate. In contrast, uracil was not significantly altered and uridine 5'-monophosphate showed only a trend after multiple-testing correction. Repeated stratified cross-validation showed that UPP1-containing candidate gene sets achieved high within-layer AUC values in RNA and protein data, while nested statistical benchmark models also performed strongly. These results prioritize a UPP1-associated nucleotide remodeling hypothesis in PCa, but do not establish causal regulation of metabolite abundance or clinical diagnostic utility. Future matched multi-omics and perturbation experiments are required.

Gastrointestinal stromal tumors (GIST) are the most common gastrointestinal soft tissue sarcoma. Tyrosine kinase inhibitors are guideline-recommended therapy; however, resistance often occurs, requiring subsequent therapy. Regorafenib is a multikinase inhibitor approved for third-line therapy. Real-world data surrounding regorafenib's use and place in therapy are limited. To understand real-world regorafenib utilization and patient characteristics among US patients with advanced GIST. This retrospective cohort claims analysis used data from Merative&#x2122; MarketScan&#xae; research databases and included patients with &#x2265;1 pharmacy claim for regorafenib during the identification period (10/2015-5/2023) and &#x2265;1 GIST diagnoses any time prior to/on index date (first regorafenib prescription claim). Primary outcomes included duration of therapy (DOT) and time to next therapy (TTNT). Outcomes were stratified based on prior GIST treatment during the baseline period (BL) and initial regorafenib dose (i.e., low dose [LD] or regorafenib standard dose [RSD]) as of the index date. Nearly half (45.2%) of patients received imatinib and sunitinib prior to regorafenib initiation, and 73.5% received RSD. Patients who received prior imatinib or sunitinib alone before regorafenib had a numerically longer median DOT with regorafenib than those who received both in the BL before regorafenib (142.5 days [IQR: 87-257.5] vs 95 days [IQR: 53-192]). Patients receiving LD and RSD demonstrated similar median DOT (103.0 days [IQR: 41.5, 210.5] vs 94.5 days [IQR: (35.0, 171.0]) and TTNT (143 days [IQR: 70-293] vs 141 days [IQR: 77-191]). Patients on LD and RSD had similar DOT and TTNT. Acknowledging the limitations from this real-world data, patients with prior imatinib or sunitinib alone appeared to have longer DOT on regorafenib than those who received both. Further research is warranted to explore the clinical benefits of these differences.

Alveolar echinococcosis (AE), caused by Echinococcus multilocularis infection, leads to destructive hepatic lesions and severe hepatic fibrosis. Lactylation, a post-translational modification, has been linked to fibrotic progression in hepatocytes. However, the role of E. multilocularis infection in hepatic lactylation remains unclear. This study aims to elucidate the relationship between hepatic fibrosis and lactylation induced by E. multilocularis infection and fill this knowledge gap. The results showed that lactate concentrations in the livers and sera of AE mice were significantly elevated compared with those in the control group. The relative mRNA expression of hexokinase isoforms in the liver tissue of AE mouse models revealed significant upregulation of hexokinase-3 (HK3), a key enzyme regulating lactate production. Immunofluorescence staining revealed substantial colocalization between HK3 and TGF-&#x3b2;1 in hepatic lesions of AE mice. Western blot analysis using a pan-lactylation antibody showed significantly elevated lactylation levels in the livers of AE mice compared with controls, with a significant increase in histone H3 lysine 18 lactylation (H3K18la). CUT&Tag analysis revealed differential enrichment of H3K18la at multiple fibrosis-associated genes in AE mouse liver. In vitro, AML-12 hepatocytes exposed to E. multilocularis culture supernatant showed significant upregulation of TGF-&#x3b2;1, HK3, and histone lactylation. HK3 knockdown significantly reduced the induction of H3K18la and fibrosis-related proteins, whereas exogenous lactate supplementation significantly increased these responses despite HK3 silencing, confirming that lactate acts downstream of HK3 to drive histone lactylation and fibrogenesis. Corosolic acid, a compound that limits HK3-mediated lactate production, attenuated histone lactylation and fibrosis-related protein expression. These findings indicate that HK3-driven histone lactylation at H3K18 contributes to hepatic fibrosis in AE, and suggest that HK3 may serve as promising therapeutic targets for AE.

Podocyte injury is a central driver of progressive glomerular diseases, yet the temporal organization of podocyte-intrinsic responses remains incompletely defined. In this study, we performed an integrated re-analysis of two publicly available mouse transcriptomic datasets (GSE108629 and GSE151869) to identify conserved molecular responses to LMB2-induced podocyte injury across comparable post-injury time points. Differential expression analysis was conducted independently at Day 4 and Day 7 in each dataset, followed by cross-dataset integration at each time point by identifying shared differentially expressed genes (DEGs) with consistent directionality. The resulting Day 4 and Day 7 shared gene sets were subsequently combined to define a final pooled shared DEG set. Functional enrichment, network analysis, upstream regulator prediction, and gene set enrichment analysis (GSEA) were used to characterize conserved biological processes and regulatory features. We identified 1,418 and 1,401 shared DEGs at Day 4 and Day 7, respectively, with 725 genes defining the final pooled shared DEGs set. At Day 4, the transcriptional response was characterized by inflammatory signaling and adaptive stress-related pathways, including endoplasmic reticulum stress. By Day 7, this response expanded to include extracellular matrix remodeling, focal adhesion reorganization, sustained inflammatory signaling, and downregulation of autophagy-lysosome pathways, together with disruption of ER-to-Golgi trafficking. Network analysis highlighted RELA-centered regulatory modules alongside epigenetic- and kinase-associated regulators. Collectively, these findings support a conserved, cross-dataset biphasic transcriptional response to podocyte injury, characterized by an early adaptive inflammatory phase followed by a later maladaptive state involving extracellular remodeling and impaired proteostasis. This framework provides a reproducible, temporally organized injury signature and is consistent with stage-specific pathways as potential targets for future mechanistic and therapeutic studies.