Nonalcoholic fatty liver disease (NAFLD) has emerged as a leading chronic liver disease globally, driven by the rising incidence of obesity, type 2 diabetes, and metabolic syndrome. Despite the increasing burden, most studies focus on prevalence rather than incidence, leaving a gap in understanding temporal patterns of NAFLD incidence. We conducted an age-period-cohort analysis of NAFLD incidence across 204 countries and territories from 1990 to 2021, utilizing data from the Global Burden of Disease Study 2021. Incidence rates were standardized per 100,000 person-years and analyzed by age, sex, region, and socio-demographic index (SDI). The global incidence of NAFLD nearly doubled from 24.9 million cases in 1990 to 48.4 million in 2021. The age-standardized incidence rate in 2021 was 593.28 per 100,000 population (95% confidence interval: 542.72-643.7). Middle SDI regions recorded the highest incidence rate (695/100,000), while low SDI regions had the lowest (483/100,000). The age-period-cohort model indicated a net drift of 0.56% (95% confidence interval: 0.53-0.6) globally. NAFLD incidence has risen substantially over the past 3 decades, particularly in middle-income regions. These findings highlight the need for targeted public health interventions and further research to address the growing global burden of NAFLD.

Several creatinine- and cystatin C-based biomarkers have been individually associated with mortality, but their comparative associations have rarely been evaluated head-to-head under a common analytic framework. We compared 6 related biomarkers in relation to all-cause mortality in older adults. In the China Health and Retirement Longitudinal Study 2015 to 2020 cohort, we studied 2987 men (428 deaths) and 2995 women (228 deaths) aged ≥60 years. Six related biomarkers (sarcopenia index [SI], predicted skeletal muscle index, total body muscle mass, creatinine-to-cystatin C ratio [CCR], eGFRcys(2012)/eGFRcr(2021), and eGFRcys(2012) - eGFRcr(2021)) were evaluated using sex-stratified Cox models, a prespecified mutually adjusted bootstrap ranking framework, and supportive external evidence from the National Health and Nutrition Examination Survey. In fully adjusted single-biomarker models, SI, predicted skeletal muscle index, and total body muscle mass showed the most consistent inverse associations with all-cause mortality, whereas CCR, eGFRcys(2012)/eGFRcr(2021), and eGFRcys(2012) - eGFRcr(2021) were weaker, particularly in women. Within the joint 6-biomarker framework, SI ranked highest in both sexes, whereas CCR showed a reversed association after mutual adjustment. Discrimination was broadly similar across single biomarkers, and the joint 6-biomarker model provided only modest improvement beyond standard covariates. Supportive analyses, including the National Health and Nutrition Examination Survey, were directionally consistent overall but less precise. Among 6 closely related creatinine-cystatin C biomarkers, SI showed the most consistent comparative association pattern with all-cause mortality. However, incremental discrimination beyond standard covariates was small, supporting SI primarily as the clearest comparative marker within this biomarker family rather than as evidence of major predictive superiority.

Intraoperative fluorescence imaging holds great promise for achieving complete cytoreduction in ovarian cancer, but its clinical utility is currently constrained by the limitations of existing imaging agents. In particular, the leading clinical probe, OTL38, operates in the near-infrared I (NIR-I; 700 to 1000 nanometers) window, which suffers from limited tissue penetration and suboptimal resolution. Here, a folate receptor α (FRα)-targeted NIR-II (1000 to 3000 nanometers) imaging probe was developed by incorporating a 4-(4-iodophenyl)butanoic acid moiety. This structural modification enables albumin binding, thereby prolonging systemic circulation and enhancing accumulation in FRα-positive tumors. In murine models of peritoneal metastasis, our probe enabled precise visualization of occult lesions undetectable by the naked eye. Compared to OTL38, this probe demonstrated superior tumor detection sensitivity (90.20% versus 78.75%) and allowed for the reliable identification of elusive lesions less than or equal to 3 millimeters in diameter. These findings highlight the potential of albumin-binding NIR-II imaging strategies to overcome the limitations of current clinical probes and enhance precision fluorescence-guided surgery.

Melanoma remains a lethal malignancy with frequent resistance to immune checkpoint blockade therapy. Clinical evidence associates elevated PAK4 expression with poor response to anti-PD-1 treatment in melanoma patients. While tumor-derived exosomes are recognized as key immunosuppressive mediators, the role of PAK4 in regulating exosome secretion to induce immunosuppression remains incompletely understood. Here, we demonstrate that PAK4-mediated phosphorylation of Annexin-A2 (ANXA2) at Ser26 promotes its nuclear-to-cytoplasmic translocation, facilitating the formation of S100A10-ANXA2 heterotetramers that drive multivesicular body docking to the plasma membrane. Furthermore, PAK4 stabilizes synaptotagmin-1 by suppressing Trim21-mediated ubiquitin degradation, enabling SNARE complex assembly for membrane fusion. PAK4-driven exosomes exhibit potent immunosuppressive activity, substantially reducing CD8+ T cell numbers and impairing their function in mouse models. Notably, melanoma cells with high PAK4 expression secrete PD-L1-enriched exosomes that promote systemic immune evasion. In patient-derived xenograft models, pharmacological inhibition of PAK4 attenuates tumor progression and reduces circulating exosomal PD-L1 levels. Our study unveils a dual mechanism through which PAK4 drives exosome-dependent immunosuppression, providing a rationale for combining PAK4 pathway inhibitors with immune checkpoint blockade and offering translational strategies to overcome melanoma immunotherapy resistance.

Osteoarthritis (OA) is the most common form of arthritis, characterized by pathological changes in joint components. Increasing evidence suggests that helper T (TH) lymphocytes play a pivotal role in the inflammatory processes associated with OA. Curcumin, the primary polyphenolic compound found in Curcuma longa, exhibits potent antioxidant and anti-inflammatory properties. This study aimed to evaluate the effects of curcumin on the gene expression of key transcription factors of TH1 and TH2 cells and to explore their associations with clinical and immunological parameters in patients with knee OA. This mechanistic sub-study presents a secondary molecular analysis of RNA biospecimens from a previously completed double-blind, placebo-controlled clinical trial involving 30 patients with knee OA. Participants were randomly assigned to receive either 80 mg/day of nano-micelle curcumin or a placebo for 3 months. Expression levels of T-box transcription factor 21 (T-bet) and GATA binding protein 3 (GATA3), the key transcription factors of TH1 and TH2 cells, respectively, were quantified using SYBR Green-based real-time PCR. Their associations with changes in visual analogue scale (VAS) score, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and percentages of CD4+ and CD8+ T cells were analyzed. Curcumin administration significantly reduced T-bet gene expression compared to baseline and showed a positive correlation with the frequency of CD8+ T cells, while GATA3 expression remained unchanged. These findings may provide a novel molecular perspective on curcumin's potential to influence CD8+ T cell dynamics by modulating TH1-associated transcriptional programs.

The increasing burden of dementia highlights the need for sensitive and ecologically relevant tools for early detection and intervention. Dual-task (DT) paradigms have emerged as promising approaches for assessing cognitive-motor alterations. This study aimed to map the 22-year evolution of DT research in cognitive aging using bibliometric analysis. We retrieved 1347 articles from the Web of Science Core Collection (January 2003-February 15, 2025) and analyzed them using CiteSpace. Co-citation, keyword burst, and collaboration network analysis were performed to identify research evolution, hotspots, knowledge structures, and international collaborations. Research showed a progressive shift from gait-focused behavioral assessment (2003-2012) to neuroimaging-based investigations (2013-2018), and subsequently toward artificial intelligence-driven, ecologically valid approaches integrating virtual reality and multimodal sensing (2019-2025). The dual-task cost emerged as a potential candidate digital biomarker associated with neural alterations and cognitive decline, while its complementary value to traditional cognitive assessment was highlighted. Dual-task training demonstrated potential benefits for improving functional outcomes and reducing fall risk; however, heterogeneity in treatment effects indicates the need for personalized intervention strategies. DT paradigms are evolving toward potential applications in precision gerontology. The proposed assessment-intervention continuum provides a conceptual framework for future research. Standardized protocols and prospective validation of DT-derived digital phenotypes are required before clinical implementation.