Strategies that specifically target the integrated stress response (ISR) as a therapeutic approach in sepsis remain largely unexplored. This study aimed to identify and validate ISR-related biomarkers in sepsis. This study used 529 ISR-related genes (ISRRGs) alongside sepsis datasets. First, differentially expressed gene between sepsis and normal samples, key module genes associated with sepsis, and ISRRGs were intersected to identify candidate genes. Next, biomarkers were selected through three machine learning methods. Subsequently, enrichment analysis, immune infiltration analysis, regulatory network analysis, and drug prediction were conducted. Finally, the biomarkers were experimentally validated using RT-qPCR. Four biomarkers of sepsis (DYRK2, BCL2, NUP93, and NFATC2) were identified; collectively, these biomarkers are associated with the enrichment of translation initiation in sepsis. A total of 783 significantly upregulated pathways and 1203 significantly downregulated pathways were identified. These biomarkers were co-regulated by multiple microRNAs and transcription factors. Importantly, 726 drugs were predicted to interact with these biomarkers. Additionally, RT-qPCR results demonstrated that the expression levels of DYRK2, BCL2, NUP93, and NFATC2 differed significantly between sepsis and normal samples. DYRK2, BCL2, NUP93, and NFATC2 were identified as biomarkers of sepsis, offering new diagnostic and therapeutic targets for its treatment.
Osteoporosis is a major public health problem, and environmental toxicants such as di(2-ethylhexyl) phthalate (DEHP) have been implicated as potential risk factors. However, the molecular mechanisms linking DEHP exposure with osteogenic impairment remain unclear. The association between DEHP exposure and osteoporosis risk using NHANES data, and employed network toxicology and molecular docking to identify key regulatory targets. To further verify these predictions, wet-lab experiments including Western blotting and quantitative PCR (qPCR) were conducted in osteoblast-related cells under control (CON), osteoporosis (OP), DEHP, and combined OP+DEHP conditions. Epidemiological analysis revealed that higher DEHP exposure was associated with increased osteoporosis risk. In the fully adjusted model, participants in the highest quartile of ln∑DEHP had higher odds of osteoporosis compared with those in the lowest quartile (OR = 1.32, 95% CI = 0.76-1.66, P for trend <0.001). Network toxicology analysis identified HDAC1 as a central hub gene, while RUNX2 emerged as a key osteogenic regulator. Western blotting and qPCR further demonstrated significant upregulation of HDAC1 and downregulation of RUNX2, with the most pronounced changes observed in the OP+DEHP group. These results suggest that DEHP exposure may contribute to osteogenic impairment and increased osteoporosis risk, potentially through epigenetic dysregulation involving HDAC1 and suppression of RUNX2.
To evaluate the effect of crossword puzzle activities on nursing students' willingness to work with older adults and their competence in gerontological nursing. Although crossword puzzles are widely used learning tools, their effects in these areas have not been sufficiently investigated. A parallel-design randomized controlled trial with a waiting list. Participants included 102 s-year nursing students with 51 assigned to the experimental group and 51 to the control group. Data were collected using Willingness to Work with Elderly People Scale and the Gerontological Nursing Competence Scale. The experimental group completed a crossword puzzle activity once a week for three weeks following standard lectures. The data were analyzed using independent and paired samples t-tests. The gerontological competence post-test mean scores in the experimental group were significantly higher than those in the control group (p = 0.031), with a medium effect size (d = 0.43). Gerontological nursing competence (p = 0.033) and willingness to work with older adults (p = 0.004) significantly increased from pre- to post-test in the experimental group. However, no significant group difference in willingness to work with older adults was found after the intervention (p = 0.654). The present study concluded that the crossword puzzle activity was associated with promotion in enhancing gerontological nursing competence among nursing students. However, no significant effect was observed on willingness to work with older adults. Crossword puzzle activities could be integrated into nursing education programs to strengthen competence in gerontological care.
Magnesium (Mg) and its alloys, as biodegradable metallic materials, possess numerous advantageous properties compared to traditional biomaterials. Furthermore, magnesium ions (Mg²⁺) are the second most abundant intracellular cations, participating in over 300 enzymatic reactions and serving as essential trace elements for various physiological processes. The release of Mg²⁺ is believed to promote osteogenic differentiation and angiogenesis, both of which are crucial for bone regeneration. However, the mechanisms underlying Mg²⁺-mediated promotion of osteogenesis and angiogenesis are not yet fully elucidated. We treated Bone marrow mesenchymal stem cells (BMSCs) with Mg²⁺ and performed transcriptome sequencing on both control and experimental groups. Bioinformatics analysis was conducted using the sequencing data, including principal component analysis, differential expression analysis, enrichment analysis, and protein-protein interaction analysis. Pathway proteins were assessed by Western blot. The osteogenic capacity of BMSCs was directly evaluated using ALP and ARS staining. Immunofluorescence staining was used to detect the expression of osteogenesis-related proteins RUNX2 and OPN. Tube formation assays were employed to evaluate the effect of magnesium ions on angiogenesis capability, while Western blotting and quantitative PCR were used to assess changes in FGF2 and CD31 expression levels. Concurrently, the functional impact of Mg²⁺ on BMSCs was assessed using Transwell and CCK8 assays. Finally, we established a bone defect model in rats and implanted magnesium alloy scaffolds to verify the conclusions drawn from the in vitro experiments. Through bioinformatics analysis, we identified the PI3K-AKT-mTOR pathway as a potential key pathway through which Mg²⁺ promotes osteogenesis and angiogenesis in BMSCs. Magnesium ion treatment enhanced the activity of pPI3K, pAKT, and pmTOR, elevated the expression of osteogenic and angiogenic proteins, increased ALP activity and mineralized nodule formation, and promoted tube-like structure formation. Additionally, the migratory ability, cell viability, and osteogenic activity of BMSCs were significantly elevated. Conversely, intervention with the activation of PI3K and mTOR directly affected the aforementioned outcomes, In vivo experiments also confirmed the above findings. This study confirms that Mg²⁺ synergistically promotes osteogenic differentiation, migration of BMSCs, and angiogenesis of vascular endothelial cells by activating the PI3K-AKT-mTOR pathway. By adopting the "activation-inhibition-reversal" experimental framework and conducting in vitro and in vivo validations, the critical upstream role of PI3K and the downstream effector function of mTOR were established. These findings reveal a unified mechanism by which Mg²⁺ coordinates bone regeneration via a single signaling pathway, providing a theoretical foundation for developing smart Mg-based bone repair materials targeting this pathway.
Consumption of Sechium edule var. nigrum spinosum has antioxidant and hypoglycemic effects. Regarding the former, certain signaling pathways that influence these effects have already been proposed; however, the underlying molecular mechanisms of the hypoglycemic effects remain unknown. It has been recognized that the sirtuin-mediated signaling cascade responds to various stressors, such as oxidative stress, and regulates glucose metabolism. Therefore, it would be of great interest to determine whether there is a link between these two properties and whether it is mediated by sirtuins. Hence, the present study aimed to evaluate the effect of Sechium edule on the gene expression of the sirtuin family (SIRT1-SIRT6) in individuals with type 2 diabetes mellitus (T2DM). A quasi-experimental study was conducted with a convenience sample of 26 older adults diagnosed with T2DM, divided into a (i) placebo group (PG; n = 14) and (ii) experimental group (EG; n = 12). Clinical, biochemical, and anthropometric measurements were performed, and total oxidant/antioxidant capacity (TOS/TAS) and mRNA expression of genes encoding sirtuins were determined. All parameters were measured at baseline, three months, and six months after the intervention. In the EG, the expression levels of SIRT1, SIRT3, SIRT5, and SIRT6 increased by 52%, 69%, 62%, and 69%, respectively, six months after treatment. A 50% decrease in TOS and a 44% increase in TAS were also observed. Our findings suggest that the bioactive components of Sechium edule enhance sirtuin expression and exhibit antioxidant effects in older adults with T2DM.
Physical resilience is a term used to describe an individual's response to physical and physiological stressors across the fields of gerontology and rehabilitation sciences. However, the term has not yet undergone a rigorous examination of its underlying assumptions, which has hindered its theoretical development and empirical measurement. This paper reviews the existing definitions of physical resilience in the context of human physical and psychological systems to examine its underlying, implicit assumptions. The aim is to clarify the conceptual foundations of physical resilience, identify its necessary components, and propose a formal ontological framework based on them. We conducted a scoping review of peer-reviewed literature using databases including PubMed and Web of Science. Definitions were extracted from experimental and conceptual papers and analyzed for shared themes and implicit assumptions. These ranged from general notions of recovery or adaptation to specific models of post-perturbation performance trajectories. Across studies, outcomes included whole-body, physiological, and occasional psychological or cognitive measures. However, the term physical was rarely explicitly defined, making it unclear how it modifies the term resilience. Only two studies referenced formal models of resilience, and few distinguished resilience from related constructs like adaptation or robustness. Findings revealed a lack of conceptual coherence in the current literature. We propose that physical resilience may be understood as an emergent, time-dependent disposition at the whole-body level involving interactions across multiple biological systems and scales. We suggest that a formal ontological framework of resilience can help clarify perturbation, recovery, and domain-specific contributions to support consistent measurement and interdisciplinary integration.
Osteoarthritis (OA) represents the most common degenerative joint disease, with emerging evidence linking it to lysosomal dysfunction and ferroptotic cell death. This study aimed to identify candidate biomarkers associated with lysosomal function and ferroptosis in OA, thereby providing a theoretical basis for subsequent experimental research. We obtained OA datasets and ferroptosis-related genes (FRGs) from publicly accessible repositories, while lysosome-related genes (LRGs) were compiled from published literature. Potential candidate genes emerged through the intersection of differentially expressed genes (DEGs), LRGs, and FRGs. Machine learning approaches, along with Receiver Operating Characteristic (ROC) analysis and gene expression profiling, enabled candidate biomarker identification. Nomogram analysis was utilized to assess the diagnostic performance of identified candidate biomarkers. We conducted functional pathway enrichment and immune cell infiltration analyses. Cell type determination was achieved through single-cell sequencing analysis, with key cellular populations characterized using the candidate biomarkers. In vitro validation of candidate biomarker expression was performed using Reverse Transcription quantitative Polymerase Chain Reaction (RT-qPCR). The intersection of 2621 DEGs, 875 LRGs, and 565 FRGs yielded 12 candidate genes. Through subsequent analysis, SLC7A5 (8140) and SLC3A2 (6520) emerged as candidate biomarkers, both showing reduced expression in OA samples with excellent discriminatory ability between sample groups. Pathway enrichment revealed involvement in lysosomal and spliceosome signaling. Strong positive correlations were observed between both SLC7A5 and SLC3A2 with eosinophil infiltration (r > 0.40, P < 0.05). Fibroblasts were identified as a major cell population in OA synovium, with both biomarkers showing markedly decreased expression in OA model cells compared to normal chondrocytes. This study identified SLC7A5 and SLC3A2 as OA candidate biomarkers associated with both lysosome and ferroptosis. Additionally, fibroblasts were identified as important contributors to OA pathology at the cellular level, providing a foundation for further investigation into their cellular mechanisms. This study identified candidate biomarkers-SLC7A5 and SLC3A2-associated with lysosomal dysfunction and ferroptosis, and highlighted fibroblasts as a potentially important cell type in OA. Collectively, these findings offer a theoretical foundation and generate testable hypotheses regarding potential molecular and cellular targets. This work may guide future research aimed at developing early diagnostic approaches and therapeutic strategies, although further experimental and clinical validation is required.
Liver fibrosis is characterized by excessive extracellular matrix deposition and hepatic stellate cell (HSC) activation, driven by chronic liver injury and inflammation. Macrophages play dual roles in fibrogenesis; the dynamic balance between pro-fibrotic and anti-fibrotic subsets is critical in determining the progression or regression of the disease. NEDD4L, an E3 ubiquitin ligase, is well-known to be involved in cell biological processes by promoting protein degradation, yet its role in macrophages and liver fibrosis remains poorly understood. Myeloid cell-specific Nedd4l knockout (Nedd4l f/f Lyz-Cre+, Nedd4l ΔMye) were generated, and subjected to carbon tetrachloride (CCl4) and choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD)-induced experimental liver fibrosis models. Single-cell RNA sequencing and transcriptomic analyses revealed significant upregulation of NEDD4L in macrophages from human and murine fibrotic livers. Strikingly, myeloid cell-specific Nedd4l deficiency exacerbated liver fibrosis in both mouse models, as evidenced by increased collagen deposition and elevated expression of fibrogenic genes in Nedd4l ΔMye mice. Notably, mice with Nedd4l deficient in macrophages had more pro-fibrotic scar-associated macrophage (SAM) infiltration compared with Nedd4l f/f mice in two experimental models. More interestingly, coculture in vitro experiments further verified that TGF-β1-treated Nedd4l deficient macrophages promoted HSC activation due to greater activation of SMAD3 signaling. Mechanistically, NEDD4L directly ubiquitinated phosphorylated SMAD3 and led to its degradation, thus limiting TGF-β1/SMAD3 signaling in macrophages. Moreover, hepatic levels of NEDD4L were significantly elevated in patients with liver fibrosis, positively correlating with hepatic levels of several fibrogenic genes. NEDD4L serves as a critical negative regulator of liver fibrosis by restraining profibrotic SAM expansion through ubiquitination and degradation of p-SMAD3 in macrophages. These findings highlight that targeting the ubiquitin-proteasome system as a potential therapeutic strategy for the treatment of fibrotic disease.
Acute lung injury (ALI) and its more severe form, acute respiratory distress syndrome (ARDS), are life-threatening pulmonary disorders with high mortality rates, and effective treatments are currently lacking. Secoisolariciresinol diglucoside (SDG), a plant lignan derived from flaxseed, possesses anti-inflammatory and antioxidative activities. However, the underlying mechanisms by which SDG ameliorates ALI remain incompletely understood. This study aimed to investigate whether SDG alleviates ALI by modulating the NF-κB/NLRP3 signaling pathway. For the in vivo study, ALI was induced in mice through intranasal administration of LPS. Key indicators included lung histopathological changes, wet/dry weight ratio (W/D), protein concentration in bronchoalveolar lavage fluid (BALF), oxidative stress markers (MDA, SOD, CAT), the expression of inflammatory cytokines and chemokines (IL-1β, IL-18, TNF-α, CCL2), and the level of NF-κB/NLRP3 pathway-related proteins. In vitro experiments using LPS-stimulated RAW264.7 further explored the effects of SDG on the NF-κB/NLRP3 pathway. SDG significantly mitigated LPS-induced lung histopathological damage and nasal mucosal injury, reduced lung W/D ratio and BALF protein, and suppressed oxidative stress. Moreover, SDG downregulated pro-inflammatory cytokines (IL-1β, IL-18, TNF-α) and macrophage infiltration. It also decreased the expression of N-κB/NLRP3 pathway-related proteins. In vitro experiments further confirmed that SDG inhibited the NF-κB/NLRP3 pathway. SDG effectively alleviates LPS-induced ALI through its antioxidant, anti-inflammatory, and NF-κB/NLRP3 pathway-inhibiting properties, providing experimental evidence for its potential as a therapeutic agent for ALI.
Dioctyl terephthalate (DOTP), a widely used plasticizer in food packaging and environmental materials, has raised concerns regarding its potential impact on human health. This study aims to investigate the neurotoxicity-related mechanisms of DOTP through an integrated approach combining network toxicology, molecular dynamics simulations, and in vivo validation. We retrieved the DOTP chemical structure from PubChem and predicted potential protein targets using the Similarity Ensemble Approach (SEA), SwissTargetPrediction, and SuperPred. We performed protein-protein interaction (PPI) network analysis using STRING and Cytoscape to identify core neurotoxicity-associated targets. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted to characterize the biological relevance of the 90 intersecting targets. We used AutoDock to assess the binding affinity of DOTP to the core proteins, and employed GROMACS for molecular dynamics (MD) simulations to explore the stability and conformational dynamics of the docked complexes. In vivo experiments, encompassing behavioral assessments, histological examinations, and molecular assays, were conducted to evaluate the effects of DOTP on neurological function, neuronal integrity, and target pathway dysregulation. We identified 90 neurotoxicity-related targets, among which EGFR, BCL2, CASP3, MAPK8, TLR4, NFKB1, and MTOR emerged as core nodes within the PPI network. GO and KEGG analyses revealed the involvement of these targets in diverse biological processes, cellular components, molecular functions, and signaling pathways. Molecular docking indicated favorable binding affinities between DOTP and the identified core targets, a finding further supported by MD simulations. Moreover, DOTP-treated mice exhibited significant neurofunctional deficits and neuronal loss, accompanied by profound oxidative stress, neuroinflammation, and apoptotic activation, substantiating its potential neurotoxicity. Our findings provide a theoretical foundation for understanding the predicted molecular mechanisms of DOTP-induced neurotoxicity. The integration of computational modeling and in vivo phenotypic validation suggests that DOTP may pose neurological risks, highlighting the need for further experimental evaluation of plasticizer alternatives.
Sleep quality critically influences amyloid beta (Aβ) clearance, yet the specific role of morning wake transition duration remains unexplored. This hypothesis-driven secondary analysis examined 97 cognitively unimpaired older adults (mean age ± SD: 74.4 ± 5.8 years) who underwent 14-day actigraphy and 18F-florbetapir positron emission tomography (PET). Cognitive function was evaluated using the National Center for Geriatrics and Gerontology-Functional Assessment Tool (NCGG-FAT). Time to wake up (TWU) was calculated as the midpoint between initial wake and final rise times. Binomial logistic regression models adjusted for age, depression, and sleep duration showed that extended TWU (>6.23 min) associated with higher Aβ positivity (27.1% vs 10.2%, odds ratio [OR] = 1.85, 95% confidence interval [CI]: 1.11-3.07, p = 0.019) and impaired word memory (OR = 2.17, 95% CI: 1.11-4.24, p = 0.023). Exploratory analyses of additional cognitive domains showed no significant associations. Prolonged morning wake transitions may represent a behavioral marker associated with Aβ accumulation and memory impairment. The cross-sectional design and modest sample size warrant cautious interpretation and replication in larger longitudinal cohorts.
Frailty, defined by progressive loss of physiological resilience, neuromuscular function, and cognitive capacity, is a central manifestation of biological aging yet remains difficult to quantify in scalable experimental systems. Here, we introduce a Composite Frailty Index (CFI) in the house cricket (Acheta domesticus) that integrates automated measures of locomotion, exploratory behavior, and freezing into a unified, quantitative framework of functional decline. Ten behavioral parameters derived from automated open-field tracking, including locomotor performance, exploratory behavior, and freezing were integrated into the CFI. Locomotor states were classified using k-means clustering (k = 2) of velocity distributions, and all features were normalized to age-or treatment-matched reference populations, discretized into quintiles, and summed to generate a 0-40 frailty score. Aging cohorts (young adult: 4-6 weeks; geriatric: 10-12 weeks, N = 103) and pharmacological cohorts treated at mid-life (8-10 weeks) with rapamycin (14 ppm), acarbose (1000 ppm), or phenylbutyrate (1000 ppm) were evaluated (N = 122). Across chronological aging cohorts, CFI increased from young adults to geriatrics in both females (d = 1.14 [95% CI: 0.53, 1.76], P = 0.0003) and males (d = -1.17 [95% CI: -1.75 to -0.59], P < 0.0001). Using pharmacological intervention cohorts, mid-life rapamycin treatment reduced late-life frailty relative to controls in both females (d = -1.31 [95% CI: -2.09, -0.53], P = 0.0017) and males (d = -1.33 [95% CI: -2.09, -0.58], P = 0.0004), whereas acarbose and phenylbutyrate produced inconclusive effects (d's = -0.54 to -0.03; P's > 0.05). Together, these findings establish the cricket CFI as a scalable, high-throughput platform for quantifying multidimensional functional aging and prioritizing candidate geroprotective interventions based on clinically relevant endpoints beyond lifespan.
Lung ultrasound (LUS) has gained increasing relevance in the evaluation of respiratory symptoms due to its bedside applicability, diagnostic accuracy, and safety. However, its adoption in geriatric care remains limited. This study aimed to assess current LUS availability, use, and technical practices among Italian geriatricians. A nationwide, cross-sectional survey was conducted among members of the Italian Society of Gerontology and Geriatrics. The 44-item questionnaire explored LUS availability, use, indications, and technical practices in acute care. LUS proficiency was operationally defined as the ability to perform the scan, interpret findings and integrate them with clinical data independently or under supervision. Responders (n = 154), representing 57 hospitals in 17 Italian regions, reported wide interest in LUS and recognized its utility for improving the care of older patients with acute respiratory failure. The main indications, which LUS was used for in their clinical experience, were assessment of volume status, pleural effusions and heart failure. Although availability of LUS equipment in the clinical units of responders was generally high (94%), 27.3% of them were non-proficient in LUS and more than 85% reported that a trained operator was not available 24/7. Heterogeneity also emerged in examination techniques and reporting among LUS-proficient responders, with only 6% adopting validated scanning protocols and 13% using standardized reporting formats. This survey reveals limited integration of LUS in geriatric care with heterogeneous practices. Structured training pathways and geriatric-specific standardized LUS protocols are urgently needed to enable broader, safer, and more consistent implementation in acute geriatric care.
Enrollees in Medicare Advantage (MA) receive less intensive post-acute care (PAC) than those in traditional Medicare, but the implications of this lower intensity, particularly for patients with complex needs, remain poorly understood. To estimate the association of MA enrollment with PAC use and patient outcomes for hospitalized beneficiaries with hip fracture or stroke. A quasi-experimental difference-in-differences analysis leveraging the geographic expansion of MA from 2012 to 2017. The study included 148,396 stroke and 126,046 hip fracture hospitalizations, representing quasi-exogenous hospitalization events in high MA-growth counties. Initial PAC setting, 30-day all-cause hospital readmission, and 30- and 90-day all-cause mortality. MA enrollment was associated with fewer discharges to inpatient rehabilitation facilities (stroke: -8.9 pp; 95% CI, -9.88 to -7.92; hip fracture: -14.4 pp; 95% CI: -15.38 to -13.42). While 30-day readmissions were modestly lower for MA enrollees in both cohorts, MA enrollees experienced a 7.1% relative increase in 30-day mortality for stroke (0.6 pp; 95% CI: 0.01 to 1.19) and an 11.9% relative increase in 90-day mortality for hip fracture (1.3 pp; 95% CI: 0.52 to 2.08). This adverse mortality effect was concentrated in markets with high baseline IRF use (> = 33.3% of discharges, top tercile), where MA enrollment was associated with an 18.0% relative increase in 90-day mortality for stroke (2.0 pp; 95% CI: 0.82 to 3.18) and a 22.3% relative increase in 90-day mortality for hip fracture (2.3 pp; 95% CI: 0.93 to 3.67). MA enrollment was associated with lower IRF use, modestly lower readmissions, and a higher mortality risk for hip fracture and stroke. These findings suggest that MA's strategy of shifting patients to lower-cost settings may carry unintended adverse consequences for clinically complex patients.
Sarcopenia (SP) and idiopathic pulmonary fibrosis (IPF) are debilitating diseases, but share ferroptosis-related biomarkers and their regulatory mechanisms in both remain unclear, hindering targeted research and therapy. In this study, ferroptosis-related genes (FeRGs), as well as training sets and test sets related to SP and IPF, were obtained from public databases. After the identification of disease-related differentially expressed genes (DEGs), DEGs shared by SP and IPF were obtained through intersection (genes with consistent DEG change trends across each disease) and union analyses. These shared DEGs were then intersected with FeRGs to obtain candidate genes. Machine learning algorithms and the Wilcoxon rank-sum test were used to confirm the biomarkers, and nomograms were constructed and evaluated. Meanwhile, in-depth studies such as functional enrichment, immune infiltration, drug prediction, and molecular docking were conducted on the biomarkers. Initially, a total of 26 candidate genes were identified. After screening, DDIT4 and MGST1 were identified as ferroptosis-related biomarkers shared by the two diseases, and both were significantly upregulated in the SP and IPF groups. The area under the curve values of the constructed nomograms were 0.91 (for SP) and 0.79 (for IPF), respectively. The p-values of the Hosmer-Lemeshow test for the calibration curves (0.856 and 0.205) were both >0.05, and the DCA showed good performance. The two biomarkers showed differences in enriched pathways. A total of 5 differential immune cells shared by the two diseases were identified, and the biomarkers participated in immune regulation by targeting specific immune cells. Good binding activity (Vina Score < -5.0) was observed between Trichostatin A and both biomarkers. DDIT4 and MGST1 were shared ferroptosis-related biomarkers for SP and IPF. Nomograms enabled reliable prediction, and trichostatin A was a potential targeted drug. These findings supported mechanistic research and targeted therapy for both diseases.
Many studies have reported the role of genetic polymorphisms in osteoarthritis (OA). While, there lacks of a comprehensive synthesis of bibliometric trends on this topic. This study aims to summarize global research progress and identify current hotspots by a bibliometric analysis. Publications on genetic polymorphisms and OA were retrieved from the Web of Science Core Collection database between January 1, 2005 and December 31, 2024. Bibliometric analyses were conducted to evaluate contributions from countries, institutions, authors, journals, and keywords by using CiteSpace, VOSviewer, and the Bibliometrix package. Overall, 1330 articles were eligible to final data analysis. The number of publications showed a gradual upward trend with some fluctuations over time. China produced the largest number of publications (n = 518), whereas Canada led in average citations per article (n = 55.3). Xi'an Jiaotong University had the highest number of publications (n = 64), whereas the University of Oxford and Rikagaku KENkyusho ranked first in total citations (n = 2847) and average citations (n = 69.7), respectively. Osteoarthritis and Cartilage was the most productive journal in terms of publication count (n = 72), whereas Arthritis and Rheumatism had the highest average citations (n = 79.9). The most active authors were predominantly from the United Kingdom. Keyword analysis identified several major research hotspots, including Mendelian randomization study, causal link, SMAD3 gene rs12901499 polymorphism, GDF5, obesity, metabolism, and inflammation. Over the past two decades, the increasing number of publications highlights the expanding attention on genetic polymorphisms in OA. China leads in terms of publication output, whereas researchers from the United Kingdom demonstrate substantial academic impact. Keyword analysis highlighted emerging research hotspots, including Mendelian randomization, causal link, SMAD3 gene rs12901499 polymorphism, GDF5, metabolism, obesity, and inflammation. These findings provide a valuable resource for researchers, guiding future studies and reducing redundant efforts in this rapidly evolving field.
Sarcopenia is an age-related muscle disorder driven by complex interactions between chronic inflammation and nutritional imbalance. The neutrophil percentage-to-albumin ratio (NPAR), an emerging biomarker integrating systemic inflammatory burden and nutritional status, has been associated with adverse outcomes in several chronic diseases. However, population-based evidence regarding the relationship between NPAR and sarcopenia remains limited. Using data from the U.S. National Health and Nutrition Examination Survey (NHANES) 2011-2018, we conducted a cross-sectional analysis of 10,287 adults aged ≥20 years. Sarcopenia was defined according to the Foundation for the National Institutes of Health (FNIH) criteria using the sarcopenia index derived from dual-energy X-ray absorptiometry. NPAR was calculated as neutrophil percentage divided by serum albumin concentration. Survey-weighted logistic regression models were applied to examine the association between NPAR and sarcopenia. Restricted cubic spline and threshold effect analyses were used to assess nonlinear dose-response relationships. The incremental predictive value of NPAR was evaluated using receiver operating characteristic curves, net reclassification improvement (NRI), and integrated discrimination improvement (IDI). Machine learning-based models were further constructed to evaluate the predictive contribution of NPAR, with SHapley Additive exPlanations (SHAP) applied to enhance model interpretability. Among the study population, 900 participants (8.7%) had sarcopenia. Higher NPAR levels were independently associated with increased odds of sarcopenia after full adjustment for sociodemographic factors, lifestyle behaviors, and comorbidities (odds ratio per unit increase = 1.11, 95% CI: 1.06-1.15). When analyzed by quartiles, participants in the highest NPAR quartile had a 69% higher risk of sarcopenia compared with those in the lowest quartile. A significant nonlinear association was observed, with an inflection point at NPAR = 13.042; above this threshold, sarcopenia risk increased markedly. Adding NPAR to conventional risk models significantly improved discrimination and reclassification (NRI = 0.170, IDI = 0.004; all P < 0.001). Machine learning analyses consistently identified NPAR as an important predictor of sarcopenia, with SHAP analyses demonstrating a positive and monotonic association between NPAR and sarcopenia risk. Elevated NPAR is independently and nonlinearly associated with a higher risk of sarcopenia in U.S. adults and provides incremental predictive value beyond traditional risk factors. As a simple, inexpensive, and routinely available biomarker, NPAR may serve as a promising tool for early identification and risk stratification of sarcopenia in both clinical and public health settings.
Kidney stones represent a prevalent and economically burdensome urinary system disorder with rising global incidence. Although dyslipidemia is a recognized risk factor for nephrolithiasis, the association of the Triglyceride-Cholesterol-Body Weight Index (TCBI)-a novel measure integrating lipid metabolism and body weight-with both incident and recurrent kidney stones has not been investigated in the general population. Data from the 2007-2016 cycles of the National Health and Nutrition Examination Survey (NHANES) formed the basis of this cross-sectional analysis. Analyses included 9929 participants for kidney stone risk evaluation and 724 for assessing recurrence risk. We employed multivariable logistic regression, extensively controlling for demographic, socioeconomic, and clinical factors, to assess associations. The dose-response relationship and effect consistency were then examined using restricted cubic splines (RCS) and subgroup analyses. We further analyzed an independent external validation dataset of 201 participants to validate the results. A positive association was observed between TCBI and kidney stone prevalence after full adjustment: each 1-unit increase in log-transformed TCBI (Lg TCBI) was associated with a 50.3% higher risk. A strong association was found between the highest Lg TCBI quartile and increased prevalence of both incident and recurrent kidney stones, relative to the lowest quartile. This positive association followed a monotonic dose-response pattern (P for nonlinearity >0.05), as confirmed by RCS, and was upheld across subgroups. External validation reinforced the positive link between Lg TCBI and kidney stone development and recurrence. TCBI was demonstrated to be independently associated with the presence of both new-onset and recurrent kidney stones. Given its ease of calculation, TCBI holds value as a clinical indicator for assessing associated risk and identifying individuals who may benefit from evaluation, notably those with underlying metabolic abnormalities.
We aimed to examine the relationship between acute events and frailty trajectories of community-dwelling adults aged 60 and older. We included 3146 participants, aged 60+, from the Swedish National Study on Aging and Care in Kungsholmen (SNAC-K). We considered all myocardial infarctions (MIs), lower respiratory tract infections (LRTIs) and falls that resulted in a hospitalization 5 years before to 12 years after SNAC-K baseline (2001-2004). Frailty was operationalized using a data-driven frailty index (FI), scored from 0 to 1. Linear quantile mixed models were used to examine the relationship between number and type of acute events and FI trajectories over a median follow-up of 11 years. Falls (n = 690) were most common, followed by LRTIs (n = 353) and MIs (n = 205). Those with more acute events showed significantly higher frailty levels over time from age 75 to 95. The greatest differences in frailty trajectories by event count were observed at age 80, with increases between zero to one, one to two and two to three or more events of 0.04 (95% confidence interval [CI] = 0.03-0.05), 0.08 (95% CI = 0.05-0.11) and 0.09 (95% CI = 0.05-0.13) FI units, respectively. Falls emerged as most deleterious, but there were also clear differences by MI and LRTI count after imputing frailty at death. Older adults who experience falls, LRTIs and MIs are more likely to sustain unfavourable frailty trajectories, with increasingly higher frailty levels with each additional acute event. Prevention, before age 75, should be optimized to avoid a vicious cycle of acute events and frailty progression as well as reduced lifespan.
Conventional obesity definitions overlook heterogeneity related to metabolic health and muscle strength. This study examined the associations between dynapenic-metabolic obesity (DMO) and incident stroke among middle-aged and older Chinese adults. Our study included 11,770 participants aged ≥45 years from the China Health and Retirement Longitudinal Study (CHARLS, 2011-2018) with 2011 as baseline. Dynapenia was defined by handgrip strength (<28 kg for men, <18 kg for women); metabolic dysfunction by ≥2 of 4 criteria (hypertension, dyslipidemia, impaired glycemia, or low HDL-C); and obesity by BMI ≥25 kg/m2 (general obesity) or waist circumference ≥ 90 cm for men and ≥ 85 cm for women (abdominal obesity). Cox models estimated hazard ratios (HRs) for stroke, adjusting for covariates. Mediation analysis evaluated the roles of C-reactive protein (CRP) and intrinsic capacity (IC). During follow-up, 787 participants (6.7%) experienced stroke. Obesity alone, without dynapenia or metabolic dysfunction, was associated with elevated stroke risk (general obesity: HR 1.50, 95% CI 1.15-1.95; abdominal obesity: HR 1.55, 95% CI 1.21-1.98). The highest risk was observed in participants with combined dynapenia and metabolic dysfunction (DMGO: HR 2.97, 95% CI 2.01-4.37; DMAO: HR 2.96, 95% CI 2.08-4.21). Mediation analyses indicated that systemic inflammation and reduced intrinsic capacity partially explained these associations. Findings were consistent across subgroups and sensitivity analyses. Dynapenic-metabolic obesity is strongly associated with incident stroke, but even obesity alone increases risk. Systemic inflammation and impaired intrinsic capacity partially mediate these effects, highlighting the importance of integrated strategies targeting adiposity, metabolic health, and muscle function to prevent stroke in aging populations.