OBJECTIVE To investigate the influence of CYP2C19 gene polymorphism on platelet function and inflammatory cytokines in elderly patients with ischemic stroke， and to analyze potential factors associated with poor prognosis. METHODS A retrospective study was conducted on elderly patients with ischemic stroke admitted to our hospital from June 2024 to June 2025， wh o underwent CYP2C19 genotype testing and received antiplatelet therapy with clopidogrel. The levels of platelet function indicators and inflammatory cytokines before and after treatment were compared among patients with different metabolic phenotypes. Based on the prognosis at 6 months post-treatment， patients were divided into poor prognosis group and good prognosis group. Univariate analysis was performed on general data， metabolic phenotype， the levels of platelet function indicators and inflammatory cytokines. Variables with P ＜0.05 and the levels of inflammatory cytokines before treatment were included in a multivariate Logistic regression analysis to identify independent risk factors for poor prognosis. Multiple linear regression was used to further analyze the relationship between metabolic phenotypes and inflammatory cytokines. RESULTS A total of 448 elderly patients with ischemic stroke were included； among them， 162 cases were normal metabolic phenotype， 218 were intermediate metabolic phenotype， and 68 were poor metabolic phenotype. No rapid or ultrarapid metabolic phenotypes were observed. After treatment， platelet aggregation rate， the levels of P-selectin and platelet activated complex-1 （PAC-1）， high-sensitivity C-reactive Protein （hs-CRP）， interleukin-1β （IL-1β）， IL-6 and tumor necrosis factor-α （TNF-α） in the normal metabolic phenotype group， intermediate metabolic phenotype group， and poor metabolic phenotype group （except for platelet aggregation rate， and the levels of P-selectin and PAC-1 in the poor metabolic phenotype group） were significantly lower than those before treatment in the same group. Moreover， the above indicators in the normal metabolic phenotype group were significantly lower than those in the intermediate and poor metabolic phenotype groups at the corresponding time， and the levels of platelet function indicators in the intermediate metabolic phenotype group were significantly lower than those in the poor metabol ic phenotype group at the corresponding time （ P ＜0.05）. Univariate and multivariate Logistic regression analyses showed that combined with hypertension， combined with diabetes mellitus， and intermediate or poor metabolic genotypes were independent risk factors for poor prognosis in elderly patients with ischemic stroke （ P ＜0.05）. Multiple linear regression analysis showed that serum levels of hs-CRP， IL-1β， IL-6 and TNF-α before treatment were significantly higher in patients with intermediate and poor metabolic genotypes compared to those with normal metabolic genotype （ P ＜0.05）， with a greater magnitude of increase in inflammatory cytokines observed in the patients with poor metabolic genotype. CONCLUSIONS The elderly ischemic stroke patients with CYP2C19 intermediate and poor metabolic genotypes have poor inhibition effect on platelet and higher levels of inflammatory cytokines than normal metabolic genotype； CYP2C19 gene polymorphism， and in combination with hypertension and diabetes， can be used as independent predictors of poor prognosis.

Objective To analyze the genetic characteristics and variations of influenza A (H3N2) viruses in Ma'anshan from 2022 to 2024, and to provide a scientific basis for local influenza prevention and control. Methods From April 2022 to March 2024, influenza-like illness (ILI) specimens were collected from three national influenza surveillance sentinel hospitals in Ma’anshan. Samples positive for influenza by real-time PCR were subjected to virus culture and identification. A total of 40 representative A/H3N2 strains with hemagglutination titers ≥8 were selected for whole-genome sequencing. Genetic evolution, homology, amino acid variations, and glycosylation sites were analyzed. Results All H3N2 representative strains from the 2022–2023 influenza season belonged to clade 3C.2a1b.2a.1a.1, while those from the 2023–2024 season fell into clade 3C.2a1b.2a.2a.3a.1. The nucleotide and amino acid sequence similarities of HA and NA between the 40 representative strains and the vaccine strain A/Darwin/6/2021 were all above 97.35%. Compared with the vaccine strain, amino acid mutations were identified in antigenic sites A, B, C, and E, as well as in receptor-binding sites of the HA protein. An I222V substitution was detected in the NA protein. The HA protein contained four additional glycosylation sites compared to the vaccine strain, while the glycosylation pattern of the NA protein remained consistent. Conclusion No antigenic drift was observed in the influenza A/H3N2 viruses in Ma'anshan City from 2022 to 2024, but genetic changes such as branching variations, key amino acid substitutions, and an increase in HA glycosylation sites were observed. These findings underscore the importance of sustained molecular surveillance of local influenza viruses.

Background Prehospital emergency medical personnel (PEMP) are exposed to long-term high-pressure work, which can exacerbate psychological distress and impair job satisfaction and sleep quality. However, in-depth research on the interactions among these factors is lacking. Objective To assess the status of psychological distress, job satisfaction, and sleep quality of PEMP in Guangzhou and to explore the mediating role of sleep quality in the relationship between psychological distress and job satisfaction. Methods From February to May 2025, 1085 PEMP from "120" emergency network hospitals in Guangzhou were selected using convenience sampling. Data were collected via the General Information Questionnaire, Kessler Psychological Distress Scale, Minnesota Satisfaction Questionnaire, and Pittsburgh Sleep Quality Index. Statistical analyses were performed using SPSS 25.0, and The mediation model of sleep quality in linking psychological distress and job satisfaction was constructed using AMOS 28.0. The bias-corrected Bootstrap method was employed to assessed the significance of the mediating effect. Results A total of 1063 valid responses were received (97.97% valid response rate). The mean scores were: psychological distress (27.99±10.75), job satisfaction (69.45±15.84), and sleep quality (9.82±4.47). Significant differences in the three scores were found across gender, age, monthly night shift frequency, and hospital grade (P<0.05). Higher job satisfaction was linked to lower psychological distress and better sleep quality and its dimensions, while psychological distress directly correlated with poorer sleep quality (P<0.01). Sleep quality partially mediated the relationship between psychological distress and job satisfaction, with a mediating effect of −0.195, accounting for 43.62% of the total effect. Conclusion The participants report moderate psychological distress, moderate-to-high job satisfaction, and poor sleep quality. Psychological distress directly affects job satisfaction and indirectly through its impact on sleep quality. Interventions aimed at improving sleep health and mental health are essential to improve personnel well-being and work efficiency.

Background Prehospital emergency medical personnel (PEMP) are exposed to long-term high-pressure work, which can exacerbate psychological distress and impair job satisfaction and sleep quality. However, in-depth research on the interactions among these factors is lacking. Objective To assess the status of psychological distress, job satisfaction, and sleep quality of PEMP in Guangzhou and to explore the mediating role of sleep quality in the relationship between psychological distress and job satisfaction. Methods From February to May 2025, 1085 PEMP from "120" emergency network hospitals in Guangzhou were selected using convenience sampling. Data were collected via the General Information Questionnaire, Kessler Psychological Distress Scale, Minnesota Satisfaction Questionnaire, and Pittsburgh Sleep Quality Index. Statistical analyses were performed using SPSS 25.0, and The mediation model of sleep quality in linking psychological distress and job satisfaction was constructed using AMOS 28.0. The bias-corrected Bootstrap method was employed to assessed the significance of the mediating effect. Results A total of 1063 valid responses were received (97.97% valid response rate). The mean scores were: psychological distress (27.99±10.75), job satisfaction (69.45±15.84), and sleep quality (9.82±4.47). Significant differences in the three scores were found across gender, age, monthly night shift frequency, and hospital grade (P<0.05). Higher job satisfaction was linked to lower psychological distress and better sleep quality and its dimensions, while psychological distress directly correlated with poorer sleep quality (P<0.01). Sleep quality partially mediated the relationship between psychological distress and job satisfaction, with a mediating effect of −0.195, accounting for 43.62% of the total effect. Conclusion The participants report moderate psychological distress, moderate-to-high job satisfaction, and poor sleep quality. Psychological distress directly affects job satisfaction and indirectly through its impact on sleep quality. Interventions aimed at improving sleep health and mental health are essential to improve personnel well-being and work efficiency.

Objective To analyze the efficacy and safety of ustekinumab(UST)in patients with moderate-to-severe Crohn's disease(CD),and to identify factors influencing clinical outcomes.Methods Data were retrospectively collected from patients with moderate-to-severe CD treated with UST in the First Affiliated Hospital of Zhejiang Chinese Medical University and Hangzhou Hospital of Traditional Chinese Medicine between November 2020 and May 2023.Patients were categorized into first-line(not treated with biologic agents,n=68)and second-line(treated with biologic agents,n=66)treatment groups based on prior use of biologic agents.Baseline characteristics,including age,sex,smoking status,disease duration,age at diagnosis,lesion site,disease behavior,perianal disease,history of intestinal surgery,and CD-related drug use,were compared between the two groups.Crohn's disease activity indices(CDAI)were recorded at baseline,week 14,and week 52 to assess the clinical efficacy at weeks 14 and 52.Endoscopic evaluations were performed at baseline and week 52 to evaluate endoscopic efficacy at week 52.The 52-week drug persistence rate and safety profile were also analyzed.Influencing factors related to clinical outcomes were evaluated using univariate and multivariate logistic regression.Results A total of 134 patients with moderate-to-severe CD treated with UST were included.At week 14,clinical response and remission rates were 75.4%(101/134)and 33.6%(45/134),respectively,with no significant difference in clinical efficacy between first-line and second-line groups(clinical response rate:77.9%vs.72.7%,P=0.484;clinical remission rate:38.2%vs.28.8%,P=0.247).At week 52,clinical response and remission rates were 79.9%(107/134)and 56.0%(75/134),respectively.The rates of endoscopic response and remission were 70.9%(95/134)and 38.8%(52/134),respectively.There were no significant differences in clinical efficacy(clinical response rate:80.9%vs.78.8%,P=0.763;clinical remission rate:60.3%vs.51.5%,P=0.306)and endoscopic efficacy(endoscopic response rate:76.5%vs.65.2%,P=0.149;endoscopic remission rate:42.6%vs.34.8%,P=0.354)between the two groups.The 52-week drug persistence rate was 85.8%(115/134),and the adverse reaction rate was 4.5%(6/134).Compared with first-line treatment group,biologic-experienced patients had a significantly higher proportion of dose-optimized therapy in second-line treatment group(45.5%vs.22.1%,P=0.004).Multivariate logistic regression showed that the 14-week clinical response was a significant predictor of 52-week clinical remission,while perianal disease and intestinal surgery history were significant factors associated with treatment failure(P<0.05).Conclusions UST demonstrates significant efficacy in improving clinical and endoscopic outcomes for moderate-to-severe CD patients,with a favorable safety profile.Clinical response at 14 weeks is strongly predictive of clinical remission at 52 weeks.Patients with perianal disease or a history of intestinal surgery were at higher risk of treatment failure.

Iron metabolism is a critical factor in tumorigenesis and development. Although TP53 mutations are prevalent in glioblastoma (GBM), the mechanisms by which TP53 regulates iron metabolism remain elusive. We reveal an imbalance iron homeostasis in GBM via TCGA database analysis. TP53 mutations disrupted iron homeostasis in GBM, characterized by elevated total iron levels and reduced ferritin (FTH). The gain-of-function effect triggered by TP53 mutations upregulates itchy E3 ubiquitin-protein ligase (ITCH) protein expression in astrocytes, leading to FTH degradation and an increase in free iron levels. TP53-mut astrocytes were more tolerant to the high iron environment induced by exogenous ferric ammonium citrate (FAC), but the increase in intracellular free iron made them more sensitive to Erastin-induced ferroptosis. Interestingly, we found that Erastin combined with FAC treatment significantly increased ferroptosis. These findings provide new insights for drug development and therapeutic modalities for GBM patients with TP53 mutations from iron metabolism perspectives.
Ferroptosis/drug effects* ; Humans ; Iron/metabolism* ; Glioblastoma/metabolism* ; Tumor Suppressor Protein p53/metabolism* ; Homeostasis/physiology* ; Ferritins/metabolism* ; Brain Neoplasms/genetics* ; Mutation ; Astrocytes/drug effects* ; Cell Line, Tumor ; Piperazines/pharmacology* ; Quaternary Ammonium Compounds/pharmacology* ; Ferric Compounds

Periodontitis is a common oral disease characterized by progressive alveolar bone resorption and inflammation of the periodontal tissues. Dimethyl fumarate (DMF) has been used in the treatment of various immune-inflammatory diseases due to its excellent anti-inflammatory and antioxidant functions. Here, we investigated for the first time the therapeutic effect of DMF on periodontitis. In vivo studies showed that DMF significantly inhibited periodontal destruction, enhanced mitophagy, and decreased the M1/M2 macrophage ratio. In vitro studies showed that DMF inhibited macrophage polarization toward M1 macrophages and promoted polarization toward M2 macrophages, with improved mitochondrial function, inhibited oxidative stress, and increased mitophagy in RAW 264.7 cells. Furthermore, DMF increased intracellular mitochondrial Tu translation elongation factor (TUFM) levels to maintain mitochondrial homeostasis, promoted mitophagy, and modulated macrophage polarization, whereas TUFM knockdown decreased the protective effect of DMF. Finally, mechanistic studies showed that DMF increased intracellular TUFM levels by protecting TUFM from degradation via the ubiquitin-proteasomal degradation pathway. Our results demonstrate for the first time that DMF protects mitochondrial function and inhibits oxidative stress through TUFM-mediated mitophagy in macrophages, resulting in a shift in the balance of macrophage polarization, thereby attenuating periodontitis. Importantly, this study provides new insights into the prevention of periodontitis.
Dimethyl Fumarate/pharmacology* ; Mitophagy/drug effects* ; Animals ; Mice ; Macrophages/metabolism* ; Periodontitis/prevention & control* ; RAW 264.7 Cells ; Oxidative Stress/drug effects* ; Peptide Elongation Factor Tu/metabolism* ; Mice, Inbred C57BL ; Male ; Mitochondria/drug effects*

Cemental tear is a rare and indetectable condition unless obvious clinical signs present with the involvement of surrounding periodontal and periapical tissues. Due to its clinical manifestations similar to common dental issues, such as vertical root fracture, primary endodontic diseases, and periodontal diseases, as well as the low awareness of cemental tear for clinicians, misdiagnosis often occurs. The critical principle for cemental tear treatment is to remove torn fragments, and overlooking fragments leads to futile therapy, which could deteriorate the conditions of the affected teeth. Therefore, accurate diagnosis and subsequent appropriate interventions are vital for managing cemental tear. Novel diagnostic tools, including cone-beam computed tomography (CBCT), microscopes, and enamel matrix derivatives, have improved early detection and management, enhancing tooth retention. The implementation of standardized diagnostic criteria and treatment protocols, combined with improved clinical awareness among dental professionals, serves to mitigate risks of diagnostic errors and suboptimal therapeutic interventions. This expert consensus reviewed the epidemiology, pathogenesis, potential predisposing factors, clinical manifestations, diagnosis, differential diagnosis, treatment, and prognosis of cemental tear, aiming to provide a clinical guideline and facilitate clinicians to have a better understanding of cemental tear.
Humans ; Dental Cementum/injuries* ; Consensus ; Diagnosis, Differential ; Cone-Beam Computed Tomography ; Tooth Fractures/therapy*

Metachromatic leukodystrophy (MLD) is an inherited disease caused by a deficiency of the enzyme arylsulfatase A (ARSA). Lentivirus-modified autologous hematopoietic stem cell gene therapy (HSCGT) has recently been approved for clinical use in pre and early symptomatic children with MLD to increase ARSA activity. Unfortunately, this advanced therapy is not available for most patients with MLD who have progressed to more advanced symptomatic stages at diagnosis. Patients with late-onset juvenile MLD typically present with a slower neurological progression of symptoms and represent a significant burden to the economy and healthcare system, whereas those with early onset infantile MLD die within a few years of symptom onset. We conducted a pilot study to determine the safety and benefit of HSCGT in patients with postsymptomatic juvenile MLD and report preliminary results. The safety profile of HSCGT was favorable in this long-term follow-up over 9 years. The most common adverse events (AEs) within 2 months of HSCGT were related to busulfan conditioning, and all AEs resolved. No HSCGT-related AEs and no evidence of distorted hematopoietic differentiation during long-term follow-up for up to 9.6 years. Importantly, to date, patients have maintained remarkably improved ARSA activity with a stable disease state, including increased Functional Independence Measure (FIM) score and decreased magnetic resonance imaging (MRI) lesion score. This long-term follow-up pilot study suggests that HSCGT is safe and provides clinical benefit to patients with postsymptomatic juvenile MLD.
Humans ; Leukodystrophy, Metachromatic/genetics* ; Pilot Projects ; Genetic Therapy/methods* ; Hematopoietic Stem Cell Transplantation ; Male ; Follow-Up Studies ; Female ; Lentivirus/genetics* ; Child ; Child, Preschool ; Hematopoietic Stem Cells/metabolism* ; Cerebroside-Sulfatase/metabolism* ; Adolescent

Clathrin-mediated endocytosis (CME) is a critical process by which cells internalize macromolecular substances and initiate vesicle trafficking, serving as the foundation for many cellular activities. Central to this process are clathrin-coated structures (CCSs), which consist of clathrin-coated pits (CCPs) and clathrin plaques. While clathrin-coated pits are well-established in the study of endocytosis, clathrin plaques represent a more recently discovered but equally important component of this system. These plaques are large, flat, and extended clathrin-coated assemblies found on the cytoplasmic membrane. They are distinct from the more typical clathrin-coated pits in terms of their morphology, larger surface area, and longer lifespan. Recent research has revealed that clathrin plaques play roles that go far beyond endocytosis, contributing to diverse cellular processes such as cellular adhesion, mechanosensing, migration, and pathogen invasion. Unlike traditional clathrin-coated pits, which are transient and dynamic structures involved primarily in the internalization of molecules, clathrin plaques are more stable and extensive, often persisting for extended periods. Their extended lifespan suggests that they serve functions beyond the typical endocytic role, making them integral to various cellular processes. For instance, clathrin plaques are involved in the regulation of intercellular adhesion, allowing cells to better adhere to one another or to the extracellular matrix, which is crucial for tissue formation and maintenance. Furthermore, clathrin plaques act as mechanosensitive hubs, enabling the cell to sense and respond to mechanical stress, a feature that is essential for processes like migration, tissue remodeling, and even cancer progression. Recent discoveries have also highlighted the role of clathrin plaques in cellular signaling. These plaques can serve as scaffolds for signaling molecules, orchestrating the activation of various pathways that govern cellular behavior. For example, the recruitment of actin-binding proteins such as F-actin and vinculin to clathrin plaques can influence cytoskeletal dynamics, helping cells adapt to mechanical changes in their environment. This recruitment also plays a pivotal role in regulating cellular migration, which is crucial for developmental processes. Additionally, clathrin plaques influence receptor-mediated signal transduction by acting as platforms for the assembly of signaling complexes, thereby affecting processes such as growth factor signaling and cellular responses to extracellular stimuli. Despite the growing body of evidence that supports the involvement of clathrin plaques in a wide array of cellular functions, much remains unknown about the precise molecular mechanisms that govern their formation, maintenance, and turnover. For example, the factors that regulate the recruitment of clathrin and other coat proteins to form plaques, as well as the signaling molecules that coordinate plaque dynamics, remain areas of active research. Furthermore, the complex interplay between clathrin plaques and other cellular systems, such as the actin cytoskeleton and integrin-based adhesion complexes, needs further exploration. Studies have shown that clathrin plaques can respond to mechanical forces, with recent findings indicating that they act as mechanosensitive structures that help the cell adapt to changing mechanical environments. This ability underscores the multifunctional nature of clathrin plaques, which, in addition to their role in endocytosis, are involved in cellular processes such as mechanotransduction and adhesion signaling. In summary, clathrin plaques represent a dynamic and versatile component of clathrin-mediated endocytosis. They play an integral role not only in the internalization of macromolecular cargo but also in regulating cellular adhesion, migration, and signal transduction. While much has been learned about their structural and functional properties, significant questions remain regarding the molecular mechanisms that regulate their formation and their broader role in cellular physiology. This review highlights the evolving understanding of clathrin plaques, emphasizing their importance in both endocytosis and a wide range of other cellular functions. Future research is needed to fully elucidate the mechanisms by which clathrin plaques contribute to cellular processes and to better understand their implications for diseases, including cancer and tissue remodeling. Ultimately, clathrin plaques are emerging as crucial hubs that integrate mechanical, biochemical, and signaling inputs, providing new insights into cellular function and the regulation of complex cellular behaviors.