Objective: To examine the changing trajectories of sleep problems and teacher support among first year middle school students and their covariant relationship,so as to provide theoretical basis for the prevention strategy of sleep problems for the first year junior high school students. Methods: In September 2020, a multistage cluster random sampling method was used to select 1 027 first year junior high school students from two schools of Anshun and Guiyang cities in Guizhou Province for survey and follow up assessments (T1:September 2020, T2:October 2020, T3:November 2020, T4:December 2020). The Student Perceived Teacher Support Behavior Questionnaire and Pittsburgh Sleep Quality Index Scale were administered to assess sleep problems and teacher support among first year junior high school students. Spearman correlation analysis was used to examine the relationship between sleep problems and teacher support. A multivariate latent growth curve model was employed to analyze the changing trajectories and covariant relationship between teacher support and sleep problems, followed by a multi group analysis. Results: For first year junior high school students, teacher support scores at T1-T4 were 4.00 (3.47, 4.53), 4.00 (3.47, 4.58), 3.95 (3.47, 4.61) and 4.00 (3.48, 4.67), respectively; sleep problem scores were 0.83 (0.50, 1.17), 0.67 (0.50, 1.17), 0.83 (0.50, 1.17) and 0.67 (0.33, 1.17), respectively. Spearman correlation analysis revealed that teacher support and sleep problems were negatively correlated across all four period ( r =-0.28 to -0.14, all P <0.01). Teacher support perceived by students showed a linear increasing trend (intercept=3.98, slope=0.02), while sleep problems showed a linear decreasing trend (intercept=0.86, slope= -0.02 ) (all P <0.05). The multivariate latent growth model indicated that the rate of increase in teacher support after enrollment effectively predicted the rate of decrease in sleep problem levels ( β=-0.34, P <0.01). Multigroup analysis showed that the covariant relationship was not moderated by gender or boarding status (both P >0.05). Conclusions The increase in teacher support experienced by first year junior high school students during the transition period after enrollment, accompanied by a reduction in sleep problems, constitutes a dynamic protective process. The process is not moderated by gender or boarding status.

ObjectiveThis study aims to investigate the effectiveness and mechanisms of Polygonati Rhizoma polysaccharides （PRP） on improving cognitive and emotional functions in the ovariectomy （OVX）-Alzheimer's disease （AD） model rats. MethodsAfter being randomly divided into blank group， model group， estradiol group （0.18 mg·kg^-1·d^-1）， low-PRP group （200 mg·kg^-1）， medium-PRP group （400 mg·kg^-1）， and high-PRP group （800 mg·kg^-1）， 60 SPF female Sprague-Dawley （SD） rats were subjected to OVX. One week later， vaginal smear examination as well as D-galactose intraperitoneal injection （150 mg·kg^-1·d^-1， once daily， for eight weeks） were adopted to establish the OVX-AD model， and drug intervention was initiated nine weeks after surgery. Upon completion of the treatment course， cognitive and emotional functions， as well as hippocampal CA3 region damage were assessed in all rats by open-field test， new object recognition test， Morris water maze test， and transmission electron microscopy. Indicators of inflammation ［interleukin-6 （IL-6）， tumor-necrosis-factor-α （TNF-α）， interleukin-1β （IL-1β））， oxidative-stress （superoxide-dismutase （SOD）， glutathione-peroxidase （GSH-Px）］ were measured by enzyme-linked immunosorbent assay （ELISA） and biochemical methods. The mRNA and protein expression levels of estrogen-receptor α （ERα）/phosphoinositide 3kinase （PI3K）/protein-kinase-B （Akt） signaling pathway， apoptosis ［Bcl-2 associated X protein （Bax）， B-cell lymphoma/leukemia-2 （Bcl-2）］ and the indicators of pathological sedimentary proteins ［amyloid β-protein_1-42 （Aβ_1-42）， microtubule-associated protein Tau， phosphorylated site 404 of microtubule-associated protein Tau ［p-Tau （Ser404）］ were detected by using real-time polymerase chain reaction （Real-time PCR） and western blot analysis. ResultsCompared with those in blank group， the rats in model group exhibited marked ultra-structural damage to hippocampal CA3 neurons， along with the reduction of activity time and shuttle frequency in central area， the index and exploration frequency of new object recognition， and the platform crossings and time spent in target quadrant， as well as the prolonged latency （P<0.05， P<0.01）. Furthermore， the contents and expression levels of IL-6， TNF-α， IL-1β， Bax， Aβ_1-42， Tau， and p-Tau （Ser404） were significantly increased， and the activity and expression of SOD， GSH-Px， ERα， PI3K， Akt， and Bcl-2 were significantly decreased （P<0.05， P<0.01）. Compared to those in model group， the rats in estradiol group and groups with different doses of PRP noticeably presented with amelioration of neuronal damage， along with increased activity time and shuttle frequency in the central zone， elevated new object recognition index and exploration frequency， shortened latency， prolonged activity time， and increased platform crossings in the target quadrant （P<0.05， P<0.01）. What is more， the contents and expression levels of IL-6， TNF-α， IL-1β， Bax， Aβ_1-42， Tau， and p-Tau （Ser404） were significantly reduced， whereas the activity and expression levels of SOD， GSH-Px， ERα， PI3K， Akt， and Bcl-2 were markedly elevated （P<0.05， P<0.01）. ConclusionPRP can improve the cognitive and emotional functions of AD model rats， and its mechanisms are probably related to modulating the ERα/PI3K/Akt pathway as well as inhibiting Aβ， Tau， neuro-inflammation， oxidative stress， and apoptosis， resulting in alleviation of neuronal damage.

While programmed cell death ligand 1 (PD-L1) inhibitors have yielded breakthroughs in tumor therapy, their efficacy is constrained by the heterogeneity of the tumor microenvironment and multiple immunosuppressive pathways. In recent years, research has revealed that transforming growth factor-β (TGF-β) synergistically drives tumor cell immune escape with PD-L1 via pathways such as metabolic reprogramming, epithelial-mesenchymal transition, and SOX family factors. Currently, various PD-L1/TGF-β bispecific antibodies (bsAbs) have exhibited promising therapeutic potential in early-phase clinical trials, yet they still confront challenges related to toxicity and drug resistance. This article systematically reviews the mechanisms by which PD-L1 and TGF-β synergistically regulate tumor immune escape, summarizes the clinical research progress of bsAbs, and discusses strategies for novel drug design and biomarker development, with the aim of offering new insights for the development of combined tumor immunotherapy strategies.

ObjectiveTo investigate the association of comprehensive control of multiple metabolic risk factors with the risk of all-cause mortality in patients with metabolic dysfunction-associated steatotic liver disease （MASLD） and its quantitative effect. MethodsA retrospective cohort study was conducted based on the data from National Health and Nutrition Examination Survey （NHANES） in 2003—2018. A total of 29 458 participants were enrolled， including 12 528 patients with MASLD and 16 930 non-MASLD controls. The control status of nine risk factors was assessed， i.e.， hypertension， diabetes， liver fibrosis （assessed by fibrosis-4 index ［FIB-4］）， aspartate aminotransferase （AST）/alanine aminotransferase （ALT） ratio， serum albumin， renal function （assessed by serum creatinine）， systemic inflammation （assessed by neutrophil count）， smoking， and physical activity. According to the status of comprehensive risk factor control， the patients with MASLD were further divided into low-control group with 1 107 patients， moderate-control group with 7 042 patients， and high-control group with 4 379 patients. A total of 397 participants were enrolled in the external validation cohort， among whom there were 266 participants with MASLD and 131 participants without MASLD. The Kruskal-Wallis H test was used for comparison of continuous data between multiple groups， and the chi-square test was used for comparison of categorical data between groups. The Cox proportional hazards model incorporating complex sampling weights for NHANES data were used to investigate the association between the degree of risk factor control and all-cause mortality， and the Kaplan-Meier curve， the log-rank test， restricted mean survival time （RMST）， and population attributable fraction （PAF） were used for further assessment. The robustness of the findings was validated in an independent clinical cohort （n=397）. ResultsThe cohort study based on the NHANES database showed that during the median follow-up time of 6.7 years， 1 171 deaths occurred among the 12 528 patients with MASLD. There was a significant reduction in mortality risk with the increase in the number of risk factors controlled （trend test： χ²=65.06， P<0.001）. Compared with the low-control group， the mortality risk decreased successively in the moderate-control group （hazard ratio ［HR］=0.59， 95% confidence interval ［CI］： 0.51 — 0.69） and the high-control group （HR=0.36， 95%CI： 0.27 — 0.48）， and the mortality risk was reduced by 22% for each additional risk factor controlled （HR=0.78， 95%CI： 0.74 — 0.82）. The PAF analysis showed that AST/ALT ratio control （PAF=19.2%） and physical activity （PAF=18.9%） were the largest contributors. The survival analysis of the sub-cohort constructed based on nearest neighbor matching （with a maximum follow-up time of 13.3 years） showed that there was a significant difference in cumulative survival rate between the MASLD groups with different control levels and the non-MASLD group （P<0.001）. The RMST analysis further quantified the survival benefit of each group， and the high-control group had the longest 10-year RMST （9.88 years）， which was superior to that of the non-MASLD group （9.43 years）， the moderate-control group （9.33 years）， and the low-control group （7.96 years）. The multivariable-adjusted model analysis of the complete cohort showed that compared with the non-MASLD population， the MASLD patients in the low-control group had a significant increase in mortality risk， the moderate-control group had a comparable mortality risk， and the high-control group had a significantly lower mortality risk. The subgroup analysis showed a significant protective effect of comprehensive control in both male and female individuals （P<0.05）， and the interaction analysis suggested a potentially stronger protective effect in female individuals （P_{for interaction}=0.031）. The protective effect was statistically significant in patients aged ≥60 years （P<0.05）. There was a significant difference in protective effect across the groups stratified based on waist circumference （P<0.05）， but there was no significant interaction between groups （P_{for interaction}=0.821）. In the external validation cohort， among the 397 participants， there were 72 cases of all-cause mortality （18.1%）. The survival analysis showed a significant gradient increase in the survival rate of MASLD patients with the increase in the level of control （P=0.022）. The RMST analysis showed that the moderate- and high-control groups had a better RMST than the non-MASLD group at 5 years （4.47 years vs 4.56 years vs 4.40 years）， with a more significant survival advantage at 10 years （8.67 years vs 8.95 years vs 8.44 years）. The Cox regression analysis showed that， with the low-control MASLD group as the reference， there was a significant reduction in mortality risk in the moderate-control group （HR=0.41， 95%CI： 0.21 — 0.81） and the high-control group （HR=0.32， 95%CI： 0.14 — 0.71）； with the non-MASLD population as the reference， there was a significant increase in mortality risk in the low-control group （HR=2.02， 95%CI： 1.03 — 3.95）， with a comparable mortality risk in the moderate-control group （HR=0.83， 95%CI： 0.48 — 1.44） and the high-control group （HR=0.66， 95%CI： 0.30 — 1.38）， and the point estimates of the effects were highly consistent with the main study. ConclusionAmong MASLD patients， better control of metabolic risk factors is associated with a lower mortality risk. Achieving optimal control can eliminate the excess mortality risk associated with MASLD， thereby helping patients achieve a better survival prognosis than the general population.

Pharmacovigilance runs through the whole life cycle of drugs. This paper systematically sorts out the development course of pharmacovigilance in China， from the initial establishment of the adverse drug reaction reporting system to the gradual construction of a complete pharmacovigilance system aligned with international standards. It focuses on analyzing the evolutionary features of the organizational system， legal system and monitoring system during this process. On this basis， this paper further discusses the future development trends of pharmacovigilance in China. In general， remarkable progress has been achieved in both regulatory construction and practical implementation of China’s pharmacovigilance system. In the future， efforts should be continuously made to improve the pharmacovigilance system， such as accelerating the implementation of the “one-body with two-wings” working framework and strengthening the primary responsibility of marketing authorization holders. It is also necessary to cultivate and reserve professional talents and promote information-based construction， including optimizing the spontaneous reporting system and establishing active monitoring systems. These measures can provide more solid support for ensuring public drug safety and facilitating high-quality development of the pharmaceutical industry.

Brucellosis is one of the most widespread zoonoses globally, which poses serious threats to both global public health and development of animal husbandry. Conventional brucellosis control measures suffer problems of surveillance coordination, regional joint prevention, and policy implementation, which are insufficient to address the challenges of ecological risks and crosshost transmission. The One Health approach allocates interdisciplinary and intersectoral collaborations to achieve systemic health of humans, animals, and environments, which provides new insights into brucellosis control programmes. This review describes the pathogenic biological characteristics, global epidemiological landscape, and transmission ecology of brucellosis, evaluates the main limitations of current control strategies, summarizes the experiences from successful One Health practices across countries at different stages of development, and proposes the brucellosis control strategy based on the One Health concept with adaptations to the current epidemiology of brucellosis in China, so as to provide the theoretical evidence and practical framework for the national brucellosis control programmes in China, thereby facilitating the effective control and the ultimate elimination of brucellosis.

Against the backdrop of digital transformation in higher education， the traditional teaching model has become inadequate to meet the demands for cultivating new-quality nursing talents. Nursing ethics teaching confronts several dilemmas， such as unbalanced regional development， disconnection between theory and practice， scattered teaching resources， and fragmented knowledge points. With the iterative update of modern digital technologies， the knowledge graph， due to its structured， semantic， scalable， and multi-source integrative characteristics， offers a technological pathway to address these issues. Based on the construction foundation of the Ministry of Education’s first batch of virtual teaching and research platforms for humanistic nursing courses， the nursing ethics artificial intelligence（Al）course was developed around the“thinking-research-teaching-learning”framework. By strengthening ideological and political guidance， constructing a curriculum knowledge graph， and promoting the deep integration of humanistic care and professional knowledge，the course realized intelligent support for research，learning，and teaching. This innovative education model provides a replicable paradigm for cultivating outstanding nursing talents equipped with humanistic literacy， digital competence， and advanced ethical thinking， while also offering references for the digital transformation of higher nursing education.

ObjectiveTo investigate the protective effect and underlying mechanisms of the Bawei Chenxiang Wan （BCW） against myocardial ischemic injury. MethodsMyocardial ischemia in vivo was induced in rats by subcutaneous injection of isoproterenol （ISO）， and ex vivo ischemia was established by coronary artery ligation in isolated rat hearts. The effects of BCW， alcohol extracts and its polar extracts were evaluated on ST segment on electrocardiogram （ECG）， myocardial damage， hemodynamic parameters， and infarct size. The phosphorylation level of phosphatidylinositol 3-kinase （PI3K）， the expression of cuproptosis-related proteins， and the content of Cu²⁺ in myocardial tissue were detected. The regulatory relationship of the signaling pathway was verified using an oxygen-glucose deprivation （OGD） myocardial cell injury model， combined with PI3K agonists and inhibitors. ResultsBCW ameliorated ST-segment elevation on electrocardiograms（P＜0.01）， reduced serum levels of myocardial injury markers， improved hemodynamic parameters， upregulated PI3K phosphorylation（P＜0.01）， and decreased Cu²⁺ accumulation in rats with myocardial ischemia（P＜0.01）. Moreover， BCW reduced the myocardial infarct size. In the isolated rat heart model of ischemia， both the ethanol extract and various solvent fractions of BCW exerted protective effects and reduced Cu²⁺ content， among which the n-butanol fraction exhibited the most potent activity（P＜0.01）. Specifically， the n-butanol fraction upregulated PI3K phosphorylation（P＜0.01） and downregulated the expression of cuproptosis-related proteins， including ferredoxin reductase 1（FDX1）（P＜0.05）， lipoic acid synthetase（LIAS）， and dihydrolipoamide S-acetyltransferase（DLAT） oligomerization（P＜0.05）. In the OGD-induced cardiomyocyte injury model， treatment with a PI3K agonist inhibited DLAT oligomerization（P＜0.05）， whereas co-administration of a PI3K inhibitor attenuated the inhibitory effect of the n-butanol fraction on DLAT oligomer formation（P＜0.05）. ConclusionThe n-butanol fraction of BCW exerts a significant protective effect against myocardial ischemic injury， and its mechanism may involve activation of the PI3K and inhibition of cuproptosis.

ObjectiveTo investigate the protective effect and underlying mechanisms of the Bawei Chenxiang Wan （BCW） against myocardial ischemic injury. MethodsMyocardial ischemia in vivo was induced in rats by subcutaneous injection of isoproterenol （ISO）， and ex vivo ischemia was established by coronary artery ligation in isolated rat hearts. The effects of BCW， alcohol extracts and its polar extracts were evaluated on ST segment on electrocardiogram （ECG）， myocardial damage， hemodynamic parameters， and infarct size. The phosphorylation level of phosphatidylinositol 3-kinase （PI3K）， the expression of cuproptosis-related proteins， and the content of Cu²⁺ in myocardial tissue were detected. The regulatory relationship of the signaling pathway was verified using an oxygen-glucose deprivation （OGD） myocardial cell injury model， combined with PI3K agonists and inhibitors. ResultsBCW ameliorated ST-segment elevation on electrocardiograms（P＜0.01）， reduced serum levels of myocardial injury markers， improved hemodynamic parameters， upregulated PI3K phosphorylation（P＜0.01）， and decreased Cu²⁺ accumulation in rats with myocardial ischemia（P＜0.01）. Moreover， BCW reduced the myocardial infarct size. In the isolated rat heart model of ischemia， both the ethanol extract and various solvent fractions of BCW exerted protective effects and reduced Cu²⁺ content， among which the n-butanol fraction exhibited the most potent activity（P＜0.01）. Specifically， the n-butanol fraction upregulated PI3K phosphorylation（P＜0.01） and downregulated the expression of cuproptosis-related proteins， including ferredoxin reductase 1（FDX1）（P＜0.05）， lipoic acid synthetase（LIAS）， and dihydrolipoamide S-acetyltransferase（DLAT） oligomerization（P＜0.05）. In the OGD-induced cardiomyocyte injury model， treatment with a PI3K agonist inhibited DLAT oligomerization（P＜0.05）， whereas co-administration of a PI3K inhibitor attenuated the inhibitory effect of the n-butanol fraction on DLAT oligomer formation（P＜0.05）. ConclusionThe n-butanol fraction of BCW exerts a significant protective effect against myocardial ischemic injury， and its mechanism may involve activation of the PI3K and inhibition of cuproptosis.

ObjectiveTo explore the effects of the Tibetan medicine Sanwei Doukoutang （SWDK） on cognitive dysfunction in mice suffering from Alzheimer's disease （AD） and its related mechanism. MethodsFifty SPF 5 × FAD mice were randomly divided into model group， total ginsenoside group（0.04 g·kg^-1）， high-， medium-， and low-dose groups of SWDK （32.60， 16.30， 8.15 g·kg^-1）， with 10 mice in each group， and ten wild-type mice of the same age were used as the normal group， male and female in 1∶1. Gavage administration was performed once daily for 8 weeks. The Morris water maze test and contextual fear memory experiment were used to observe learning and memory function. Hematoxylin-eosin （HE） staining was utilized to observe the changes in the pathomorphology of brain tissue in mice. The levels of synaptophysin （SYP） and postsynaptic dense substance 95 （PSD95） in mice serum were detected by enzyme-linked immunosorbent assay （ELISA）. The positive expression of brain-derived neurotrophic factor（BDNF） in the dentate gyrus （DG） region of mouse brain tissue was observed by immunohistochemistry （IHC）. The protein levels of BDNF， Wnt family member 3A（Wnt3a）， and β-catenin were detected in the hippocampus of mice by Western blot. ResultsCompared with the normal group of mice， the model group of mice had significantly more complex swimming routes and lower swimming speed （P<0.01）， significantly lower percentage of time spent in the target quadrant （P<0.01）， and a significantly lower percentage of freezing time （P<0.05）. The number of neurons in the hippocampal region of mice was obviously reduced and unevenly arranged. The levels of SYP and PSD95（P<0.01） in the serum of mice were reduced， and the positive expression of BDNF in the DG region of the brain tissue of mice was reduced. The levels of hippocampal BDNF， Wnt3a， and β-catenin proteins in the hippocampus of mice were obviously reduced （P<0.05， P<0.01）. Compared with the model group， the mice in the SWDK group and the total ginsenoside group had significantly shorter swimming routes， the high- and medium- dose SWDK groups significantly higher swimming speeds （P<0.01）， significantly higher percentage of time spent in the target quadrant （P<0.01）， obviously higher percentage of Freezing time （P<0.05）， and obviously more neurons in the hippocampal region of the mice with tighter arrangement. The mice had elevated levels of serum SYP （P<0.05， P<0.01）， PSD95 （P<0.01）， increased BDNF-positive cells in the DG region of brain tissue， and obviously elevated levels of BDNF， Wnt3a， and β-catenin proteins in the hippocampus of mice （P<0.05， P<0.01）. ConclusionSWDK can significantly improve the cognitive dysfunction of AD mice， and its mechanism may be related to regulating the Wnt/β-catenin signaling pathway， which promotes BDNF expression and thereby enhances synaptic plasticity， allowing neuronal signaling to be restored.