BACKGROUND:Several observational studies have found a strong association between thyroid function and its related disorders and osteoporosis,but the causal relationship is unclear.OBJECTIVE:To ascertain the causal relationship between genetically predicted thyroid function and its associated disorders,as well as osteoporosis,through the Mendelian randomization analysis with extensive pooled genetic data.METHODS:Pooled data from genome-wide association studies were employed to investigate the causal relationship between thyroid function and its associated disorders and osteoporosis.This was achieved through the utilization of the inverse variance weighting method as the primary Mendelian randomization analysis method,in conjunction with the MR-Egger method,weighted median method,simple model method,and weighted model method.A two-step mediated Mendelian randomization analysis was used to calculate the mediating effect of drug-mediated thyroid dysfunction on osteoporosis and the mediating proportion.Subsequently,sensitivity analyses were conducted using the MR-Egger intercept test and MR-PRESSO to detect multiplicity,Cochran's Q test to detect heterogeneity,and leave-one-out to perform sensitivity analyses.RESULTS AND CONCLUSION:(1)The results of the inverse variance weighting method showed that thyroid function had an effect on bone mineral density,and that thyrotropin,free triiodothyronine on bone mineral density,free thyroxine,and subclinical hyperthyroidism all had a causal effect on bone mineral density.(2)In addition,mediation analyses revealed a potential mediating effect of carbimazole in the causal relationship between hyperthyroidism and the risk of developing osteoporosis,as well as a potential mediating effect of levothyroxine sodium in the causal relationship between hypothyroidism and the risk of developing osteoporosis.(3)In conclusion,thyrotropin,which is high in the normal range,has been demonstrated to increase bone mineral density.Conversely,free triiodothyronine and free thyroxine,which are also high within the normal range,as well as subclinical hyperthyroidism,have been shown to decrease bone mineral density.The risk of developing osteoporosis is partially mediated by the pathway of taking the therapeutic medication in the context of pharmacologic treatment of thyroid dysfunction.(4)The present study primarily focuses on European population data.However,given the commonality of the genetic background and the generalizability of genome-wide data analysis methods,it is of significant importance to explore the pathogenesis of osteoporosis in the Chinese population,develop effective interventions,and provide genetic counseling.

Objective: To evaluate the implementation process of a school-family collaborative "online+offline" tobacco control intervention program in junior high school in Beijing and to explore the execution status, influencing factors and sustainability potential of the intervention, so as to provide evidence for optimizing youth tobacco control strategies. Methods: In November 2024, using the random number table method, four first year junior high school classes were selected from three schools each in Fengtai District, Tongzhou District, and Fangshan District of Beijing. One class served as the control group, while the other three classes were designated as intervention groups (one each for online intervention, offline intervention, and combined online offline intervention). The control group received only conventional education.The online intervention group was engaged in WeChat push interventions, including watching micro videos, viewing promotional materials, participating in online quizzes and mini games; the offline intervention group attended knowledge lectures, played peer games, and participated in offline knowledge competitions; the combined online offline intervention group integrated all the aforementioned online and offline intervention measures. The intervention period was from November 2024 to June 2025, spanning a total of 7 months. Based on the Practical, Robust Implementation and Sustainability Model(PRISM) framework, a qualitative research design was employed to conduct semi structured interviews with 48 participants (12 in each of the intervention groups and 12 organizational staff members) from the Centers for Disease Control and Prevention (CDC) in 3 districts and 3 sampled schools. The interview outlines were designed according to the intervention plan. Data was managed using Nvivo 12.0 software and analyzed following Colaizzi s seven step phenomenological analysis method. Theoretical saturation was assessed using a reserved subset of transcripts. Results: Four core themes were identified in the tobacco control intervention process. Overall fidelity of intervention implementation was largely consistent with the original plan, and students showed strong willingness and positive evaluations toward interactive formats such as knowledge contests and peer games, though occasional breakdowns in school-family communication and blurred boundaries between online and offline components were observed; the participants showed a polarized response in terms of satisfaction and participation, most students and parents recognized the significance of the activity, and some parents observed a reduction in smoking behavior; the implementation of internal tobacco control policies in the school was strict, and the atmosphere was favorable, but there was still room for improvement, such as the scarcity of community tobacco control activities and the difficulty in implementing smoke free units; implementation and sustainability infrastructure were preliminarily established, such as through homeroom teacher supervision and training student assistants to assisted in activities, while the sustainability support system required further refinement. Conclusion The school-family collaborative "online+offline" tobacco control intervention has demonstrated significant positive effects, but further optimization of activity design, enhancement of community reward mechanisms, and standardized training are required to improve the efficacy and sustainability of the intervention.

BACKGROUND:Several observational studies have found a strong association between thyroid function and its related disorders and osteoporosis,but the causal relationship is unclear.OBJECTIVE:To ascertain the causal relationship between genetically predicted thyroid function and its associated disorders,as well as osteoporosis,through the Mendelian randomization analysis with extensive pooled genetic data.METHODS:Pooled data from genome-wide association studies were employed to investigate the causal relationship between thyroid function and its associated disorders and osteoporosis.This was achieved through the utilization of the inverse variance weighting method as the primary Mendelian randomization analysis method,in conjunction with the MR-Egger method,weighted median method,simple model method,and weighted model method.A two-step mediated Mendelian randomization analysis was used to calculate the mediating effect of drug-mediated thyroid dysfunction on osteoporosis and the mediating proportion.Subsequently,sensitivity analyses were conducted using the MR-Egger intercept test and MR-PRESSO to detect multiplicity,Cochran's Q test to detect heterogeneity,and leave-one-out to perform sensitivity analyses.RESULTS AND CONCLUSION:(1)The results of the inverse variance weighting method showed that thyroid function had an effect on bone mineral density,and that thyrotropin,free triiodothyronine on bone mineral density,free thyroxine,and subclinical hyperthyroidism all had a causal effect on bone mineral density.(2)In addition,mediation analyses revealed a potential mediating effect of carbimazole in the causal relationship between hyperthyroidism and the risk of developing osteoporosis,as well as a potential mediating effect of levothyroxine sodium in the causal relationship between hypothyroidism and the risk of developing osteoporosis.(3)In conclusion,thyrotropin,which is high in the normal range,has been demonstrated to increase bone mineral density.Conversely,free triiodothyronine and free thyroxine,which are also high within the normal range,as well as subclinical hyperthyroidism,have been shown to decrease bone mineral density.The risk of developing osteoporosis is partially mediated by the pathway of taking the therapeutic medication in the context of pharmacologic treatment of thyroid dysfunction.(4)The present study primarily focuses on European population data.However,given the commonality of the genetic background and the generalizability of genome-wide data analysis methods,it is of significant importance to explore the pathogenesis of osteoporosis in the Chinese population,develop effective interventions,and provide genetic counseling.

Background/Aims: Lenvatinib resistance remains a critical barrier in advanced hepatocellular carcinoma (HCC) therapy. However, the underlying mechanisms and strategies for reversing resistance remain incompletely understood. Methods: Integrated transcriptomics of lenvatinib-resistant patient tumors and an acquired-resistance murine model identified a novel macrophage subpopulation. Functional validation employed CRISPR-SAM screening, conditioned medium (CM) assays, subcutaneous/orthotopic xenografts, patient-derived organoids (PDOs), and patient-derived xenografts (PDXs). Mechanistic studies included ChIP-qPCR, co-immunoprecipitation, and pharmacologic targeting. Clinical relevance was assessed in a retrospective cohort. Results: Resistant HCC exhibited significant enrichment of a COLEC12high TAM subset , which correlated with poor survival and treatment response. These TAMs secreted neuregulin-1 (NRG1) , activating HER2/HER3-AKT signaling in tumor cells to drive cancer stemness and lenvatinib resistance. Mechanistically, in TAMs COLEC12 sequestered STAT1 in the cytoplasm, preventing its phosphorylation, and thereby derepressing STAT3-mediated NRG1 transcription. Depletion of NRG1 reversed the stemness phenotypes and resensitized tumors to lenvatinib both in vitro and in vivo. Clinically, high NRG1 expression predicted an inferior lenvatinib response and shorter survival. Crucially, the bispecific anti-HER2/HER3 antibody zenocutuzumab restored lenvatinib efficacy in PDOs, PDXs, and murine models. Conclusions Our work establishes the COLEC12high TAM/NRG1 axis as a master regulator of therapeutic resistance and identifies NRG1 as a predictive biomarker, providing a clinically actionable strategy to overcome lenvatinib resistance in HCC.

Objective: To investigate the association between injury prevention knowledge level and injury occurrence among primary and secondary school students in Dongguan, so as to provide scientific basis for formulating targeted and evidence based intervention strategies for child injury. Methods: From March to April 2024, stratified cluster random sampling method was applied to select 5 988 primary and secondary school students in grades 4-9 for a survey. The Revised Questionnaire for the 2016-2020 Child Injury Prevention Project (senior version) was used to collect demographic characteristics, family and caregiver information, injury event characteristics, and knowledge, attitude, and practice related to injury prevention. Mann-Whitney U test was used for inter group comparison. Propensity score matching (PSM) was applied to balance confounders, and conditional Logistic regression was used to analyze the association between injury prevention knowledge score and injury occurrence among primary and secondary school students, and a restricted cubic spline (RCS) model was employed to test the dose response relationship. Furthermore, interaction terms were introduced to examine the moderating effects of sex, grade level, and caregiver’s educational level. Results: The overall incidence of injuries among primary and secondary school students was 18.15%. The knowledge score of injury prevention was significantly lower in the injury group [20.0(18.0,22.0)] than in the non injury group [21.0(19.0,22.0)] ( Z = 8.24 , P <0.01). After PSM, 1 068 pairs were successfully matched, and the standardized mean difference for all covariates was <0.1. An increase in injury prevention awareness scores was associated with a reduced risk of injury occurrence among primary and secondary school students ( OR =0.92, P <0.05). The RCS analysis showed an approximately linear negative association between injury prevention knowledge score and injury risk among primary and secondary school students ( P non linear =0.72), with a decreased injury risk when score exceeded 24 ( OR = 0.69, P <0.05). Subgroup analyses indicated that the negative correlation between cognitive level and the risk of injury was common in different gender, grade and caregivers educational level groups ( OR =0.87- 0.93 , all P <0.05). Sensitivity analyses yielded results consistent with the primary analysis. Conclusions The incidence of injuries among primary and secondary school students in Dongguan City is relatively high. Injury prevention knowledge level is negatively associated with injury occurrence risk, exhibiting an approximately linear dose response relationship.

Objective: To investigate the association between brain and muscle Arnt like protein 1( BMAL 1) gene and ambulatory blood pressure (ABP) parameters in college students, and to explore the influence of the interaction between the gene and weight status on the ABP levels, so as to provide reference for early prevention of chronic cardiovascular diseases related to hypertension. Methods: During September 2022 to June 2024, a total of 510 college students were recruited from a university in Changsha, China for on site questionnaire investigation, physical examination, ABP monitoring and genotyping testing. Multiple linear regression method was used to explore the association between the BMAL 1 gene and ABP indicators. An interaction term was included in the general linear model of multiple linear regression to analyze the interactive effects of BMAL 1 gene polymorphisms and weight status on ABP levels. Results: The prevalence of abnormal 24 hour blood pressure, abnormal daytime blood pressure, and abnormal nighttime blood pressure were 3.3%, 3.1%, and 3.9%, respectively. Multiple linear regression analysis showed that the BMAL 1/rs7950226 polymorphism was positively correlated with the 24 hour diastolic blood pressure(DBP) and the daytime DBP level after adjusting for gender, age, and body mass index( β =0.87,0.99, both P <0.05). Also, interaction between BMAL 1/ rs 11022775 and weight status on the nighttime DBP level ( P interaction =0.03) was found. The CC genotype carriers had significantly higher nighttime DBP level ( β =3.52, P <0.05) among overweight/obesity college students, but no differences in nocturnal DBP levels were observed between CC genotype carriers and TT+CT genotype carriers among college students with normal body weight( P > 0.05). Conclusions The rs 7950226 polymorphism is associated with 24 hours DBP and daytime DBP levels. Significant interaction between rs 11022775 with weight status on the nighttime DBP level is found among college students.

Objective:To construct a smart elderly education system that in line with the current situation under the Healthy China strategy and explore the constraints on its institutional implementation,in order to provide a basis for scientifically evaluating the implementation effect of this system.Methods:A questionnaire survey was conducted on 34 experts in related fields.The analytic hierarchy process(AHP)was used to perform quantitative and qualitative analyses on the construction of the smart elderly education system,and the weights of the importance of each scheme were obtained.Results:The constructed model of the smart elderly education system included 5 first-level indicators and 15 second-level indicators.Calculations of the judgment matrix for the 5 first-level indicators showed that the maximum eigenvalue(λmax)=5.071 4,the random consistency index(RI)=1.12,the consistency index(CI)=0.017 8,and the consistency ratio(CR)=0.015 9.With CR＜0.1,the result met the consistency requirement.For the second-level indicators under each first-level indicator,pairwise comparison judgment matrices were constructed.The CR values of all 5 judgment matrices were＜0.1.In summary,all judgment matrices passed the consistency test and were applicable.Among the first-level indicators,the top three by weights were guarantee mechanisms,demand orientation,and implementation effectiveness.Among the second-level indicators,the top three by combined weights were funding support capacity,health literacy improvement rate,and health demand identification mechanism.Conclusions:The indicator evaluation system for the smart elderly education system constructed based on AHP includes core dimensions such as guarantee mechanisms and demand orientation,responding to the key issues of institutional implementation.The selected indicators are both objective and practical,and can serve as reference tools for actual evaluation.

Epilepsy is a chronic neurological disorder caused by an imbalance between excitation and inhibition in the central nervous system.Recently,the role of the orexin system in the pathogenesis of epilepsy has garnered significant attention.Orex-in primarily regulates arousal states and enhances neuronal excit-ability through activation of OX1-R/OX2-R receptors.Studies have shown that elevated orexin levels lower the seizure thresh-old,while orexin receptor antagonists(ORAs)exhibit potential antiepileptic effects.ORAs suppress epileptiform discharges by reducing glutamate release,enhancing GABAergic inhibitory effects,and modulating the thalamocortical circuit.Animal ex-periments and preliminary clinical studies demonstrate that OX1R antagonists decrease excitatory synaptic transmission,whereas OX2 R antagonists primarily strengthen GABA-mediated inhibition.With the widespread application of ORAs in sleep disorders,exploring their clinical value as antiepileptic drugs will become a key focus for future research.This review summa-rizes the role of the orexin system in epileptogenesis and discus-ses the research progress and future directions of ORAs as poten-tial antiepileptic agents.

Objective To investigate the mortality and risk factors of HIV-infected patients complicated with progressive multifocal leukoencephalopathy(PML)to inform the outcomes of these patients.Methods The clinical data of people living with HIV related PML who were treated at Chongqing Public Health Medical Treatment Center from January 1,2019 to December 31,2023 were retrospectively analyzed.Kaplan-Meier method was used for survival analysis.Log-rank test was performed.Cox regression model was used for multivariate analysis.Results A total of 42 people living with HIV related PML were enrolled,including 34 males(81.0％).The median age was 44.5(36.3,51.0)years.PML was confirmed in 76.2％(32/42)of patients,and possible PML was diagnosed in 23.8％(10/42)of patients.The median time to diagnosis was 32.5(14.8,58.3)days.The median CD4+T cell count was 69.0(39.8,112.0)cells/μL.The median HIV viral load was 5.05(2.62,5.77)log10 copies/mL.The overall mortality rate was 54.8％(23/42)for patients with HIV related PML.CD4+T cell count ≤50 cells/μL and initial modified Rankin scale(mRS)score ≥4 points were independent risk factors for the overall mortality of people living with HIV related PML(P＜0.05).Conclusions People living with HIV related PML have a high mortality rate.Low CD4+T cell count and high initial mRS score were independent risk factors for the mortality of patients with HIV related PML.Currently,no definitive and effective drug treatment is available for PML.Early detection,diagnosis and initiation of antiretroviral therapy may improve the outcomes of patients.

Objective To explore the gender distribution of adverse drug event(ADE)signals of proprotein convertase subtilisin/kexin type 9(PCSK9)inhibitors(alirocumab,evolocumab and inclisiran),and to provide reference for individualized safe medication in different genders.Methods The reports of the drugs mentioned above from the first quarter of 2022 to the first quarter of 2024 were extracted from the U.S.Food and Drug Administration Adverse Events Reporting System(FAERS)database.The reporting odds ratio(ROR)method and composite criteria method from Medicines and Healthcare Products Regulatory Agency were used to mine and analyse the signals.Results All 3 PCSK9 inhibitors had more reported cases of ADE in women than in men,and a greater proportion of elderly patients in women relative to men.Signal testing revealed that men were more likely to have injection sites-related ADEs with alirocumab,and muscle-related ADEs and elevated lipoprotein a with inclisiran.While for women,using alirocumab or evolocumab was more likely to cause cardiovascular adverse events,and using inclisiran was more likely to cause a decrease in low-density lipoprotein or in triglycerides.Conclusion There are gender-specific differences in the ADE signals of PCSK9 inhibitors.Clinical use can refer to the signals of high-risk ADEs that may occur after drug use by different genders,targeting the identification of adverse drug events and exploring the possibility of gender-individualized treatment.