ObjectiveTo investigate the change in the activity of hepatitis B virus （HBV）-specific CD8⁺ T cells after pegylated interferon-α-2b （PEG-IFN-α-2b） therapy in HBeAg-negative patients with chronic HBV infection. MethodsA total of 53 HBeAg-negative patients with chronic HBV infection who attended The First Affiliated Hospital of Xinxiang Medical University and Tangdu Hospital of Air Force Mdical University from April 2020 to June 2022 were enrolled and treated with PEG-IFN-α-2b （180 μg/week， subcutaneous injection） antiviral therapy. The study endpoint was HBsAg clearance （course of treatment<48 weeks） or 48 weeks （course of treatment≥48 weeks）. Peripheral blood mononuclear cells were isolated at baseline and study endpoint， and peripheral blood T cell counts were measured. Enzyme-linked immunospot assay was used to measure the frequency of HBV-specific CD8⁺ T cells secreting perforin， granzyme B， and interferon-γ. A total of 17 HLA-A^*02-restricted patients were selected， and CD8⁺ T cells were purified to establish direct- and indirect-contact co-culture systems for HBV-specific CD8⁺ T cells and HepG2.2.15 cells. The level of lactate dehydrogenase in supernatant was measured to calculate the mortality rate of HepG2.2.15 cells， and the levels of HBV DNA， cytotoxic molecules， and cytokines in supernatant were also measured. Flow cytometry was used to measure the expression of apoptosis ligands， and the cytotoxicity of HBV-specific CD8⁺ T cells was evaluated. The independent samples t-test or the paired t-test was used for comparison of normally distributed continuous data between two groups， and the Mann-Whitney U test or the Wilcoxon rank-sum test was used for comparison of non-normally distributed continuous data between two groups. ResultsThe HBsAg clearance rate at study endpoint was 30.19% （16/53）. There were no significant differences in peripheral blood T cell counts （CD3⁺， CD4⁺， and CD8⁺ T cells） between baseline and study endpoint （P>0.05）. At study endpoint， there was a significant increase in the frequency of HBV-specific CD8⁺ T cells secreting perforin， granzyme B， and interferon-γ （U=177.50， t=11.90， U=186.50， all P<0.001）， and the patients with HBsAg clearance had a significantly higher frequency of such HBV-specific CD8⁺ T cells than those without HBsAg clearance （U=120.50， t=2.73， U=121.50， all P<0.01）. In the direct- and indirect-contact co-culture systems at study endpoint， HBV-specific CD8⁺ T cells induced a significant reduction in HBV DNA in the supernatant of HepG2.2.15 cells （all P<0.001） and significant increases in the secretion of interferon-γ and tumor necrosis factor-α （all P<0.05）； in the direct-contact co-culture system， HBV-specific CD8⁺ T cells induced significant increases in the mortality rate of HepG2.2.15 cells （13.62%±3.27% vs 11.39%±2.40%， t=2.27， P=0.030） and the secretion of perforin and granzyme B （t=72.50， U=52.50， both P<0.05）. In the direct- and indirect-contact co-culture systems， compared with HBV-specific CD8⁺ T cells from the patients without HBsAg clearance， the HBV-specific CD8⁺ T cells from patients with HBsAg clearance had a significantly greater reduction in HBV DNA （P<0.05） and significant increases in the secretion of interferon-γ and tumor necrosis factor-α （P<0.05）. ConclusionPEG-IFN-‍α‍-2b therapy can help to achieve a relatively high HBsAg clearance rate in HBeAg-negative patients with chronic HBV infection， and the activity of HBV-specific CD8⁺ T cells is significantly enhanced， which is closely associated with HBsAg clearance.

OBJECTIVE To analyze and identify the metabolites of pirtobrutinib （PTN） in rats， and clarify the possible metabolic pathways of PTN in rats. METHODS Six rats were intragastrically administered with 10 mg/kg PTN suspension. Blood samples were collected from the rats 30 minutes before administration and at 0.25， 0.5， 1， 2， 4， 6， 8， 12， 24 hours after administration. Urine and feces samples were collected 12 hours before administration and 24 hours after administration. UHPLC- Orbitrap Exploris 240 system combined with Compound Discoverer 3.0 and Xcalibur 2.0 software were adopted for structural identification and metabolic pathway analysis of PTN metabolites in rat plasma， urine， and feces. RESULTS A total of 29 PTN metabolites were identified， including 17， 19 and 22 metabolites in plasma， urine and feces， respectively. The metabolic pathways of PTN mainly included oxidation， sulfation， glucuronidation， etc.， and its metabolites were mostly combination products of two or more different metabolic forms. In detail， a total of 26 metabolites were associated with phase Ⅰ metabolic reactions （14 oxidation metabolites， 9 reduction/dehydrogenation metabolites， 8 demethylation metabolites， and 5 hydrolysis metabolites）. Meanwhile， a total of 20 products were involved in phase Ⅱ metabolites （14 sulfation metabolites and 8 glucuronic acid binding metabolites）. CONCLUSIONS PTN exhibits a diverse range of metabolites in rat fecal samples， with the primary metabolic pathways being oxidation， sulfation， glucuronidation， and others.

AIM: To investigate the mechanism of Hexue Mingmu Tablets(HXMMT)in improving diabetic retinopathy(DR)based on transcriptomics.METHODS: Zebrafish DR models were established by 3-day glucose induction(130 mmol/L)starting at 3 days post-fertilization(dpf). Larvae were randomized into four groups: control group(CG; aquaculture water), model group(MG; 130 mmol/L glucose), low-dose HXMMT treatment group(L-HX; 130 mmol/L glucose +7.5 mg/L HXMMT), and high-dose HXMMT treatment group(H-HX; 130 mmol/L glucose +75 mg/L HXMMT), with a 3-day intervention period until 6 dpf. The area and length of eyes, and body length of zebrafish were observed by stereomicroscopy, retinal morphology was observed by hematoxylin-eosin staining(HE), and retinal vessel diameter was observed under fluorescence microscope. Differentially expressed genes(DEGs)were identified by RNA-sequencing(RNA-seq)technology to further elucidate the molecular mechanism of HXMMT in improving DR in zebrafish, and the sequencing accuracy was validated through quantitative real-time polymerase chain reaction(qRT-PCR).RESULTS: HE staining demonstrated that the intervention with HXMMT significantly improved the disordered cell arrangement, widened gaps, and thickened inner nuclear layer(INL)in ganglion cell layer GCL); retinal vascular diameter quantification revealed that the retinal vessel diameter of the MG significantly increased compared with the CG, and it was significantly changed after the intervention of HXMMT, with significant efficacy in the H-HX(P<0.05); transcriptomics profiling identified 1 470 reversed DEGs, predominantly enriched in the AMPK signaling pathway, FoxO signaling pathway, retinal developmental processes, and tight junction regulation. Technical validation confirmed strong correlation between qRT-PCR and RNA-seq data(R2=0.8571, P<0.05).CONCLUSION: HXMMT may improve retinal vascular microcirculation disorders in DR by regulating core targets including vsx1, pde6c, arr3a, plk1, fbp1b, foxo1a, pcna, and cdk1, as well as synergistically modulating processes such as retinal development in camera-type eyes, visual perception, microtubule cytoskeletal organization, tight junctions, and the AMPK signaling pathway, Foxo signaling pathway.

OBJECTIVE To identify core genes associated with the treatment of coronary heart disease （CHD） with Tongmai yangxin pills， and predict their potential immunological and metabolic mechanisms. METHODS Mendelian randomization （MR） analysis was conducted using protein quantitative trait loci （pQTL） data from the UK Biobank and Icelandic，and data from genome- wide association study to screen core genes related to Tongmai yangxin pills in the treatment of CHD. Gene expression changes were further validated using transcriptomic sequencing data. Mediation analyses of immune cells and plasma metabolites were subsequently performed to explore the downstream regulatory networks of these core genes. RESULTS A total of 62 positive pQTL genes showed significant causal associations with CHD. MR analysis combined with transcriptomic sequencing validation identified three core genes FAM3D，OXT， and ENPP5-associated with Tongmai yangxin pills in the treatment of CHD. The transcriptomic sequencing results showed that after treatment with Tongmai yangxin pills， the expression levels of FAM3D and OXT were significantly reduced （P＜0.01）， while the expression level of ENPP5 was significantly increased （P＜0.05）. Mediation analyses between immune cells and plasma metabolites indicated that these genes may positively or negatively regulate CHD through immune pathways involving regulatory T cells and myeloid dendritic cells expressing CD11c and CD62L， as well as through metabolic pathways related to lipid and fatty acid metabolism， cholesterol metabolism， and bile acid metabolism. CONCLUSIONS This study identified FAM3D，OXT， and ENPP5 as core genes associated with the treatment of CHD by Tongmai yangxin pills， which may exert therapeutic effects via modulation of immune cells and plasma metabolic pathways involving fatty acids and bile acids.

Objective To establish the drug use evaluation(DUE)standard of bivalirudin for injection,and to evaluate the use of the drug by weighted TOPSIS method,so as to provide a reference for rational use of bivalirudin.Methods Based on the package insert,clinical guidelines and consensus of experts of bivalirudin,the DUE standards were developed,and the weighted TOPSIS method was used to evaluate the rationality of the discharge medical records of Shanxi Bethune Hospital from January 1st to June 30th in 2022.Results Incorporating 108 medical records involving the use of bivalirudin for injection,88 cases(81.48％)exhibited a high degree of adherence(Ci≥0.8)between the prescribed drug regimens and the optimal recommendations,which is considered reasonable.Additionally,19 cases(17.59％)fell within the range of 0.6＜Ci＜0.8,indicating a generally reasonable adherence.Only one case(0.93％)had a Ci＜0.6,suggesting an unreasonable level of adherence.The irrational situations about various evaluation indicators in the DUE were mainly manifested in the inappropriate dosages of administration(12.04％),inappropriate disposal of adverse reactions(11.11％),using medicine with contraindications(3.70％),using medicine without indication(1.85％),inappropriate monitoring of adverse reactions(0.93％),etc.Conclusion The established DUE standards for bivalirudin are intuitive and comprehensive,and the evaluation results show that there are some unreasonable situations in the use of bivalirudin in the hospital,and it is necessary to standardize the use of bivalirudin in terms of dosages,disposal of adverse reactions,indication and contraindication.

Objective To establish the drug use evaluation(DUE)criteria for bemiparin sodium injection,and evaluate the use of bemiparin sodium injection by weight technique for order prefer by similarity to ideal solution(TOPSIS),and to provide reference for improving the rational use of bemiparin sodium injection.Methods Based on the instructions of bemiparin sodium injection,and referring to relevant guidelines and literatures,the DUE criteria of bemiparin sodium injection was established by expert consultation.The weighted TOPSIS method was used to evaluate the rationality medication in the cases of inpatients who use bemiparin sodium injection from June to July 2021 in the Tongji Hospital of Tongji University.Results In the established DUE criteria of bemiparin sodium injection,the top two relative weight coefficients of ten secondary indicators were contraindications and adverse reaction disposal,and the bottom two were administration methods and indications.A total of 100 medical records were including.There was not a case close to the optimal regimen(Ci≥0.8)(reasonable);Ci was between 0.6 and 0.8(basically reasonable)in 83 cases(83.00％);and Ci＜0.6(unreasonable)in 17 cases(17.00％).The unreasonable uses of bemiparin sodium injection mainly appeared in off-lable uses of indications and the dosing method,a potential drug-drug interaction,inappropriate dosage,and violation of drug contraindications.Conclusion The drug use evaluation method of bemiparin sodium injection based on weighted TOPSIS method can synthesize multiple evaluation indexes,and the evaluation results are objective and reliable.The results showed that most clinical application of bemiparin sodium injection in this hospital was basically reasonable,but to provide basis for rational clinical drug use and to ensure patients'medication safety,it is necessary to accelerate the off-label evidence-based evaluation process and strengthen the management of rational drug use.

Objective:To analyze the early predictive value of olfactory function for cognitive decline in older adults with mild cognitive impairment (MCI) .Methods:From March 2023 to January 2024, convenience sampling was used to select 385 older adults with MCI from two community health service centers in Dongcheng District and Fengtai District of Beijing as participants. Participants were followed up for six months to collect data on general information, olfactory function testing, and cognitive function. According to whether there were changes in clinical cognitive function, older adults were divided into a cognitive function decline group and a cognitive function non-decline group. Binary Logistic regression was used to analyze the independent influencing factors of cognitive decline in older adults with MCI, and the receiver operating characteristic (ROC) curve was used to evaluate the predictive effect of olfactory function on cognitive decline.Results:Among 385 older adults with MCI, 113 (29.4%) experienced cognitive decline. Binary Logistic regression analysis showed that education level, passive cognition activity, social activity, and olfactory dysfunction were independent influencing factors for cognitive decline in older adults with MCI ( P<0.05). The area under the ROC curve was 0.819 [95% CI (0.773, 0.865), P<0.01], with an optimal cutoff value of 9.5 points, a sensitivity of 81.3% and specificity of 31.0%. Conclusions:The olfactory function has good predictive value for cognitive decline in older adults with MCI, and can be used for early screening of MCI high-risk individuals with rapid cognitive decline.

Objective: The aging demographic landscape worldwide portends a heightened prevalence of neurodegenerative disorders. Foremost among these is Alzheimer’s disease (AD), the foremost cause of dementia in older adults. The shortage of efficacious therapies and early diagnostic indicators underscores the imperative to identify non-invasive biomarkers for early detection and disease monitoring. Recently, blood metabolites have emerged as promising candidates for AD biomarkers. Methods: Leveraging nuclear magnetic resonance (NMR) spectroscopy on plasma specimens, we conducted a cross-sectional study encompassing 35 AD patients and 35 age-matched healthy controls. Cognitive function was evaluated using the mini-mental state examination in all participants, followed by peripheral blood sample collection. We utilized univariate and multivariate analyses to perform targeted lipidomic profiling via NMR spectroscopy. Results: Our study revealed significant differences in the expression profiles of low-density lipoprotein-associated subfractions in females and high-density lipoprotein-associated subfractions in males between AD patients and healthy controls (all p<0.05). However, there was no significant metabolite overlap between males and females. Furthermore, receiver operating characteristic curve analysis demonstrated that the combination of lipid metabolites had good diagnostic values (all area under the curve>0.70; p<0.05). Conclusion Our findings suggest that the blood plasma samples using NMR hold promise in distinguishing between AD patients and healthy controls, with significant clinical implications for advancing AD diagnostic methodologies.

Objective To explore and implement a differentiated management strategy for multi-campus hospitals to improve patient experience and satisfaction,and achieve the goal of homogenized management.Methods In December 2021,the Picker Patient Experience Questionnaire was used to survey the patient experience at 3 campuses of a tertiary A hospital in Hangzhou,and the reasons for the differences were analyzed.Based on policy document reviews,special group discussions,and expert meetings,differentiated management strategy for multi-campus hospitals was formulated.The patient experience and satisfaction before(December 2021)and after(December 2023)the implementation were compared.Results After the application of the one-hospital multi-campus difference management strategy,the overall medical experience score of the patients in the 3 campus was(58.54±2.36)points,which was higher than(58.13±3.24)points before the application(t=-3.223,P=0.001),and there was no statistically significant differences among the patients in the 3 campuses(F=0.781,P=0.458).After the application of the management strategy,the overall satisfaction score of the patients in the 3 campus was(98.44±6.22)points,which was higher than(97.98±6.87)points before the application of the management strategy(t=-2.490,P=0.013),and there was no statistical significance among the patients in the 3 campus(F=1.128,P=0.324).The number of banners and letters of commendation received by the 3 campuses increased from 1 661 before the application to 2 190 after the application,with a growth rate of 31.85％.Conclusion Differentiated management in a multi-campus hospital,aiming at homogenized quality through differentiated strategies,is practicable and can significantly improve the patient experience and satisfaction across different campuses.

Objective:To evaluate the safety and efficacy of the domestic robotic surgical system for general surgery.Methods:A prospective single-center, single-arm exploratory study was conducted at Gansu Provincial People's Hospital from Jun 2022 to Oct 2023, enrolling 54 patients undergoing general surgery using domestically produced Toumai? Endoscopic Surgical Robotic System. The primary study endpoint was surgical success rate, and the secondary study endpoints were intraoperative bleeding, operative time, complications, system performance, hospitalization days.Results:In this study, robotic surgery was successfully completed in 52 patients, and in 2 patients undergoing thyroid operation it was converted to open surgery due to bleeding, with a success rate of 96%, no organ injury or death during surgery, and no system failure. The types of surgery included cholecystectomy, radical gastric cancer resection, radical colorectal cancer resection, inguinal hernia repair, partial hepatectomy, total thyroidectomy and choledocho-jejunal anastomosis.Conclusion:The study provides preliminary evidence of the safety and efficacy of the Toumai? Endoscopic Surgical Robotic System for the treatment of general surgical diseases.