OBJECTIVE To identify and analyze adverse drug event （ADE） signals associated with tirzepatide based on the FDA Adverse Event Reporting System （FAERS） database， providing a reference for clinical medication safety. METHODS ADE reports from January 1， 2022， to June 30， 2024， with tirzepatide as the primary suspected drug， were extracted from the FAERS database. Medical Dictionary for Regulatory Activities was used to systematically categorize the selected system organ class （SOC） and preferred term of ADE. Signal mining and analysis were performed using the reporting odds ratio method and the proportional reporting ratio method. RESULTS A total of 39 229 ADE reports related to tirzepatide were obtained， including 3 934 severe ADE reports （10.03%）. The majority of severe ADE reports were related to hospitalization or prolonged hospitalization （3.82%）， involving 131 positive ADE signals. Among the reports with documented patient gender and age， 26 195 were female （66.77%）， 7 869 were male （20.06%）， and the majority of patients were aged 18-64 years （54.26%）. The top three most frequently reported ADE were injection site pain， nausea， and injection site hemorrhage. Strong ADE signals not mentioned in the tirzepatide instruction included injection site coldness， starvation ketoacidosis， injection site hemorrhage， hunger， elevated adrenaline， injection site skin cracking， binge eating， skin laxity， intestinal sepsis， lack of satiety， and dysesthesia. Subgroup analysis for patient’s gender and age showed differences in the proportion of ADE reports across different SOC. Male patients or those aged≥65 years had a higher risk of gastrointestinal system disorders compared to female patients or those aged ＜65 years. CONCLUSIONS In clinical use of tirzepatide， in addition to monitoring ADE listed in the instruction， attention should also be paid to ADE not mentioned in the instruction， such as injection site coldness， starvation ketoacidosis， injection site hemorrhage， elevated adrenaline， and intestinal sepsis， to ensure patient safety.

OBJECTIVE To evaluate the cost-effectiveness of ripretinib versus sunitinib as a second-line treatment option for patients with advanced gastrointestinal stromal tumors （GIST）. METHODS Based on the data of INTRIGUE study， a dynamic Markov model was constructed， with a cycle of 6 weeks； this model was used to simulate patients’ direct medical costs and quality- adjusted life years （QALYs） over 15 years. Using the incremental cost-effectiveness ratio （ICER） as the evaluation metric， a comparison was made between the ICER and the willingness-to-pay （WTP） threshold （3 times the per capita gross domestic product， which amounts to 268 200 yuan/QALY）. One-way sensitivity analyses and probabilistic sensitivity analyses were performed on the model outputs to examine the stability of the model. RESULTS The health benefits of ripretinib were lower than those of sunitinib （1.21 QALYs vs. 1.31 QALYs）. Still， the costs were higher （323 401.88 yuan vs. 227 532.40 yuan）， making it an inferior regimen. The results of the one-way sensitivity analysis suggested that the cost of ripretinib and sunitinib， and the health utility value in progression-free survival status had a greater impact on the ICER of the model. Probabilistic sensitivity analysis suggested that the results of the study were stable， and the probability of the cost-effectiveness advantage of ripretinib was always much lower than that of sunitinib with the increase of WTP threshold， and showed a decreasing trend. CONCLUSIONS In the current economic context of China， ripretinib does not have a cost-effectiveness advantage over sunitinib as a second-line treatment for advanced GIST.

Objective To investigate whether ginsenoside Rh1(G-Rh1)can alleviate liver fibrosis induced by a choline-deficient,L-amino acid-defined,high-fat diet(CDAHFD)and to explore its underlying mechanisms.Methods Male C57BL/6J mice were randomly divided into 6 groups(n=8 in each group),including a standard diet group(or the control group),a high-fat diet group(or the CDAHFD group),a silymarin group(given silymarin at 5 mg/kg),a low-dose G-Rh1 group(given G-Rh1at 5 mg/kg),a medium-dose G-Rh1 group(given G-Rh1at 10 mg/kg),and a high-dose G-Rh1 group(given G-Rh1 at 20 mg/kg).The control group was given a standard feed,while the other groups were fed CDAHFD for 7 weeks to establish the mouse model of liver fibrosis.Starting from the first week,the mice in the treatment groups were administered the corresponding drugs by intragastric gavage once daily for 7 weeks in succession.After the administration of the final drug treatment,the body mass and organ mass of the mice in different groups were measured,and the organ index was obtained according.Liver tissues were examined using HE staining,Sirius red staining,and immunohistochemistry(IHC)staining.Western blot was performed to measure α-smooth muscle actin(α-SMA)and transforming growth factor-β1(TGF-β1),two liver fibrosis-related proteins,and fibroblast growth factor 12(FGF-12),a pathway-related protein.The serum biochemical indicators,including aspartate transferase(AST),alanine aminotransferase(ALT),total bilirubin(TBIL),and direct bilirubin(DBIL),were measured.Additionally,RAW246.7 cells were randomly divided into 5 groups,including a control group,a lipopolysaccharide(LPS)group,and 3 G-Rh1 treatment groups.The control group had only RAW246.7 cells in the culture medium.The other groups were given LPS(500 ng/mL),and the 3 treatment groups received G-Rh1 at 10,20,and 40 μmol/L in addition.The supernatants from the 5 groups of RAW246.7 cells were collected and cocultured with HSC-T6 cells for 24 hours to observe and compare the effects of G-Rh1 and LPS on the expression of fibrosis-related proteins,including α-SMA,Col1a1,etc,in HSC-T6 cells and on the expression of fibrotic signaling pathway-related proteins,including fibroblast growth factor 12(FGF-12)and signal transducer and activator of transcription 3(STAT3)/phosphorylated STAT3(p-STAT3),in RAW264.7 cells.Flow cytometry was conducted to analyze the phenotypes of RAW246.7 cells,and ELISA was performed to measure fibrosis-related factors,including monocyte chemoattractant protein-1(MCP-1)and transforming growth factor-β(TGF-β).Results Compared with the control mice,the mice in the CDAHFD group exhibited obvious liver fibrosis.Compared with CDAHFD mice,mice in the G-Rh1 treatment groups all showed alleviation of liver fibrosis of was alleviated to some extent in a dose-dependent manner,and the improvement effect was superior to that of silymarin,a reference drug.G-Rh1 also alleviated CDAHFD-induced body mass loss(P＜0.01),reduced the liver index(P＜0.01),and significantly decreased the serum levels of AST,ALT,DBIL,and TBIL(P＜0.0001).Significant differences in the protein expression ofα-SMA,TGF-β1,and FGF-12 in the liver were observed(P＜0.01).Compared with the LPS group,the LPS+G-Rh,groups exhibited significant differences in the expression of FGF-12 and p-STAT3/STAT3 in RAW246.7 cells,and α-SMA and Col1a1 in HSC-T6 cells(P＜0.001).In the LPS+G-Rh,groups(the 20 μmol/L and 40 μmol/L treatment groups),the conversion ratio of Ly6C-low expressing RAW246.7 cells into Ly6C-high expressing RAW246.7 cells decreased significantly(P＜0.0001),while the secretion of fibrosis-related factors MCP-1 and TGF-β decreased(P＜0.0001),which was consistent with the trend of the activation levels of HSC-T6 cells.Conclusions G-Rh1 can prevent and improve CDAHFD-induced liver fibrosis in mice,potentially through mechanisms involving the reduction of RAW264.7 phenotype transformation mediated by FGF-12 overexpression.

Objective To analyze the effect of Physio Space balance board motor control training on rehabilitation of ankle joint injuries in a prospective randomized controlled study.Methods A total of 96 patients with ankle joint injuries treated at Yunnan Provincial Hospital of Traditional Chinese Medicine from May 2022 to May 2023 were selected and randomly divided into the study group(n=48)and the control group(n=48).Both groups received conventional physical therapy.The control group underwent standard rehabilitation training,while the study group added Physio Space balance board exercise control training on top of the control group's regimen.The therapeutic effect,ankle stability[Cumberland Ankle Instability Tool(CAIT)score],ankle joint range of motion(dorsoextension,plantar flexion),pain levels,balance ability of the affected limb[mean displacement on the X-axis(Mcd)and mean displacement on the Y-axis(Msd)scores],and serum inflammatory pain factor levels[Substance P(SP),Tumor necrosis factor-α(TNF-α),interleukin-6(IL-6),Neuropeptide(NPY)]were compared between the two groups.Results The rate of excellent and good treatment in the study group(93.75%vs.79.17%)was higher than that in the control group(P<0.05).After 1,2,3 and 4 weeks of treatment,the CAIT score of the study group was higher than that of the control group,and the VAS score was lower than that of the control group(P<0.05).After 2 and 4 weeks of treatment,the dorsiflexion and plantarflexion range of motion in the study group were higher than those in the control group(P<0.05).The Mcd and Msd scores in the study group were lower than those in the control group after 2 and 4 weeks of treatment(P<0.05).After 2 and 4 weeks of treatment,the serum levels of TNF-α,IL-6,SP and NPY in the study group were lower than those in the control group(P<0.05).Conclusion Physio Space balance board motion control training shows significant efficacy in the rehabilitation treatment of ankle joint injuries and is worthy of promotion and application.

Objective:To investigate the clinical efficacy of 3D printed metal augment or tibial prosthesis for reconstruction of large bone defects in total knee arthroplasty (TKA) and knee revision surgery.Methods:A total of 7 patients (7 knees) with TKA or knee revision who were admitted to the Department of Orthopaedics of the Second Affiliated Hospital of Zhejiang University School of Medicine with large bone defects from July 2018 to December 2023 were retrospectively analyzed, including 4 patients with TKA and 3 patients with knee revision. There were 3 males and 4 females, aged 58.7±7.6 years (range, 54-68 years), 3 patients with left knee and 4 patients with right knee. All the patients had bone defects in the knee joint (AORI type III), 2 cases had bone defects only in the femur, 4 cases had bone defects only in the tibia, and 1 case had bone defects in both the tibia and femur, which were treated with personalized reconstruction using 3D printing. Hip-knee-ankle angles, American Knee Society score (KSS) before and after surgery were compared, and postoperative complications were observed.Results:All patients successfully completed the operation, and the operation time was 189.3±35.5 min (range, 125-240 min). Complex TKA was performed in 4 cases with surgical times of 175, 195, 210, and 240 min, and revision surgery was performed in 3 cases with surgical times of 125, 180, and 200 min, respectively. Intraoperative blood loss was 114±24.4 ml (range, 100-150 ml). Five cases used 3D printed metal augment, and two used 3D printed one-piece tibial components. All patients were followed up for 2, 2, 5, 6, 7, 20, 57 months, respectively. The KSS of the five patients at 3 months postoperatively were 56, 61, 66, 56, and 56 points, respectively, greater than the preoperative scores of 35, 44, 36, 27, and 41 points. The KSS functional scores of the five patients at 3 months postoperatively were 45, 45, 45, 30, and 45 points, respectively, which were greater than the preoperative scores of 30, 30, 15, 20, and 20 points. The hip-knee-ankle angle was 181.8°±3.4° (range, 177.9° to 188.0°) at the final follow-up and 175.8°±12.4° (range, 153.3° to 192.1°) before surgery, with no significant difference ( t=-1.230, P=0.242). At the final follow-up, the 3D printed component was well integrated with the bone surface, the prosthesis was securely positioned, and the force lines of the lower limbs were normal. There were no postoperative complications such as poor wound healing, infection, fat liquefaction, nerve injury, deep vein thrombosis of lower limbs, knee joint stiffness, periprosthesis infection and loosening. Conclusion:Using 3D printed metal augment or tibial prosthesis to reconstruct the huge bone defect in TKA and revision has a satisfactory early clinical effect, satisfactory joint function and good surgical safety.

This paper summarized Professor LI Haisong's clinical experience in treating spermatorrhea based on the view of "spirit controlling essence and qi". It is emphasized that the heart spirit has the function of controlling the essence and qi of the human body， believing the frenetic stirring of heart spirit and the insecurity of essence gate are the core pathogenesis of spermatorrhea， LI advocates to regulate the heart spirit first and take into account of the zang-fu organs， essence and qi simultaneously for the treatment. Treatment should be performed according the clinical syndromes differentiatied. For those with heart spirit failing to nourish syndrome， it is recommended to supplement heart qi， nourish spirit and consolidate essence with self-made Yangxin Mijing Formula （养心秘精方）. In case of heart fire hyperactivity， the method of clearing heart heat and draining fire， calming spirit and consolidating essence should be used， and self-made Xiexin Gujing Formula （泻心固精方） is recommended. For heart-liver qi constraint， it is advised to soothe the liver and calm heart， calm the mind and regulate essence with self-made Jieyu Anshen Tiaojing Formula （解郁安神调精方） which is a modifcation to Chaihu Shugan Powder （柴胡疏肝散）. In terms of deficiency of both heart and liver， the treatment principle is supplementing spleen and nourishing heart， calming the mind and controlling essence， for which self-made Xinpi Tongtiao Shejing Formula （心脾同调摄精方） modified from Guipi Decoction （归脾汤） can be used. For deficiency of both heart and kidney， it is better to nourish the kidney and calm heart， calm the mind and consolidate essence with self-made Xinshen Liangzi Tianjing Formula （心肾两滋填精方） that modified from Shuilu Erxian Elixir （水陆二仙丹） and Wuzi Yanzong Pill （五子衍宗丸）. Prescriptions are used to treat the root by harmonizing the zang-fu organs， nourish the spirit by regulating qi and blood， and calm the mind by taking special medi-cinals， and they should be flexibly modified according to the disease.

OBJECTIVE To assess the long-term cost-effectiveness of five glucagon-like peptide-1 receptor agonists （GLP- 1RAs） in the treatment of poorly controlled type 2 diabetes mellitus （T2DM） treated with metformin. METHODS Baseline data from patients in previously published meta-analysis and included randomized controlled trials （RCTs） were extracted to predict survival， long-term efficacy， and costs for each group using the United Kingdom prospective diabetes study outcome model 2.1. The cost-effectiveness of 5 GLP-1RAs （liraglutide， lixisenatide， exenatide， dulaglutide， and semaglutide） was analyzed by cost- utility analysis. Sensitivity analysis and scenario analysis were also performed to verify the uncertainty of basic analysis results. RESULTS A total of 21 RCTs with 6 796 patients were included. Survival analysis curves showed the superiority of semaglutide in reducing the risk of death from cardiovascular disease and dulaglutide in reducing the risk of all-cause mortality over other GLP- 1RAs. The cost-utility analysis showed that the five drugs were economically superior to inferior in the order of lixisenatide， semaglutide， exenatide， dulaglutide， and liraglutide； one-way and probabilistic sensitivity analyses indicated that the results were robust. The scenario analysis results indicated that the price of semaglutide should decrease by at least 54.64% to 369.21 yuan， which is cost-effectiveness compared to lixisenatide. CONCLUSIONS For T2DM patients in China with poor glycemic control after treatment with metformin， lixisenatide and semaglutide may be considered as the preferred regimen.

OBJECTIVE To evaluate the effectiveness and safety of trastuzumab biosimilars and original drugs in the treatment of human epidermal growth factor receptor -2（HER-2）positive breast cancer systematically ，and to provide evidence -based basis for the selection of clinical treatment . METHODS Retrieved from PubMed ，Embase，Web of Science ，Cochrane Library ，CNKI， CBM，VIP，Wanfang database ，ClinicalTrials and Clinical Trial Center of China ，randomized controlled trials （RCTs）about trastuzumab biosimilars （trial group ）versus original drugs （control group ）in the treatment of HER -2 positive breast cancer were collected. After data extraction and quality evaluation ，RevMan 5.4 statistical software was used for meta -analysis. RESULTS Totally 11 RCTs were enrolled ，involving 5 812 patients. Results of meta -analysis showed that there was no significant difference in objective response rate （based on whether intention -to-treat population nor per -protocol population ），pathologic complete response ， proportion of progression free survival population ，proportion of overall survival population ，anti-drug antibody positive rate ， neutralizing antibody positive rate ，and incidence of adverse drug reactions between 2 groups（P＞0.05）. CONCLUSIONS The effectiveness and safety of trastuzumab biosimilars are equivalent to those of trastuzumab original drugs .

OBJECTIVE To compare the efficacy ，safety and immunogenicity of bevacizumab biosimilars and original drugs for non-small cell lung cancer （NSCLC），and to provide evidence-based reference for clinical use. METHODS PubMed，Embase， Web of Science ，Cochrane Library ，CBM，CNKI，VIP，Wanfang database ，ClinicalTrials.gov，and Clinical Trial Center of China were searched from the establishment of the database to September 25，2021，randomized controlled trials （RCTs）about bevacizumab biosimilars（trial group ）versus bevacizumab original drugs （control group ）for NSCLC were collected. After literature screening ， data extraction and quality evaluation of included RCTs with bias risk assessment tool recommended by Cochrane Handbook 5.1.0， meta-analysis，sensitivity analysis and publication bias analysis were performed by using RevMan 5.3 software. RESULTS A total of 11 RCTs were included ，involving 6 596 patients in total. Meta-analysis showed that there was no statistical significance in the difference of overall response rate [RR＝0.97，95％CI（0.92，1.02），P＝0.22]，the total incidence of adverse reaction [RR＝1.00， 95％CI（0.99，1.01），P＝0.79]，the incidence of severe adverse reaction [RR＝1.04，95％CI（0.96，1.13），P＝0.38]，positive rate of anti-drug antibody [RR ＝1.10，95％CI（0.88，1.36，P＝0.41] and the incidence of common adverse reactions （except for vomiting）among 2 groups（P＞0.05）. The sensitivity analysis results showed that the obtained results were robust. The results of publication bias analysis showed that there was little possibility of publication bias. CONCLUSIONS The efficacy ，safety and immunogenicity of bevacizumab biosimilars used for NSCLC are equivalent to those of bevacizumab original drugs.

A 9-year-old boy presented with pruritic erythema and erosions of the scalp for 1 month, which spread all over the body for 1 week. Histopathological examination of the skin lesions showed blisters forming under the granular layer of the epidermis, a large number of acantholytic cells in the blisters, and perivascular infiltration of lymphocytes and eosinophils in the superficial dermis. Direct immunofluorescence study showed reticular deposition of IgG and complement C3 between epidermal cells, and negative staining for IgM and IgA. Enzyme-linked immunosorbent assay showed the presence of serum anti-Dsg1 antibody (157.00 U/ml) . The patient was diagnosed with pemphigus foliaceus. After admission, the patient showed poor response to the treatment with prednisone at a dose of 40 mg/d. After the treatment with low-dose rituximab (100 mg per week, 4 weeks) combined with prednisone (20 mg/d) , her condition was well controlled. The dosage of prednisone gradually decreased to 7.5 mg/d for maintenance treatment, and no recurrence was observed during 24-month follow-up.