Objective:To evaluate the clinical equivalence between a domestic calcipotriol/betamethasone dipropionate ointment and the originator product in the treatment of stable plaque psoriasis.Methods:A multicenter, randomized, double-blind, three-arm, parallel-group, active- and placebo-controlled study was conducted, and 449 patients aged 18 - 65 years with stable plaque psoriasis were enrolled from 25 hospitals (such as the First Affiliated Hospital of China Medical University). Eligible patients had a baseline physician's global assessment (PGA) score of ≥ 3 points, baseline body surface area (BSA) involvement of 5% - 30%, and a target lesion psoriasis area and severity index (TL-PASI) for plaque elevation of ≥ 3 points. Participants were randomly assigned in a 2:2:1 ratio to the test group ( n = 179), reference group ( n = 180), and placebo group ( n = 90), and applied the domestic calcipotriol/betamethasone dipropionate ointment, originator product, and ointment base respectively, once daily in the evening for 4 weeks. Efficacy and safety were assessed at weeks 1, 2, and 4. The primary efficacy endpoints were the treatment success rates and clinical success rates in each group at week 4. The per-protocol set (PPS) was used for the primary efficacy analysis, and the intention-to-treat (ITT) set for supplementary efficacy analysis. Equivalence between the test and reference preparations was tested using the Cochran-Mantel-Haenszel method adjusted for randomization strata. Superiority of the test and reference preparations over the placebo was also tested. Measurement data were compared among the 3 groups using analysis of variance or non-parametric tests, while treatment success rates, clinical success rates, and incidence rates of adverse reactions were compared using the chi-square test. Results:The ITT, PPS, and safety sets included 447, 420, and 448 patients, respectively. In the ITT set, patients were aged 43.6 ± 12.8 years, including 320 (71.6%) males and 127 (28.4%) females, and the disease duration was 11.21 ± 9.05 years; 316 (70.7%) had a PGA score of 3 points and 131 (29.3%) had a PGA score of 4 - 5 points. No significant differences in the baseline characteristics (including age, sex, disease duration and disease severity) were observed among the 3 groups (all P > 0.05). Based on the PPS analysis, the treatment success rates were 57.9% (99/171) in the test group, 50.3% (86/171) in the reference group, and 7.7% (6/78) in the placebo group, and the clinical success rates were 57.9% (99/171), 50.3% (86/171), and 10.3% (8/78), respectively; both the test and reference groups were superior to the placebo group in both treatment and clinical success rates (all P < 0.001) ; the rate differences for treatment success (90% confidence interval [ CI]: -1.3% - 16.4%) and clinical success (90% CI: -1.3% - 16.3%) between the test and reference groups were entirely within the pre-defined equivalence margin (-20% - 20%). Subgroup analyses by baseline PGA scores: for patients with a baseline PGA score of 3 points, the treatment success rates in the test, reference, and placebo groups were 60.8% (73/120), 52.1% (62/119), and 11.1% (6/54), respectively, and the corresponding clinical success rates were 61.7% (74/120), 53.8% (64/119), and 13% (7/54), respectively; the test and reference groups did not differ significantly in treatment or clinical success rates (both P > 0.05), but both showed higher success rates than the placebo group (all P < 0.001) ; the results of statistical comparisons among the 3 groups in patients with a baseline PGA score of 4 - 5 points were consistent with those observed in patients with a baseline PGA score of 3 points. The percentage reductions in PGA and TL-PASI scores from baseline to weeks 1, 2, and 4 showed significant differences among the 3 groups, which were significantly higher in the test and reference groups than in the placebo group (all P < 0.001), but did not differ between the test and reference groups (all P > 0.05). The primary adverse reactions were local skin reactions, such as pruritus, pain, and erythema. The incidence rates of adverse reactions were 8.9% (16/179) in the test group, 7.3% (13/179) in the reference group, and 7.8% (7/90) in the placebo group, with no significant difference among the 3 groups ( P > 0.05) . Conclusions:The domestic calcipotriol/betamethasone dipropionate ointment demonstrated clinical equivalence to the originator product in the treatment of stable plaque psoriasis, and the two agents exhibited comparable efficacy for patients with varying degrees of disease severity, and were comparable in the speed and degree of clinical improvement, with similar favorable safety profiles.

Objective: To establish a prediction model for high-risk cardiovascular disease (CVD) among residents aged 35 to 75 years, so as to provide the basis for improving CVD prevention and control measures. Methods: Permanent residents aged 35 to 75 years were selected from Dongcheng District, Beijing Municipality using the stratified random sampling method from 2018 to 2023. Demographic information, lifestyle, waist circumference and blood biochemical indicators were collected through questionnaire surveys, physical examinations and laboratory tests. Influencing factors for high-risk CVD among residents aged 35 to 75 years were identified using a multivariable logistic regression model, and a prediction model for high-risk CVD was established. The predictive effect was evaluated using the receiver operating characteristic (ROC) curve. Results: A total of 6 968 individuals were surveyed, including 2 821 males (40.49%) and 4 147 females (59.51%), and had a mean age of (59.92±9.33) years. There were 1 155 high-risk CVD population, with a detection rate of 16.58%. Multivariable logistic regression analysis showed that gender, age, smoking, central obesity, systolic blood pressure, fasting blood glucose, triglyceride and low-density lipoprotein cholesterol were influencing factors for high-risk CVD among residents aged 35 to 75 years (all P<0.05). The area under the ROC curve of the established prediction model was 0.849 (95%CI: 0.834-0.863), with a sensitivity of 0.693 and a specificity of 0.863, indicating good discrimination. Conclusion The model constructed by eight factors including demographic characteristics, lifestyle and blood biochemical indicators has good predictive value for high-risk CVD among residents aged 35 to 75 years.

Clinical data of a patient with alveolar soft part sarcoma (ASPS) treated at Zhongshan Hospital, Fudan University were retrospectively analyzed. The patient was initially diagnosed with abdominal ASPS with multiple lung metastases. After 6 weeks of treatment with nivolumab and ipilimumab, the patient achieved stable disease (SD). In the 7th week, the treatment was changed to a combination of nivolumab (30 mg, d1, q3w), anlotinib (8 mg, d1-14, q3w) and ipilimumab (50 mg, d1, q6w). The patient remained SD at the 12th week. The patient then underwent iliac artery embolization and intensity-modulated radiation therapy for the lesion in the psoas major muscle, while continuing the combination treatment. By the 24th week, the evaluation showed partial remission (PR) of both primary tumor and lung metastases. The patient experienced mild adverse reactions during treatment.

Objective:To evaluate the clinical equivalence between a domestic calcipotriol/betamethasone dipropionate ointment and the originator product in the treatment of stable plaque psoriasis.Methods:A multicenter, randomized, double-blind, three-arm, parallel-group, active- and placebo-controlled study was conducted, and 449 patients aged 18 - 65 years with stable plaque psoriasis were enrolled from 25 hospitals (such as the First Affiliated Hospital of China Medical University). Eligible patients had a baseline physician's global assessment (PGA) score of ≥ 3 points, baseline body surface area (BSA) involvement of 5% - 30%, and a target lesion psoriasis area and severity index (TL-PASI) for plaque elevation of ≥ 3 points. Participants were randomly assigned in a 2:2:1 ratio to the test group ( n = 179), reference group ( n = 180), and placebo group ( n = 90), and applied the domestic calcipotriol/betamethasone dipropionate ointment, originator product, and ointment base respectively, once daily in the evening for 4 weeks. Efficacy and safety were assessed at weeks 1, 2, and 4. The primary efficacy endpoints were the treatment success rates and clinical success rates in each group at week 4. The per-protocol set (PPS) was used for the primary efficacy analysis, and the intention-to-treat (ITT) set for supplementary efficacy analysis. Equivalence between the test and reference preparations was tested using the Cochran-Mantel-Haenszel method adjusted for randomization strata. Superiority of the test and reference preparations over the placebo was also tested. Measurement data were compared among the 3 groups using analysis of variance or non-parametric tests, while treatment success rates, clinical success rates, and incidence rates of adverse reactions were compared using the chi-square test. Results:The ITT, PPS, and safety sets included 447, 420, and 448 patients, respectively. In the ITT set, patients were aged 43.6 ± 12.8 years, including 320 (71.6%) males and 127 (28.4%) females, and the disease duration was 11.21 ± 9.05 years; 316 (70.7%) had a PGA score of 3 points and 131 (29.3%) had a PGA score of 4 - 5 points. No significant differences in the baseline characteristics (including age, sex, disease duration and disease severity) were observed among the 3 groups (all P > 0.05). Based on the PPS analysis, the treatment success rates were 57.9% (99/171) in the test group, 50.3% (86/171) in the reference group, and 7.7% (6/78) in the placebo group, and the clinical success rates were 57.9% (99/171), 50.3% (86/171), and 10.3% (8/78), respectively; both the test and reference groups were superior to the placebo group in both treatment and clinical success rates (all P < 0.001) ; the rate differences for treatment success (90% confidence interval [ CI]: -1.3% - 16.4%) and clinical success (90% CI: -1.3% - 16.3%) between the test and reference groups were entirely within the pre-defined equivalence margin (-20% - 20%). Subgroup analyses by baseline PGA scores: for patients with a baseline PGA score of 3 points, the treatment success rates in the test, reference, and placebo groups were 60.8% (73/120), 52.1% (62/119), and 11.1% (6/54), respectively, and the corresponding clinical success rates were 61.7% (74/120), 53.8% (64/119), and 13% (7/54), respectively; the test and reference groups did not differ significantly in treatment or clinical success rates (both P > 0.05), but both showed higher success rates than the placebo group (all P < 0.001) ; the results of statistical comparisons among the 3 groups in patients with a baseline PGA score of 4 - 5 points were consistent with those observed in patients with a baseline PGA score of 3 points. The percentage reductions in PGA and TL-PASI scores from baseline to weeks 1, 2, and 4 showed significant differences among the 3 groups, which were significantly higher in the test and reference groups than in the placebo group (all P < 0.001), but did not differ between the test and reference groups (all P > 0.05). The primary adverse reactions were local skin reactions, such as pruritus, pain, and erythema. The incidence rates of adverse reactions were 8.9% (16/179) in the test group, 7.3% (13/179) in the reference group, and 7.8% (7/90) in the placebo group, with no significant difference among the 3 groups ( P > 0.05) . Conclusions:The domestic calcipotriol/betamethasone dipropionate ointment demonstrated clinical equivalence to the originator product in the treatment of stable plaque psoriasis, and the two agents exhibited comparable efficacy for patients with varying degrees of disease severity, and were comparable in the speed and degree of clinical improvement, with similar favorable safety profiles.

G protein-coupled receptors (GPCRs) are a large family of membrane protein receptors, and Takeda G protein-coupled receptor 5 (TGR5) is a member of this family. As a membrane receptor, TGR5 is widely distributed in different parts of the human body and plays a vital role in regulating metabolism, including the processes of energy consumption, weight loss and blood glucose homeostasis. Recent studies have shown that TGR5 plays an important role in glucose and lipid metabolism disorders such as fatty liver, obesity and diabetes. With the global obesity situation becoming more and more serious, a comprehensive explanation of the mechanism of TGR5 and filling the gaps in knowledge concerning clinical ligand drugs are urgently needed. In this review, we mainly explain the anti-obesity mechanism of TGR5 to promote the further study of this target, and show the electron microscope structure of TGR5 and review recent studies on TGR5 ligands to illustrate the specific binding between TGR5 receptor binding sites and ligands, which can effectively provide new ideas for ligand research and promote drug research.

Objective To use the high-speed fluorescence photography to investigate the regulatory effect of nitric oxide(NO)on calcium transient state in skeletal muscle cells of adult zebrafish.Methods The skeletal muscle cells were separated and extracted from adult zebrafish and then incubated with Fluo-4 and AM fluorescent probe.The fluorescence change of calcium transient state in zebrafish free skeletal muscle cells after single electrical stimulation was recorded by a high-speed fluorescence camera,and the biophysical pa-rameters related to the intracellular calcium transient state were quantitatively calculated.The experimental groups were divided into the control group,S-nitroso-n-acetyl-DL-penicillamine(SNAP)group and n-nitroso-L-arginine methyl ester(L-NAME)group.NO donor SNAP and non-specific nitric oxide synthase(NOS)in-hibitor L-NAME were used to investigate the regulatory effect of NO on calcium transient state in adult skele-tal muscle cells of zebrafish.The experimental groups were redivided into the control group,N-ethylmaleimide(NEM)group,1H-[1,2,4]dioxalin and[4,3-a]quinoxalin-1-one(ODQ)group,SNAP group and SNAP+ODQ group.The regulatory mechanism of NO on calcium transients state in adult zebrafish skeletal muscle cells was investigated by using sGC-cGMP-PKG pathway inhibitor ODQ and S-nitrosation inhibitor NEM.Re-sults The fluorescence changes of calcium transient state in adult zebrafish skeletal muscle cells could be re-corded by high speed fluorescence photography and the biophysical parameters related to intracellular calcium transients state were calculated.Compared to the control group,the calcium transient state of skeletal muscle cells in the SNAP group was significantly decreased,while the calcium transient state of skeletal muscle cells in the L-NAME group was significantly enhanced compared to the control group.The calcium transient state of skeletal muscle cells in the ODQ group was significantly stronger than that in the control group,while there was no statistical difference in the related parameters of calcium transient state between the NEM group and control group.The calcium transient state of skeletal muscle cells in the SNAP+ODQ group was also signifi-cantly stronger than that in the SNAP group.Conclusion NO could negatively regulate the process of calcium transient state in adult zebrafish skeletal myocytes by the sGC-cGMP-PKG pathway.

OBJECTIVE Alzheimer's disease(AD)and vascular dementia(VD)are the primary causes of dementia in elderly individuals,and therapeutic options for both conditions are limited.Overactivation of N-methyl-D-aspartate(NMDA)receptors,decreased cerebral blood flow,and subsequent pathological events,play signifi-cant roles in the progression of AD and VD.METHODS In this study,we investigated the therapeutic effects and underlying mechanisms of MN-08,a novel memantine nitrate,in mouse models of AD and rats with VD.RESULTS MN-08 was found to inhibit Aβ accumulation,prevent neuronal and dendritic spine loss,and attenuate cognitive deficits in 2-month-old APP/PS1 transgenic mice(following a 6-month preventative course)and in 8-month-old triple-transgenic(3×Tg-AD)mice(following a 4-month therapeutic course),as well as in rat models of VD with preventive and therapeutic treatments.In vitro,MN-08 was shown to bind to and antagonize NMDA receptors,inhibit calcium influx,and reverse dysregula-tions of the ERK and PI3K/Akt/GSK3β pathway,subse-quently preventing glutamate-induced neuronal loss.Additionally,MN-08 exhibited favorable pharmacokinet-ics,blood-brain barrier penetration,and safety profiles in rats and beagle dogs.CONCLUSION These findings suggest that the novel memantine nitrate MN-08 may be a useful therapeutic agent for AD and VD.

An 11-year-old boy received tofacitinib (oral 7.5 mg once daily) on the basis of methotrexate therapy (oral 10 mg once a week) due to poor control of juvenile idiopathic arthritis, and the symptoms were relieved. The boy′s liver function was normal before using tofacitinib. After more than 2 months of combined use of the 2 drugs, laboratory tests showed alanine aminotransferase (ALT) 178 U/L and aspartate aminotransferase (AST) 78 U/L. No intervention was given because there were no clinical symptoms. His liver enzyme elevated significantly (ALT 586 U/L, AST 170 U/L) after continued medication for 1 month. After excluding viral hepatitis, autoimmune hepatitis, and other liver diseases, drug-induced liver injury was considered. Methotrexate was discontinued, tocilizumab was added, and liver protection therapy with reduced glutathione and magnesium isoglycyrrhizinate was given. Eleven days of methotrexate withdrawal, the laboratory tests showed ALT 512 U/L and AST 194 U/L. Then tofacitinib was discontinued and hepatic enzyme decreased significantly (ALT 150 U/L, AST 41 U/L) 3 days later. The liver injury was considered to be related to tofacitinib. The liver protection therapy was continued for 1 week, and the liver function examination showed ALT 41 U/L and AST 35 U/L.

An 11-year-old boy received tofacitinib (oral 7.5 mg once daily) on the basis of methotrexate therapy (oral 10 mg once a week) due to poor control of juvenile idiopathic arthritis, and the symptoms were relieved. The boy′s liver function was normal before using tofacitinib. After more than 2 months of combined use of the 2 drugs, laboratory tests showed alanine aminotransferase (ALT) 178 U/L and aspartate aminotransferase (AST) 78 U/L. No intervention was given because there were no clinical symptoms. His liver enzyme elevated significantly (ALT 586 U/L, AST 170 U/L) after continued medication for 1 month. After excluding viral hepatitis, autoimmune hepatitis, and other liver diseases, drug-induced liver injury was considered. Methotrexate was discontinued, tocilizumab was added, and liver protection therapy with reduced glutathione and magnesium isoglycyrrhizinate was given. Eleven days of methotrexate withdrawal, the laboratory tests showed ALT 512 U/L and AST 194 U/L. Then tofacitinib was discontinued and hepatic enzyme decreased significantly (ALT 150 U/L, AST 41 U/L) 3 days later. The liver injury was considered to be related to tofacitinib. The liver protection therapy was continued for 1 week, and the liver function examination showed ALT 41 U/L and AST 35 U/L.

Objective:To study the use of percutaneous transhepatic one-step biliary fistulation based on three-dimensional visualization technology (3D-PTOBF) in the treatment of complex hepatolithiasis.Methods:A retrospective analysis was conducted on 116 patients with complex hepatolithiasis treated in the First Affiliated Hospital of Guangzhou Medical University from January 2016 to December 2019. There were 56 patients in the 3D-PTOBF group (treated by 3D-PTOBF), and 60 patients in the traditional PTOBF group (received traditional PTOBF approach). The stone clearance rate, postoperative complication rate, intraoperative blood loss, hospitalization time, number of cholangioscopic treatment procedures and stone recurrence rate were compared between the two groups.Results:When compared with the traditional PTOBF group, the 3D-PTOBF group had significantly less procedures (1.43±0.71 vs. 2.07±1.22, P<0.05), and shorter hospital stay (4.6±2.3 d vs. 6.1±2.9 d, P<0.05). There were no significant differences in the immediate stone clearance, final stone clearance, postoperative complications and stone recurrence rates between the two groups (all P>0.05). Conclusion:3D-PTOBF was safe and feasible to treat complex hepatolithiasis. When compared with PTOBF, it had the advantages of shorter operation time and decreased hospital stay.