OBJECTIVE To evaluate the cost-utility of iguratimod combined with methotrexate in the treatment of patients with active rheumatoid arthritis （RA） who failed monotherapy with conventional synthetic disease-modifying antirheumatic drugs （csDMARDs）.METHODS A cost-utility analysis was performed. A Markov model was constructed from the perspective of China’s healthcare system with a cycle length of 6 months to simulate the costs and health outcomes [quality-adjusted life years （QALYs）] of iguratimod combined with methotrexate versus different combined csDMARDs regimens over a 30-year time horizon. Efficacy and safety data were synthesized from randomized controlled trials via network meta-analysis. Cost parameters were derived from the Menet Database， published literature and other sources. The discount rate was set at 4.5%， and the willingness-to-pay （WTP） threshold was twice China’s per capita gross domestic product in 2025 （199 330.00 yuan/QALY）. One-way sensitivity analysis， probabilistic sensitivity analysis and scenario analysis were conducted to verify the robustness of the results.RESULTS Compared with methotrexate+sulfasalazine and sulfasalazine+leflunomide， iguratimod+methotrexate was a dominant regimen. Compared with methotrexate+leflunomide， the incremental cost-effectiveness ratio of iguratimod+methotrexate was 60 577.10 yuan/QALY， which was lower than the WTP threshold. Sensitivity analyses and scenario analysis confirmed favorable robustness of the above findings.CONCLUSIONS From the perspective of China’s healthcare system， iguratimod+methotrexate is cost-effective for active RA patients failing csDMARD monotherapy， in comparison with methotrexate+leflunomide， methotrexate+sulfasalazine and sulfasalazine+leflunomide regimens.

ObjectiveTo observe the dynamic changes in heparin-binding protein (HBP), coagulation function indicators, and vascular endothelial injury markers in SD rats with sepsis, analyze the associations among these indicators, and elucidate the regulatory role of HBP in sepsis-associated coagulation disorders. MethodsEighteen specific pathogen-free (SPF) male SD rats aged 8–12 weeks were selected to establish a sepsis model using cecal ligation and puncture (CLP). Blood samples were collected from the heart at 0 hours before modeling and at 3, 6, and 9 hours post-modeling. Thromboelastography (TEG) with standard and heparinase cups was used to determine the difference in reaction time (R value) between the two cups (ΔR), thereby evaluating coagulation function and the endogenous heparin effect. Plasma levels of HBP, heparan sulfate (HS), syndecan-1 (SDC-1), and thrombomodulin (TM) were measured by enzyme-linked immunosorbent assay (ELISA). Samples with ΔR≥2 min were grouped as the ΔR≥2 min group, while those with ΔR<2 min were grouped as the ΔR<2 min group. Correlation and receiver operating characteristic (ROC) curve analyses were performed to evaluate the relationship between HBP and various indicators, as well as its predictive efficacy for ΔR values. ResultsΔR, HS, SDC-1 and HBP significantly increased after modeling compared with 0 hours (P<0.01). The HS, SDC-1, and HBP levels in the ΔR≥2 min group were significantly higher than those in the ΔR<2 min group (P<0.05 or P<0.01). HBP showed a significant positive correlation with ΔR and HS (P<0.05), while ΔR was significantly positively correlated with HS (r=0.799, P<0.01) and weakly positively correlated with SDC-1 (r=0.289, P<0.05). HS, HBP, and SDC-1 demonstrated significant predictive value for ΔR≥2 min (P<0.01). ConclusionIn the early stages of sepsis, the release of HS-like anticoagulant substances from the glycocalyx following its degradation can lead to coagulation disorders, while HBP can reflect the pathological process and play an important regulatory role in the occurrence and development of sepsis-related coagulation disorders.

Colorectal cancer （CRC） ranks as the second leading cause of cancer death worldwide. Although preventive colonoscopy screening has improved the survival rate of CRC patients in the past few years， there are still many patients diagnosed after symptoms appear. The surgery for CRC carries high risks and high recurrence， and ideal therapies remain to be developed. The Janus kinase/signal transducer and activator of transcription （JAK/STAT） signaling pathway has become a focus of research due to its central role in cellular activities. As a classic oncogenic pathway， the JAK/STAT signaling pathway offers new possibilities for diagnosing and treating various malignancies， and it paves a new way for developing therapies for CRC. This pathway not only participates in basic cellular processes， such as proliferation， differentiation， and apoptosis but also plays a crucial role in immune responses and inflammation. Abnormal activation of the JAK/STAT signaling pathway is closely related to the occurrence and development of CRC. Studies have shown that the active components and compound prescriptions of traditional Chinese medicine （TCM） can inhibit the proliferation， invasion， migration， and angiogenesis while promoting the apoptosis and autophagy of CRC cells by interfering with the JAK/STAT signaling pathway. Furthermore， this pathway may also play a role in regulating the sensitivity of tumor cells to chemotherapy and radiotherapy， thus influencing the effectiveness of tumor treatment and impeding the progression of CRC. In recent years， research results have been updated rapidly， and previous literature summaries have failed to incorporate the latest findings， creating obstacles to accessing current literature. Therefore， this article supplements and summarizes information from the definition of the JAK/STAT pathway， association of this pathway with CRC， and TCM intervention of CRC. This review aims to provide references for future development of molecular biology regarding CRC and the research and development of new drugs.

Medication reconciliation plays a key role in improving patient medication safety,reducing inappropriate polypharmacy,and promoting the high-quality development of pharmaceutical services.Compared to advanced international guidelines,China's medication reconciliation service standards have deficiencies in areas such as definition and process design,and multidisciplinary team building.There is a need to establish a comprehensive medication reconciliation effect evaluation index system,develop pharmacist-led multidisciplinary teams,promote the advancement of artificial intelligence and big data technologies,and strengthen outpatient and community medication reconciliation coverage,thereby contributing to the high-quality development of pharmaceutical services in China.

This article retrospectively analyzed the clinical data of three recipients who developed acute antibody mediated rejection (AMR) after receiving different courses of immunotherapy prior to liver transplantation for hepatocellular carcinoma. It focused on their diagnostic and therapeutic processes, including the immunosuppressive induction regimen [rabbit anti-human thymocyte globulin (rATG) + methylprednisolone] , postoperative liver function changes, diagnostic methods for acute AMR (such as allograft liver biopsy, panel reactive antibody testing, and donor-specific antibody testing) , and the combination treatment strategies used (rATG, rituximab, intravenous immunoglobulin, and plasma exchange). The aim of this article is to summarize the clinical characteristics, diagnosis, and treatment experiences of acute AMR occurring after liver transplantation in patients with liver cancer who had received immunotherapy, explore the potential risks involved, and provide a reference for clinicians in managing such cases.

To address the issue of reduced signal quality of photoplethysmography caused by local fluctuation,an approach called locally orthogonal weighted polynomial fitting(LOWPF)is proposed for signal smoothing.After determining the positions of the fluctuation sequences using the forward-backward difference XOR method,weighted polynomial fitting is applied to these sequences,and the fitted values are used to replace the fluctuation sequences to achieve signal smoothing.By constructing orthogonal basis functions,the condition number of the coefficient matrix is reduced,and the stability of the equation system solution for higher-order fitting is improved.Simulation results demonstrate that the smoothed signal's XOR smoothness of the proposed method surpasses that of the moving average algorithm and the empirical mode decomposition reconstruction algorithm.The smoothing results on 241 sets of measured PPG signals show that LOWPF achieves an efficiency of smoothness of 89.10%,significantly higher than the 78.05%of empirical mode decomposition and the 59.13%of the 5-point moving average algorithm.LOWPF has promising application prospects for smoothing signals with significant local fluctuations.

Objective To investigate the impact of dietary protein intake on the prevalence of type 2 diabetes in adult residents, and to provide a reference for formulating diabetes prevention and control measures. Methods The research was based on cross-sectional survey data from the Nutrition and Health Follow-up Study of Chinese Residents in Chongqing (2021). Energy and nutrient intake was calculated in combination with the Chinese food composition table. Multivariate logistic regression was used to analyze the association between dietary protein and diabetes, and then restricted cubic spline regression (RCS) was used to analyze the dose-response relationship between dietary protein intake and the development of diabetes. Results Among the 1 415 adult residents, dietary intake of total protein, animal protein, and plant protein was 69.69g/d, 26.26g/d, and 43.43g/d, respectively. The ratio of protein to energy supply was 14.31%, and the prevalence of diabetes was 18.02%. Comparing with the residents in the first percentile of total dietary protein intake, the multivariable-adjusted odds ratios of those in the second and third percentile were 1.754 and 2.453 respectively. Comparing the residents in the third percentile with those in the first percentile, the multivariable-adjusted odds ratios of diabetes were 1.592 for protein energy supply ratio, and 1.558 for animal protein intake. Conclusion High protein intake, high protein energy supply ratio and high animal protein intake may increase the risk of diabetes, and different types of protein may have different effects on diabetes.

Objective:To investigate the correlation between non-Hodgkin lymphoma (NHL) and chronic hepatitis B virus (HBV) infection by using the method of two-sample bidirectional Mendelian randomization (MR) analysis.Methods:Genetic variation data for NHL came from the Finnish database (FinnGen) Consortium 2021 public genome-wide association study (GWAS) dataset including 1 088 patients with NHL and 299 952 control subjects. The GWAS dataset for chronic HBV infection was derived from GWAS analysis published in 2021, including 145 NHL patients and 351 740 control subjects. NHL was used as an exposure factor, single nucleotide polymorphism (SNP) significantly associated with NHL was used as an instrumental variable (IV), chronic HBV infection was used as an outcome variable. The two-sample MR analysis was performed by using inverse-variance weighted (IVW) method. Chronic HBV infection was taken as an exposure factor, SNP significantly associated with chronic HBV infection was taken as IV, and NHL was taken as outcome variable, and then reverse two-sample MR analysis was performed. The IVW method used the inverse variance of each IV as the weight to fit, and the ratio method was used to measure SNP one by one and make weighted regression analysis, so as to obtain the overall estimate. MR-Egger regression and the weighted median (WME) method were also used to supplement the IVW method. In sensitivity analysis, leave-one-out sensitivity analysis was used to evaluate the impact of a single SNP. Cochran Q test was used to analyze the heterogeneity of the selected IV. MR-Egger regression was used to measure the average horizontal pleiotropy of IV, and the P-value of directivity was calculated. The MR-pleiotropy residual sum and outlier (MR-PRESSO) Global Test was used to exclude possible horizontal pleiotropic outliers and reduce bias. Results:In the leave-one-out sensitivity analysis, SNP with significant effects on causal associations was excluded. In forward MR analysis, IVs were 10 SNPs associated with NHL; the IVW method indicated that there was no causal association between NHL and chronic HBV infection ( OR = 0.979, 95% CI: 0.925-1.036, P = 0.465). MR-Egger regression ( OR = 0.992, 95% CI: 0.926-1.062, P = 0.825) and WME method ( OR = 0.992, 95% CI: 0.934-1.055, P = 0.805) were used as supplementary methods to obtain the consistent results. In sensitivity analysis, Cochran Q test showed no heterogeneity among IVs (IVW method: P = 0.271, MR-Egger regression: P = 0.239). Horizontal pleiotropy was not found in the MR-Egger regression (intercept was -0.01, P = 0.778) and the MR-PRESSO Global Test ( P > 0.05), suggesting robust results. In the reverse MR analysis, IVs were 8 SNPs associated with NHL; the IVW method ( OR = 1.117, 95% CI: 0.942-1.324, P = 0.202) also found no significant causal relationship between chronic HBV infection and NHL; MR-Egger regression ( OR = 0.777, 95% CI: 0.450-1.343, P = 0.401) and WME method ( OR = 1.120, 95% CI: 0.887-1.415, P = 0.351) also showed similar risk estimates. Sensitivity analysis also suggested the consistency and reliability of the results. Cochran Q test showed no heterogeneity among IVs (IVW method: P = 0.775, MR-Egger regression: P = 0.903). Horizontal pleiotropy was not found by MR-Egger regression (intercept was 0.102, P = 0.548) and MR-PRESSO Global Test ( P > 0.05). Conclusions:MR analysis suggests no causal relationship between NHL and chronic HBV infection.

Background: s/Aims: Non-invasive models stratifying clinically significant portal hypertension (CSPH) are limited. Herein, we developed a new non-invasive model for predicting CSPH in patients with compensated cirrhosis and investigated whether carvedilol can prevent hepatic decompensation in patients with high-risk CSPH stratified using the new model. Methods: Non-invasive risk factors of CSPH were identified via systematic review and meta-analysis of studies involving patients with hepatic venous pressure gradient (HVPG). A new non-invasive model was validated for various performance aspects in three cohorts, i.e., a multicenter HVPG cohort, a follow-up cohort, and a carvediloltreating cohort. Results: In the meta-analysis with six studies (n=819), liver stiffness measurement and platelet count were identified as independent risk factors for CSPH and were used to develop the new “CSPH risk” model. In the HVPG cohort (n=151), the new model accurately predicted CSPH with cutoff values of 0 and –0.68 for ruling in and out CSPH, respectively. In the follow-up cohort (n=1,102), the cumulative incidences of decompensation events significantly differed using the cutoff values of <–0.68 (low-risk), –0.68 to 0 (medium-risk), and >0 (high-risk). In the carvediloltreated cohort, patients with high-risk CSPH treated with carvedilol (n=81) had lower rates of decompensation events than non-selective beta-blockers untreated patients with high-risk CSPH (n=613 before propensity score matching [PSM], n=162 after PSM). Conclusions Treatment with carvedilol significantly reduces the risk of hepatic decompensation in patients with high-risk CSPH stratified by the new model.

Objective To design and synthesize PROTAC degraders targeting the SARS-CoV-2 main protease （M^pro）based on PROTAC technology. Methods Compound 3w was used as the M^pro ligand, and the indole N atom in the solvent-exposed region was selected as the linker attachment site. A series of M^pro PROTACs were designed and synthesized by conjugating compound 3w with the CRBN ligand pomalidomide through alkane linkers of different lengths. The structures of the target compounds were confirmed by ¹H NMR, ¹³C NMR, and HRMS. Western Blot analysis was employed to evaluate their degradation activity and explore its mechanism in M^pro-HEK-293T cells. Results Four novel M^pro PROTACs（A1-A4）were successfully synthesized. The most potent compound A4 demonstrated M^pro degradation activity with a DC₅₀ value of 5.2 μmol/L, and its degradation mechanism was validated. Conclusion A novel class of M^pro PROTAC degraders were successfully designed and synthesized, and their protein degradation capability and mechanism of action were demonstrated. These results provided lead compounds for the research and development of antiviral degraders against SARS-CoV-2.