OBJECTIVE To investigate the use of drugs and the development of pharmaceutical care in the tight medical alliance （shorted for “medical alliance”） of Wanzhou District of Chongqing， and provide reference for the further construction of the medical alliance. METHODS A survey form was designed and distributed to 21 constituent units （5 leading units and 16 member units） of 5 medical alliances in Wanzhou District of Chongqing. The statistical analysis was conducted in aspects of basic drug allocation and use， pharmaceutical personnel team construction， the development of pharmaceutical care， and rational use of antibiotics. RESULTS Among the 21 constituent units， 4 leading units and 14 member units achieved the target for the proportion of essential drug procurement varieties， with a total compliance rate of 85.71%； 4 leading units and 13 member units achieved the target for the proportion of national essential drug allocation and usage amount， with a total compliance rate of 80.95%. The proportions of personnel with doctoral degrees in the 5 leading units and 16 member units were 1.71% and 0 respectively， and the proportions of personnel with senior professional titles were 8.56% and 1.63%， respectively. A total of 5 pharmacy or pharmaceutical combined outpatient clinics were set up in the 21 medical alliance units， and 5 clinical pharmacy information service platforms were established； all 5 leading units were able to regularly carry out clinical pharmacy projects， while only 4 out of 16 member units had conducted medical order review and evaluation. The proportions of irrational use of antibiotics in outpatient prescriptions and inpatient medical records of the 16 member units （4.81%， 5.21%） were significantly higher than those of the 5 leading units （2.80%， 4.00%）. CONCLUSIONS The allocation and usage of national essential drugs in 21 constituent units from Wanzhou District of Chongqing are both in good standing. However， the data on the allocation of pharmaceutical professionals and the number， qualifications， and job titles of clinical pharmacists in member units are generally low. Moreover， the pharmaceutical service projects and service quality in member units need to be further improved.

Abstract: Cancer immunotherapy, which is an attractive strategy harnessing the host's own immune system to remove tumor cells, has been widely used in clinical practice, yet with low response rate and immune-related adverse events. Unlike traditional chemotherapy, the targets of immunotherapy exhibit high spatial heterogeneity and are distributed in different cell types or secondary organelles, resulting in off-target and on-target toxicity, which greatly reduces the efficacy and safety of treatment. Due to the altered metabolic level, tumor tissues often display a lower pH than normal tissues. In addition, the endocytosis pathway is accompanied by continuous pumping of protons. Therefore, the variation of environmental pH values could serve as an ideal stimulus for precise drug delivery and release. In recent years, pH-responsive materials (e.g., polymers, biomacromolecules, lipid nanoparticles, biofilm, inorganic nanoparticles, and metal-organic frameworks) have been widely investigated in the field of cancer immunotherapy. This paper summarizes recent strategies of pH-responsive drug delivery systems based on different types of carriers, aiming to provide some reference for the design of next generation of tumor-targeting formulations in cancer immunotherapy.

Objective To summarize the clinicopathological characteristics and prognostic factors of salivary duct carcinoma(SDC)patients.Methods This study was reviewed and approved by the Ethics Committee,and informed consent was obtained from the patients.The clinical data of 30 SDC patients who were admitted to the Fourth Hospital of Hebei Medical University from 2014 to 2022,including case records,pathological diagnoses,immunohistochemical indicators,treatment methods,follow-up data,and other data,were retrospectively analyzed.SPSS 26.0 software was used to process the data and construct relevant curves.The chi-square test was used to analyze the correlation between different immunohistochemical indices and the recurrence and metastasis of SDC,and a single factor was used to ana-lyze clinical prognostic factors.Results Among the 30 SDC patients,the male-to-female ratio was 5∶1,with a median age of 61.5 years.Approximately 60％of cases occurred in the parotid gland,whereas the remainder occurred in the submaxillary gland,sublingual gland,or minor salivary gland.Among them,19 patients were androgen receptor-positive,23 patients were human epidermal growth factor receptor-2 positive,and 26 patients were Ki-67 positive.Postoperative follow-up was 18-94 months,with a median follow-up of 37 months.There were 13 cases of recurrence and 14 cases of distant metastasis.The 5-year overall survival rate was only 31.2％.The long-term survival of patients who underwent postoperative radiotherapy and chemoradiotherapy was better than that of patients who underwent surgery alone(P=0.027).T stage and lymph node invasion were associated with prognosis and survival(P＜0.05).There was a correlation between a Ki-67-positive cell count ≥ 40％and postoperative recurrence or metastasis(P=0.025).Conclusion Radi-cal surgery combined with postoperative radiotherapy and chemoradiotherapy is helpful for improving long-term overall survival,and tumor T stage and lymph node metastasis may be the main factors affecting the prognosis of patients with SDC.Patients with Ki-67-positive cell counts ≥ 40％are prone to postoperative recurrence or metastasis.

Objective:To explore the risk factors of short-term prognosis of severe Budd-Chiari syndrome (BCS) patients,established and verified the nomogram prediction model for these BCS patients and evaluated its clinical application value.Methods:This study is a retrospective cohort study. The clinical data of 171 patients with severe BCS diagnosed were retrospectively analyzed in the Department of Hepatopancreatobiliary Surgery First Affiliated Hospital of Zhengzhou University from January 2018 to December 2023. There were 105 males and 66 females, aged (52.1±12.8) years (range: 18 to 79 years). The patients were divided into two groups based on whether they died within 28 days: the death group ( n=38) and the survival group ( n=133). The risk factors for short-term death of patients were analyzed,and independent risk factors were screened by univariate and multivariate analysis. Furthermore,these factors were used to establish the nomogram prediction model. The area under the curve(AUC),the Bootstrap Resampling,the Hosmer-Lemeshow test and the Decision Curve Analysis(DCA) were used to verify the model′s differentiation,internal verification,calibration degree and clinical effectiveness,respectively. Results:Univariate and multivariate Logistics regression analysis showed that the history of hepatic encephalopathy,white blood cell,glomerular filtration rate and prothrombin time were independent risk factors ( P<0.05). The above factors were used to successfully establish the prediction model with 0.908 of AUC and 0.895 of the internal verification of AUC,indicating that the predictive model was valuable. The 0.663 P-values in the Hosmer-Lemeshow test indicated the high calibration degree of the model. The clinical effectiveness of the model was proved by the 18% clinical benefit population using the DCA curve with the 17% probability threshold. Conclusions:The independent risk factors are the history of hepatic encephalopathy,white blood cell,glomerular filtration rate and prothrombin time. An adequate basis was acquired by establishing a nomogram prediction model of the short-term prognosis of severe BCS,which was helpful for early clinical screening and identification of high-risk patients with severe BCS who could die in the short term and timely providing timely intervention measures for improving the prognosis.

Objective:To explore the risk factors of short-term prognosis of severe Budd-Chiari syndrome (BCS) patients,established and verified the nomogram prediction model for these BCS patients and evaluated its clinical application value.Methods:This study is a retrospective cohort study. The clinical data of 171 patients with severe BCS diagnosed were retrospectively analyzed in the Department of Hepatopancreatobiliary Surgery First Affiliated Hospital of Zhengzhou University from January 2018 to December 2023. There were 105 males and 66 females, aged (52.1±12.8) years (range: 18 to 79 years). The patients were divided into two groups based on whether they died within 28 days: the death group ( n=38) and the survival group ( n=133). The risk factors for short-term death of patients were analyzed,and independent risk factors were screened by univariate and multivariate analysis. Furthermore,these factors were used to establish the nomogram prediction model. The area under the curve(AUC),the Bootstrap Resampling,the Hosmer-Lemeshow test and the Decision Curve Analysis(DCA) were used to verify the model′s differentiation,internal verification,calibration degree and clinical effectiveness,respectively. Results:Univariate and multivariate Logistics regression analysis showed that the history of hepatic encephalopathy,white blood cell,glomerular filtration rate and prothrombin time were independent risk factors ( P<0.05). The above factors were used to successfully establish the prediction model with 0.908 of AUC and 0.895 of the internal verification of AUC,indicating that the predictive model was valuable. The 0.663 P-values in the Hosmer-Lemeshow test indicated the high calibration degree of the model. The clinical effectiveness of the model was proved by the 18% clinical benefit population using the DCA curve with the 17% probability threshold. Conclusions:The independent risk factors are the history of hepatic encephalopathy,white blood cell,glomerular filtration rate and prothrombin time. An adequate basis was acquired by establishing a nomogram prediction model of the short-term prognosis of severe BCS,which was helpful for early clinical screening and identification of high-risk patients with severe BCS who could die in the short term and timely providing timely intervention measures for improving the prognosis.

Objective:To study the clinical value of the Naples prognostic score (NPS) in predicting the prognosis of patients with intrahepatic cholangiocarcinoma (ICC) after radical resection and establish a nomogram prediction model.Methods:Clinical data of 77 patients with ICC undergoing radical hepatectomy for the first time in the First Affiliated Hospital of Zhengzhou University from January 2018 to December 2022 were retrospectively collected, including 46 males and 31 females, aged (58.9±11.0) years old. The area under the receiver operating characteristic curve for NPS to predict the death after radical hepatectomy in ICC patients was 0.673, and the optimal cut-off value for NPS based on the Youden's index was 2.5. According to the optimal cut-off value of NPS, patients were divided into two groups: the low NPS group (patients with NPS≤2.5, n=37) and high NPS group (patients with NPS>2.5, n=40). The clinicopathological data including resection extent, blood transfusion, tumor differentiation, lymphovascular invasion, lymph node metastasis and postoperative complications were compared between the groups. Follow-ups were conducted via outpatient or telephone reviews. Kaplan-Meier method was used for survival analysis, and log-rank test was used for survival comparison. Cox proportional hazards regression was used to analyze the risk factors affecting postoperative survival. A prediction nomogram was established and evaluated. Results:Compared to the low NPS group, the proportion of patients with tumor length ≥5 cm, lymphovascular invasion, lymph node metastasis, tumor carbohydrate antigen 19-9 ≥37 U/ml and the level of neutrophil to lymphocyte ratio were increased in the high NPS group, while the proportion of patients with serum albumin ≥40 g/L was decreased (all P<0.05). The cumulative survival rate of patients in the high NPS group was lower than that of the low NPS group ( P=0.001). Multivariate Cox analysis showed that ICC patients with lymphovascular invasion, lymph node metastasis, and NPS>2.5 had a higher risk of short survival after surgery (all P<0.05). The nomogram model based on NPS has a good predictive capacity. Conclusion:High preoperative NPS score indicates poor postoperative prognosis, and NPS score is an independent risk factor affecting the prognosis of ICC patients.

Objective:To investigate the predictive value of controlled nutritional status (CONUT) score for overt hepatic encephalopathy (OHE) after transjugular intrahepatic portosys-temic stent-shunt (TIPSS) in Budd-Chiari syndrome patients.Method:The retrospective case-control study was conducted. The clinicopathological data of 48 Budd-Chiari syndrome patients who underwent TIPSS in the First Affiliated Hospital of Zhengzhou University from August 2014 to March 2021 were collected. There were 26 males and 22 females, aged (46±13)years. Observation indicators: (1) surgical situations and follow-up; (2) analysis of influencing factors of OHE after TIPSS; (3) predic-tion of OHE after TIPSS. Measurement data with normal distribution were represented as Mean± SD, and comparison between groups was performed using the t test. Measurement data with skewed distribution were represented by M( Q1, Q3), and comparison between groups was performed using the Mann-Whitney U test. Count data were expressed as absolute numbers or percentages, and comparison between groups was performed using the chi-square test or Fisher exact probability. Multivariate analysis was performed using the Logistic regression model with forward method. The receiver operating characteristic (ROC) curve was drawn and the area under the curve (AUC) was calculated to evaluate the efficacy. Comparison among AUC was performed using the Delong test. Results:(1) Surgical situations and follow-up. All 48 patients underwent TIPSS successfully, and the operation time of the 48 patients was (131±29)minutes. All patients were implanted with 8 mm covered stent. All 48 patients were followed up for 46(25,71)months, and there were 14 cases with OHE and 34 cases without OHE after TIPSS. Of the 14 cases with OHE, 12 cases were evaluated as West-Haven Ⅱ grade and 2 cases were evaluated as West-Haven Ⅲ grade. (2) Analysis of influencing factors of OHE after TIPSS. Results of multivariate analysis showed that history of hepatic encephalo-pathy and CONUT score were independent factors influencing the incidence of OHE of Budd-Chiari syndrome patients who underwent TIPSS ( odds ratio=8.36, 1.74, 95% confidence interval as 1.02?68.75, 1.12?2.69, P<0.05). (3) Prediction of OHE after TIPSS. Results of ROC curve showed that the AUC of the CONUT score, the Child-Pugh score of liver function and the integrated model of end-stage liver disease (iMELD) score in predicting the incidence of OHE after TIPSS was 0.77(95% confidence interval as 0.64?0.91, P<0.05), 0.71(95% confidence interval as 0.56?0.87, P<0.05) and 0.71(95% confidence interval as 0.53?0.88, P<0.05), respectively, and there was no significant difference between the AUC of the CONUT score and the Child-Pugh score of liver function or the iMELD score ( Z=0.84, 0.59, P>0.05). The optimal cutoff value of CONUT score in predicting the incidence of OHE after TIPSS was 7, with the sensitivity, specificity and Yodon index as 78.6%, 61.8% and 0.40, respectively. Conclusion:The CONUT score can be used to predict the incidence of OHE in Budd-Chiari syndrome patients who underwent TIPSS, and the discrimination of CONUT score is equivalent to the Child-Pugh score of liver function and the iMELD score.

Transthyretin cardiac amyloidosis myocardiopathy （ATTR-CM） is an infiltrative cardiomyopathy characterized by the deposition of amyloidogenic material in the myocardial interstitium due to the misfolding of monomers following the dissociation of unstable transthyretin （TTR） tetramers. Previous treatments for ATTR-CM lacked specificity，primarily targeting symptomatic management of heart failure and arrhythmias. In recent years，researchers have developed two major classes of drugs addressing the pathogenesis of ATTR-CM. The first class stabilizes TTR tetramer structure （such as tafamidis and acoramidis）， while the second class interferes with TTR synthesis （such as patisiran）. Among these，tafamidis has been confirmed as the only currently effective treatment for ATTR-CM，while other drugs are still in clinical trial stages with limited clinical evidence. Concerning the management of comorbidities in ATTR-CM，treatment mainly focuses on common cardiac comorbidities （such as heart failure and arrhythmias）. Traditional drugs used to improve heart failure prognosis （such as β-blockers and renin-angiotensin- receptor blocker），have not demonstrated prognosis improvement in ATTR-CM patients and may even lead to adverse reactions. For ATTR-CM patients with concurrent atrial fibrillation，anticoagulation therapy is recommended to prevent thrombus formation，and amiodarone can be used for rhythm control. Despite significant advancements in pharmaceutical treatments for ATTR-CM，the overall prognosis remains poor，necessitating further research into the pathogenesis and target development to enhance the prognosis of ATTR-CM patients.

Circadian Clocks ; ARNTL Transcription Factors

Objective:To explore the mechanism of mTOR/HIF-1α signaling pathway in Budd-Chiari syndrome (B-CS) liver fibrosis.Methods:Twenty male C57 mice were randomly divided into Sham operation group (Sham), sham operation+ rapamycin (Sham+ Ra) group, B-CS group, B-CS+ rapamycin (B-CS+ Ra) Group, 5 in each group. The B-CS mouse model was constructed by partial ligation of the inferior vena cava(IVC) at the posterior segment of the liver; IVC was not ligated in the Sham group. Mice in Sham+ Ra and B-CS+ Ra groups were intraperitoneally injected with rapamycin (2 mg/kg, 5% DMSO solution preparation) every other day, Sham group and B-CS group were injected with the same dose of 5% DMSO solution.After 6 weeks, samples were taken, and part of the liver tissue was used to make paraffin sections for hematoxylin-eosin (HE) and Sirus Red staining to observe the pathological changes, and immunohistochemical staining to detect the expression of α-SMA and Fibrinogen in liver tissues; Protein and RNA were extracted from fresh liver tissue, and Western-blot was used to detect α-SMA, Fibrinogen, p-mTOR, mTOR, HIF-1α, Collagen I, and VEGF protein levels. Real-time fluorescent quantitative PCR was used to detect mTOR, HIF-1α, CollagenⅠ, VEGF mRNA levels.Measurement data were expressed as mean±standard deviation ( ± s), and the comparison between groups was performed by one-way ANOVA test. Results:The results of pathological staining showed that in the B-CS group, there was severe congestion around the central vein of the liver and sinusoids, widening of the sinus space, and increased collagen deposition, indicating that this study successfully established a mouse B-CS liver fibrosis model. The expression levels of fibrosis indicators α-SMA and Collagen I protein, mTOR pathway related indicators p-mTOR and HIF-1α protein, and microthrombus indicator Fibrinogen protein in the Sham group were 0.027±0.012, 0.337±0.008, 0.138±0.024, 0.296±0.113, 0.733±0.192; B-CS group were 0.986±0.001, 0.927±0.055, 0.936±0.044, 1.693±0.443, 1.612±0.068, and the differences were statistically significant ( P<0.05). The expression levels of B-CS+ Ra group were 0.707±0.078, 0.311±0.024, 0.332±0.094, 0.254±0.117, 0.569±0.075, which were statistically significant compared with B-CS group ( P<0.05). Conclusions:The mTOR/HIF-1α signaling pathway is significantly activated in mouse B-CS liver fibrosis. This pathway may participate in the development of liver fibrosis by regulating microthrombosis.