ObjectiveTo investigate the therapeutic effects and mechanism of decoctions from four kinds of processed products of Aconiti Radix Lateralis Praeparata（ARLP） in deficiency-cold syndrome. MethodsA total of 36 SD rats were randomly divided into the control group， model group， Shengfupian（SFP） group， Paofuzi（PFZ） group， Heishunpian（HSP） group and Paofupian（PFP） group with 6 rats in each group. Except for the control group， rats in other groups were administered hydrocortisone sodium succinate via intramuscular injection to induce a cold deficiency syndrome model. After 14 consecutive days， each ARLP decoction pieces was administered via continuous gastric lavage at a dose of 12 g·kg^-1·d^-1 for 7 d， while the control and model groups received an equivalent volume of physiological saline. After the end of administration， body weight， spleen weight and thymus weight were measured for calculating the spleen and thymus indexes. Hematoxylin-eosin（HE） staining was used to observe the pathological morphology of adrenal tissue. The fully automatic biochemistry analyzer was used to measure the total cholesterol（TC）， triglyceride（TG）， lactic dehydrogenase（LDH） and lactate（LAC） levels in serum. Enzyme-linked immunosorbent assay（ELISA） was employed to measure the contents of 17-hydroxycorticosteroid（17-OHCS）， cortisol（CORT）， triiodothyronine（T₃）， thyroxine（T₄）， thyrotropin（TSH）， immunoglobulin（Ig） M， IgG， cyclic adenosine monophosphate（cAMP） and cyclic guanosine monophosphate（cGMP）. Western blot was used to measure the protein expression levels of protein kinase A（PKA）， cAMP response element-binding protein（CREB）， silent information regulator 1（Sirt1） and peroxisome proliferator-activated receptor γ coactivator-1α（PGC-1α）. And high performance liquid chromatography（HPLC） was used to determine the content of major alkaloids， followed by Pearson correlation analysis with pharmacodynamic indicators. ResultsAfter modeling， compare with the control group， the model rats exhibited symptoms such as lethargy and loose stools， mild abnormalities were observed in adrenal tissue structure， and both spleen and thymus indices were significantly reduced（P<0.01）. Thyroid， adrenal and immune system functions were suppressed， with decreased serum cAMP level and significantly elevated cGMP level（P<0.01）. Compared with the model group， the adrenal injury by hydrocortisone sodium succinate were repaired and the spleen index were increased significantly in all four ARLP groups（P<0.05， P<0.01）. The thymus index in SFP and PFZ groups were increased significantly（P<0.05）. The contents of T₃， TSH， 17-OHCS and CORT were increased significantly in SFP and PFZ groups（P<0.05）. In addition， the content of IgG in SFP， PFZ and PFP groups were increased significantly（P<0.01）， while the content of IgM in PFZ and HSP groups were also increased significantly（P<0.05）. Regarding the cyclic nucleotide system， PFZ significantly elevated cAMP level while reducing cGMP level（P<0.05）， exhibiting the most pronounced effect among the four decoction pieces. For energy metabolism indicators， PFZ significantly improved abnormal markers including TC， TG， LDH， and LAC（P<0.05）. HSP showed marked improvement effects on TG， LDH， and LAC（P<0.05）. Both PFZ and SFP significantly elevated the expression levels of PKA， CREB， Sirt1， and PGC-1α proteins（P<0.01）. Additionally， the diester alkaloids in ARLP showed a strong positive correlation with TG， IgG， and CORT， a strong negative correlation with LAC， a moderate positive correlation with T₄， and moderate negative correlations with cAMP and spleen index. Monomeric alkaloids showed strong positive correlations with TG and IgG， strong negative correlations with LAC， moderate positive correlations with CORT and T₄， and moderate negative correlations with cAMP and spleen index. However， the content of water-soluble alkaloids showed strong positive correlations with TC， LDH， 17-OHCS， T₃， TSH， and thymus index， moderate positive correlations with cAMP， CORT， T₄， and spleen index， and moderate negative correlation with cGMP. ConclusionAmong different processed ARLP decoction pieces， PFZ processed according to ZHANG Zhongjing's method exhibits the most potent warming and cold-dispelling effects. Its pharmacological actions are mediated through regulating the thyroid， adrenal， immune， cyclic nucleotide systems， and material-energy metabolism pathways. Among these， water-soluble alkaloids show strong or moderate correlations with more indicators of deficiency-cold syndrome and exhibit the highest content in PFZ. Therefore， PFZ processed according to ZHANG Zhongjing's method may exert its warming and cold-dispelling effects through water-soluble alkaloids.

Pharmacovigilance runs through the whole life cycle of drugs. This paper systematically sorts out the development course of pharmacovigilance in China， from the initial establishment of the adverse drug reaction reporting system to the gradual construction of a complete pharmacovigilance system aligned with international standards. It focuses on analyzing the evolutionary features of the organizational system， legal system and monitoring system during this process. On this basis， this paper further discusses the future development trends of pharmacovigilance in China. In general， remarkable progress has been achieved in both regulatory construction and practical implementation of China’s pharmacovigilance system. In the future， efforts should be continuously made to improve the pharmacovigilance system， such as accelerating the implementation of the “one-body with two-wings” working framework and strengthening the primary responsibility of marketing authorization holders. It is also necessary to cultivate and reserve professional talents and promote information-based construction， including optimizing the spontaneous reporting system and establishing active monitoring systems. These measures can provide more solid support for ensuring public drug safety and facilitating high-quality development of the pharmaceutical industry.

[Purpose]To evaluate the liver and kidney safety of traditional Chinese medicine(TCM)compounds in the treatment of gastric cancer.[Methods]The clinical data of gastric cancer patients who attended in Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine from January 2012 to February 2022 were collected.The results of liver and renal func-tion tests were rated according to National Cancer Institute-Common Terminology Criteria for Ad-verse Events(NCI-CTCAE)V5.0.The patients were divided into 4 groups:TCM group,TCM+chemotherapy/targeted/antivascular therapy group,TCM+TCM preparation group and TCM+chemotherapy/targeted/antivascular therapy+TCM preparation group,and the effects of TCM on liver and renal functions were analyzed.[Results]A total of 7 943 patients were included in the analysis,of which 2 941 cases receiving TCM ≥12 months,1 468 months ≥36 months,and 687 months≥60 months.The highest incidence rate of liver function abnormality was 13.71％,the highest in-cidence rate of grade 3/4 abnormality was 2.58％;the highest incidence of creatinine abnormality was 2.32％,the highest incidence rate of grade 3/4 abnormality was 0.37％in patients with differ-ent duration of taking TCM.Most of liver and renal function abnormalities occurred in the early stage of drug taking.The incidence of liver and renal function abnormalities in the TCM group was lower than that of the other three groups.The incidence of grade 3/4 abnormality for direct biliru-bin(DBIL)in the TCM group was 0.14％,for aspartate transaminase(AST)was 0.11％,for alka-line phosphatase(ALP)was 0.16％,for alanine aminotransferase(ALT)was 0.06％and for total bilirubin(TBIL)was 0.07％,and there was no grade 3/4 creatinine abnormality observed.The ab-normal liver and renal function indexes were not increased with the increase of the length of herbal medicine taking.[Conclusion]The study shows that long term taking TCM drugs and stan-dardized prescriptions for gastric cancer patients are safe.

Purpose To explore the consistency between T2 mapping and three-dimensional water-selective cartilage(3D-WATSc)sequence measurement of knee cartilage volume.Materials and Methods A total of 30 healthy volunteers were recruited and underwent 3D-WATSc and T2 mapping sequence scans of the left knee joint in the Affiliated Lihuili Hospital of Ningbo University from May to December 2022.A total of 20 subjects'T2 mapping sequences were randomly selected and eight groups of raw images with different TE(13,26,39,52,65,78,91,104 ms)were analyzed.The quality of the raw images was rated by two observers,and the consistency of two observers'scores were subjected by Kappa test.The TE value with the best image quality was determined via Welch analysis of variance and Games-Howell text post hoc test.Based on T2 mapping and 3D-WATSc sequences,semi-automatic segmentation measurements were performed on the cartilage volume of femoral condyle,tibial plateau and patellar posterior margin in 30 subjects.Intra group correlation coefficient(ICC)and Bland-Altman plot were used to test the consistency of cartilage volume between two observers under T2 mapping sequence,as well as between T2 mapping and 3D-WATSc sequences.Results The consistency of the scores of the two observers was moderate except for poor consistency at TE 104 ms(Kappa=0.318)and no statistical difference at TE 78 ms(P=0.052),with Kappa values greater than 0.40 and P<0.05,further analysis showed that the cartilage display quality score was optimal at TE 26 ms(M=2.90).Comparing TE 26 ms with the scores of the other seven groups in Games Howell text,except for TE 26 ms and TE 13 ms(M=2.55),TE 26 ms and TE 39 ms(M=2.62),which had no statistically significant difference in scores(P>0.05),there were significant differences in scores between TE 26 ms and the other TE groups(all P<0.05).On the T2 mapping(TR 2 000 ms,TE 26 ms)sequence,the ICC values of the cartilage volumes of each part segmented by two observers were all greater than 0.6,P<0.05,with the consistency of femoral condyle cartilage volume being the best(ICC=0.877,P<0.01).The consistency of the cartilage volumes of each part measured by 3D-WATSc and T2 mapping sequences was good(ICC>0.75,P<0.01),with the consistency of tibial plateau cartilage volume being the best(ICC=0.857,P<0.01).Conclusion The T2 mapping original grayscale image(TR 2 000 ms,TE 26 ms)can clearly display the morphology of knee joint cartilage,the consistency between T2 mapping and 3D-WATSc sequences in quantifying knee cartilage volume is good,and the T2 mapping single sequence provides a reliable scanning scheme for one-stop quantitative analysis of knee joint cartilage morphology and function.

Purpose To explore the consistency between T2 mapping and three-dimensional water-selective cartilage(3D-WATSc)sequence measurement of knee cartilage volume.Materials and Methods A total of 30 healthy volunteers were recruited and underwent 3D-WATSc and T2 mapping sequence scans of the left knee joint in the Affiliated Lihuili Hospital of Ningbo University from May to December 2022.A total of 20 subjects'T2 mapping sequences were randomly selected and eight groups of raw images with different TE(13,26,39,52,65,78,91,104 ms)were analyzed.The quality of the raw images was rated by two observers,and the consistency of two observers'scores were subjected by Kappa test.The TE value with the best image quality was determined via Welch analysis of variance and Games-Howell text post hoc test.Based on T2 mapping and 3D-WATSc sequences,semi-automatic segmentation measurements were performed on the cartilage volume of femoral condyle,tibial plateau and patellar posterior margin in 30 subjects.Intra group correlation coefficient(ICC)and Bland-Altman plot were used to test the consistency of cartilage volume between two observers under T2 mapping sequence,as well as between T2 mapping and 3D-WATSc sequences.Results The consistency of the scores of the two observers was moderate except for poor consistency at TE 104 ms(Kappa=0.318)and no statistical difference at TE 78 ms(P=0.052),with Kappa values greater than 0.40 and P<0.05,further analysis showed that the cartilage display quality score was optimal at TE 26 ms(M=2.90).Comparing TE 26 ms with the scores of the other seven groups in Games Howell text,except for TE 26 ms and TE 13 ms(M=2.55),TE 26 ms and TE 39 ms(M=2.62),which had no statistically significant difference in scores(P>0.05),there were significant differences in scores between TE 26 ms and the other TE groups(all P<0.05).On the T2 mapping(TR 2 000 ms,TE 26 ms)sequence,the ICC values of the cartilage volumes of each part segmented by two observers were all greater than 0.6,P<0.05,with the consistency of femoral condyle cartilage volume being the best(ICC=0.877,P<0.01).The consistency of the cartilage volumes of each part measured by 3D-WATSc and T2 mapping sequences was good(ICC>0.75,P<0.01),with the consistency of tibial plateau cartilage volume being the best(ICC=0.857,P<0.01).Conclusion The T2 mapping original grayscale image(TR 2 000 ms,TE 26 ms)can clearly display the morphology of knee joint cartilage,the consistency between T2 mapping and 3D-WATSc sequences in quantifying knee cartilage volume is good,and the T2 mapping single sequence provides a reliable scanning scheme for one-stop quantitative analysis of knee joint cartilage morphology and function.

Purpose To investigate the value of radiomics nomogram for the prediction of p53 abnormal in patient with endometrial carcinoma based on intratumoral and peritumoral MRI.Materials and Methods A total of 145 female patients were pathologically confirmed endometrial carcinoma who underwent pelvic MRI before treatment in Baoding First Central Hospital from January 2020 to April 2024,including 96 patients with p53 wild type and 49 with p53 abnormal.Radiomics features were extracted from both intratumoral and peritumoral regions(2 mm)in diffusion weighted imaging and equilibrium phase of dynamic contrast enhanced MRI,which were selected using least absolute shrinkage and selection operator.Three machine learning algorithms of random forest,K-nearest neighbors and extra trees were conducted to develop the intratumoral,peritumoral and intratumoral combined peritumoral radiomics models.Multivariate Logistic regression was used to constitute the clinical model and nomogram.The performance of these models was evaluated using receiver operating characteristic curve,decision curve analysis and calibration curve.Results The K-nearest neighbors model of the intratumoral combined peritumoral regions performed the best in all radiomics models,the area under the curve were 0.921 and 0.773 in the training cohorts and test cohorts.The radiomics nomogram,which was composed of age,apparent diffusion coefficient and radiomics signatures,achieved the best performance with area under the curve of 0.970 and 0.777 in the training cohorts and test cohorts,respectively.Calibration curve analysis and decision curve analysis demonstrated favorable calibration and clinical utility of the nomogram model.Conclusion The nomogram based on intratumoral and peritumoral MRI radiomics yields a favorable diagnostic value for predicting p53 abnormal in patient with endometrial carcinoma.

Objective:To explore the effect of arrhythmia in early and intermediate postoperative stages of the Fontan procedure.Methods:Patients undergoing Fontan procedure at Shanghai Children's Medical Center within 2015 to 2018 were included.Identified data obtained from retrospective，observational dataset including demographic information，patient diagnoses，baseline characteristics，operation details，ECG data，ultrasound cardiograph data，in-hospital medical intervention，in-hospital mortality，out-patient medical intervention，readmission，and complications.Results:Among the 277 children，early arrhythmia occurred in 173 cases（62.5%），medium- and long-term arrhythmia occurred in 35 cases（12.6%），and 69 cases（24.91%）had no arrhythmia，of which only 55 cases（19.9%）needed early intervention with drugs.Malignant arrhythmia was an independent predictor of poor prognosis（ OR 5.835 95% CI 1.738-19.596, P=0.004）.Among all arrhythmia，atrioventricular junction arrhythmia had the highest incidence.During the follow-up，we found that most of the arrhythmia that had occurred in the early postoperative period could return to normal in three months after the operation，while the rhythm gradually stabilized at four years after the operation，the persistent arrhythmia almost no longer returned to normal，and the normal rhythm basically did not recur.For patients who did not develop arrhythmia in the early postoperative period，the peak of new arrhythmia occurred within one year after surgery，and most of them were persistent arrhythmia. Conclusion:The development of an arrhythmia is associated with a heightened risk of subsequent failure of the Fontan circulation，especially malignant arrhythmia.However，the incidence of malignant arrhythmia is not high.In addition，most of the arrhythmias that had occurred in the early postoperative period could return to normal in three months after surgery，and the rhythm gradually stabilized in four years after surgery.While no arrhythmia in the early postoperative period，the peak of new arrhythmia occur within one year after surgery，and most of them are persistent arrhythmia.

Objective To establish an optimized diagnostic model for hepatocellular carcinoma(HCC),designated as G-GADA,in chronic hepatitis B(CHB)patients based on the parameters of age,sex,alpha-fetoprotein(AFP),des-γ-carboxy prothrombin(DCP),and Golgi protein 73(GP73),to address the problems of low sensitivity and specificity in the early diagnosis of hepatitis B virus(HBV)-related liver cancer,and to assess the value of this model in the diagnosis of HCC.Methods A retrospective analysis was performed for 201 CHB patients(CHB group),137 patients with HBV-related liver cirrhosis(LC group),and 111 treatment-na?ve patients with newly diagnosed HCC(HCC group)who were admitted to Mengchao Hepatobiliary Hospital of Fujian Medical University from June 2015 to June 2020.Serological markers(AFP,DCP,alpha-fetoprotein L3%[AFP-L3%],and GP73)were compared between groups and were analyzed in terms of their differences from the clinical and tumor characteristics of HCC patients,and the Spearman correlation analysis was used to assess the correlation between different markers.A Logistic regression analysis was used to establish a diagnostic model for liver cancer,and the receiver operating characteristic(ROC)curve was used to assess the diagnostic performance of each marker.Results Comparison of clinical features between CHB,LC,and HCC patients showed that HCC patients had significantly higher age,proportion of male patients,and serum levels of DCP,AFP,GP73,and AFP-L3%(all P<0.05).In HCC patients,DCP levels are associated with tumor size and microvascular invasion;AFP levels are related to patient age,tumor size,tumor number,distant metastasis,and microvascular invasion;AFP-L3%levels are associated with patient age,tumor size,tumor number,distant metastasis,Milan staging,and microvascular invasion;GP73 levels are linked to tumor number,distant metastasis,and microvascular invasion(all P<0.05).The correlation analysis of the serum markers showed a strong positive correlation between AFP and AFP-L3%(r=0.71,P<0.05)and a moderate positive correlation between AFP and GP73(r=0.33,P<0.05)and between AFP-L3%and GP73(r=0.41,P<0.05).Based on the features of age,sex,DCP,AFP,and GP73,the multivariate Logistic regression analysis was used to establish a G-GADA diagnostic model for HCC,and for all patients,the G-GADA model had an area under the ROC curve(AUC)of 0.915(95%confidence interval[CI]:0.875-0.945)in the derivation cohort and 0.913(95%CI:0.862-0.950)in the validation cohort for the diagnosis of HCC.In the AFP-negative patients,the G-GADA model achieved an AUC of 0.884(95%CI:0.833-0.924)in the derivation cohort and 0.851(95%CI:0.779-0.907)in the validation cohort,and in the patients with liver cirrhosis,the G-GADA model achieved an AUC of 0.901(95%CI:0.841-0.944)in the derivation cohort and 0.885(95%CI:0.806-0.940)in the validation cohort.Conclusion The G-GADA diagnostic model based on multiple variables significantly improves the detection rate of HCC,and demonstrates superior diagnostic performance in patients with low AFP expression and those with liver cirrhosis.The G-GADA model has a better clinical application value in the noninvasive diagnosis of HCC.

Objective To investigate the protective effect and mechanism of schisandrin A(SA)on hydrogen peroxide(H2O2)-induced oxidative stress injury in renal tubular epithelial cells(HK-2).Methods HK-2 cells were cultured in vitro and divided into five groups:blank control group,model control group(treated with 600 μmol·L-1 H2O2 for 2 h),low-dose SA group(0.125 μmol·L-1 SA,24 h pretreatment+H2O2),medium-dose SA group(0.5 μmol·L-1 SA,24 h pretreatment+H2 O2),high-dose SA group(0.75 μmol·L-1 SA,24 h pretreatment+H2O2).The cell survival was assessed by CCK-8 assay;apoptosis level was tested by Annexin V-FITC/PI double staining;cell cycle distribution was detected by propidium iodide staining;oxidative markers(ROS,SOD,MDA,GSH,LDH)was determined with commercial kits;and apoptosis-related proteins(Bax,Bcl-2,Caspase-3,Cytochrome C)was evaluated by Western blot.Results Compared with the blank control,the model group reduced in cell viability and increased in apoptosis(P＜0.01),elevated in the ratio of G0/G1-phase cells and decreased in S-phase cells(P＜0.05),decreased in SOD activity and GSH content(P＜0.01),and increased in the levels of ROS,LDH,and MDA levels(P＜0.01).In all SA dose,cell apoptosis reduced(P＜0.01).In medium/high dose groups,the G0/G1-phase arrest reduced(P＜0.05).In high dose group,the S-phase cells ratio increased(P＜0.05).And in medium/high dose groups,ROS(P＜0.01)decreased in a dose-dependent manner.The SOD activity increased non-significantly in all SA groups.In SA medium/high dose groups,the LDH activity decreased in a dose-dependent manner.In all SA groups,GSH increased(P＜0.01)and MDA decreased,both in a dose-dependent manner.The Bax/Bcl-2 ratio significantly decreased(P＜0.05)in all SA groups.The caspase-3 activity decreased in medium/high dose group(P＜0.05);and Cytochrome C reduced in all SA groups(P＜0.05).Conclusion SA protects HK-2 cells against H2O2-induced oxidative injury by modulating oxidative stress,inhibiting apoptosis,and ameliorating cell cycle arrest.

Both cold stress and ischemia-reperfusion injury significantly contribute to poor prognosis after liver transplantation(LT).However,limited animal models incorporating both stimuli hinder the advance-ment of transplant-related research.Here,a simplified and reproducible isolated perfused liver model is established to simulate the stresses experienced by livers maximally during transplantation.We provide a detailed protocol for a straightforward technique that requires 20-30 min for harvesting,24-48 h for static cold storage(SCS),and 2 h for normothermic machine perfusion(NMP)to induce LT-like stresses in the liver.Hepatic injury from SCS and NMP(LT-like stresses)is evaluated using three types of parameters.The pH values and hepatic enzyme levels of cold preservation solutions and perfusate serve as dynamic indicators of hepatic injury.Bile production and portal venous resistance directly reflect liver function,whereas pathological analysis visually illustrates the location and extent of injury.This animal model eliminates the influence of hemodynamic and immune factors,yielding highly reproducible results,and is strongly recommended as a standardized animal model for inducing LT-like stresses.