OBJECTIVE To confirm trigger items for adverse drug reaction （ADR） induced by bevacizumab， to identify and analyze the occurrence of related ADR， and to establish a predictive model for severe adverse reaction （SAR） caused by this drug. METHODS Based on the global trigger tool （GTT） theory， and referencing the GTT White Paper， drug package inserts and relevant literature， trigger items for bevacizumab-related ADR were confirmed using a single-round Delphi method. Utilizing these established items， electronic medical records of relevant patients at Guilin People’s Hospital from January 2020 to September 2024 were actively screened via the China Hospital Pharmacovigilance System. Pharmacists then identified and tallied the occurrence of bevacizumab-induced ADR. Data from patients with any positive trigger item served as the study subjects （divided into training and test sets at a ratio of 7∶3）， candidate feature variables were selected from 39 related variables using the Boruta algorithm， and the multivariable Logistic regression analysis was performed with the occurrence of SAR as the dependent variable. Based on these candidate features， Logistic Regression， Extreme Gradient Boosting， Light Gradient Boosting Machine， Random Forest， and Categorical Boosting models were constructed. Model performance was evaluated using metrics including the area under the curve （AUC） of receiver operating characteristic curve and recall rate. The Shapley Additive exPlanations （SHAP） method was applied to analyze and interpret the contribution of each variable. A nomogram was constructed based on the optimal model. RESULTS A total of 38 trigger items for active monitoring of bevacizumab-related ADR were determined， comprising 17 laboratory indicators， 13 clinical manifestations， and 8 intervention measures. In total， 483 patients with positive trigger items were included， and 318 patients with bevacizumab-induced ADR were identified， including 83 SARs. The positive predictive values for the trigger items and cases were 43.57% （708/1 625） and 63.84% （318/483）， respectively. Bevacizumab-induced ADR involved 7 systems/organs， with the hematological system being the most frequently involved （64.15%）. The Boruta algorithm selected 7 vari ables： serum potassium， hematocrit， albumin-to-globulin ratio， prealbumin， hypertension history， age and red blood cell count. Multivariable Logistic regression showed that elevated serum potassium levels were associated with a decreased risk of bevacizumab-induced SAR （OR＝0.234， P ＝0.002）， while a history of hypertension （OR＝2.642， P ＝0.006） and increased age （OR＝1.040， P ＝0.025） were associated with an increased risk. The Logistic Regression model demonstrated superior performance with higher AUC， F1 score and recall rate （0.761， 0.447， 0.607）， compared to other models. SHAP evaluation results indicated that variables such as serum potassium， hematocrit， and age ranked highest in importance. CONCLUSIONS Totally 38 trigger entries have been successfully identified for active screening of bevacizumab-related ADR. Elevated serum potassium levels are a protective factor against bevacizumab-induced SAR， whereas the hypertension history and increased age are risk factors. The Logistic Regression model is the optimal predictive model.

Background Procymidone (PCM) exposure can cause damage to reproductive organs of male mice, but whether its mechanism is related to the retinoic acid (RA) signaling pathway is unclear. Objective To explore the possible mechanism of PCM-induced testes damage in adolescent mice. Methods Three-week-old ICR mice (n=64) were randomly divided into a control group and three dose groups (low, medium, and high), with 16 mice in each group. PCM was administered orally at 0, 50, 100, and 200 mg·kg⁻¹·d⁻¹ for 21 consecutive days. Serum and bilateral testes in each mouse were collected to detect content of testosterone in serum and to observe histological changes in testis section after the mice were sacrificed one week after cessation of drug administration. Real-time fluorescence quantitative PCR and Western blotting were used to detect the mRNA expression abundances of genes related to the RA signaling pathway and apoptosis genes Casp9 and Casp12, and the protein expression levels of CYP26A1, ALDH2, and CASP9 respectively. Results Compared with the control group, there was no significant change in the overall appearance and testicular appearance of mice in each dose group after the PCM exposure. According to pathological section observation, the testicular seminiferous tubules of mice in the low-dose group showed slight atrophy and reduced sperm production; the testes of mice in the medium- and the high-dose groups showed obvious pathological damage (e.g. dilated lumen of seminiferous tubules, damaged spermatogenic epithelium, decreased number of spermatogonia, and partial absence of sertoli cells); as the concentration of PCM increased, the degree of spermatogenic epithelial damage in mice gradually increased and the number of spermatozoa in the seminiferous tubules decreased. There were no significant differences in the distance between the anus and the genitals, testicular mass, testicular volume, and testicular organ coefficient among the four groups of mice (P>0.05). The body weights of the mice in the low-, medium-, and high-dose groups were (34.91±1.89), (34.88±1.75), and (32.94±1.37) g respectively, and that in the high-dose group was lower than that in the control group, (35.93±1.99) g, (P<0.05); the serum testosterone concentrations were (313.77±5.32), (305.31±3.47), and (304.80±5.28) pg·mL⁻¹ respectively, which were lower than that in the control group, (319.05±1.92) pg·mL⁻¹ (P<0.05); as the dose of PCM increased, the body weight and serum testosterone concentration showed decreasing trends. The mRNA expression levels of Stra6 and Rbp1 in the high-dose group were higher than those in the control group (P<0.05); the mRNA expression levels of Aldh2, Aldh1a1, Aldh1a3, Rarα, Rar\begin{document}$\beta $\end{document}, Rxrα and Rxr\begin{document}$\beta $\end{document} in the medium-and the high-dose groups were higher than those in the control group (P<0.05); the mRNA expression levels of Cyp26a1 and Cyp26b1 in the medium- and high-dose groups were lower than those in the control group(P<0.05); the mRNA expression levels of apoptosis genes Casp9 and Casp12 in the medium-and the high-dose groups were higher than those in the control group (P<0.05). The protein expression level of CYP26A1 in each exposure group was lower than that in the control group (P<0.05), and the expression level decreased with increasing concentration of PCM; the expression level of ALDH2 protein in the medium- and the high-dose groups and the protein expression level of CASP9 in each exposure group were higher than those in the control group (P<0.05), and the levels increased with increasing concentration of PCM. Conclusion PCM can damage the testis tissues of adolescent mice, where RA signaling pathway, Casp9 and Casp12 genes, and CASP9 protein are activated.

Objective To explore the effect of radiofrequency heating on type Ⅱ collagen expression in a rabbit model of osteoarthritis.Methods Knee osteoarthritis was induced in the right hind legs of 54 male rabbits using modified Hulth modeling.The rabbits were randomly divided into a model group which was not given any special treatment,a Lugua polypeptide group and a radiofrequency hyperthermia group.The Lugua polypeptide group was injected with Lugua polypeptide;the radiofrequency hyperthermia group was treated with radiofrequency irradiation.Six,12 and 18 days after the treatment,the morphological condition of the rats' right femoral medial condyle cartilages were evaluated using modified Mankins scoring and the type Ⅱ collagen content of the cartilage was detected using a quantitative PCR technique.Results At the same time points after treatment,the average Mankins scores were decreased in all the 3 groups,with that of the model group was significantly higher than those of both of the other groups,and the radiofrequency hyperthermia group's average score was significantly better than that of the Lugua polypeptide group.The average type Ⅱ collagen content was significantly increased in all the 3 groups to various extent (the radiofrequency hyperthermia group ＞ Lugua polypeptide group ＞ model group).For the radiofrequency hyperthermia group,the average Mankins score decreased significantly and the average type Ⅱ collagen content increased significantly as the treatment continued.Conclusion Radiofrequency hyperthermia is superior to Lugua polypeptide for treating knee osteoarthritis,at least in rabbits.Its therapeutic effectiveness may be related to a significant increase of type Ⅱ collagen in the cartilage.

Objective To explore the effect of radiofrequency-induced hyperthermia on the morphology of articular cartilage and any changes in serum-1 interleukin-1 (IL-1β) and tumor necrosis factor-alpha (TNF-α) in the process of knee osteoarthritis in rabbits.Methods Fifty-four male rabbits were selected and knee osteoarthritis was introduced to their right hind limbs using the modified Huhh model.They were then randomly divided into a model group,a cervus and cucumis polypeptide (CCP) group and a radiofrequency thermotherapy (RT) group,each of 18.The CCP group was injected with deer melon peptide intramuscularly.The RT group was given radiofrequency hyperthermia treatment.The model group was not provided with any special treatment.On the 7th,13th and 19th day of the treatment,6 rabbits in each group were sacrificed to resect the right medial femoral condyle cartilage.The morphological characteristics of the cartilage were evaluated using the modified Mankins score,while the content of IL-1βand TNF-α in the serum were detected using enzyme-linked immuno-sorbent assays (ELISAs).Results At the same time points,the average Mankins score and the average content of IL-1βand TNF-α in the serum of the model group were significantly higher than in the CCP group,with the values in the latter group significantly higher than in the RT group.In the RT group,the average Mankins score,as well as the IL-1 beta and TNF-alpha levels in the serum,decreased significantly with longer treatment.Conclusion Radiofrequency-induced hyperthermia is superior to deer melon polypeptide in treating knee osteoarthritis,at least in rabbits.Its therapeutic mechanism may be related to the control of serum IL-1 beta and TNF-alpha levels.