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.

Objective: To analyze the developmental trajectories of clustered health risk behaviors and their association with self-esteem and lonelinesss among junior high school students, so as to provide a reference for formulating comprehensive prevention and control measures of health risk behaviors among adolescents. Methods: In October 2023, 1 165 first year junior high school students from two schools of Jishou City in Hunan Province were selected by convenient sampling method for three follow up surveys (T1:October 2023; T2:April 2024; T3:October 2024). The Adolescent Health Risk Behavior Questionnaire, Rosenberg Self esteem Scale and Loneliness Scale were used to assess health risk behaviors, self esteem and loneliness, respectively. Latent growth curve modeling and latent growth mixture modeling were applied to analyze the developmental trajectories of clustered health risk behaviors among junior high school students. Logistic regression was used to analyze the association of the developmental trajectories of clustered health risk behaviors with self esteem and loneliness among junior high school students. Results: The overall developmental trajectories among junior high school students showed a declining trend (intercept=0.15, slope=-1.65, both P <0.05), with three heterogeneous categories:low risk improvement group ( n =862, 74.0%), moderate risk stable group ( n =260, 22.3%), and high risk deterioration group ( n =43, 3.7%). After adjusting the status of the left behind individuals，using the low risk improvement group as the reference category in multinomial Logistic regression analysis, results indicated that higher loneliness scores among junior high school students increased the risks of belonging to the moderate risk stable group ( OR=1.02, 95%CI =1.00- 1.04 ) and the high risk deterioration group ( OR=1.04, 95%CI =1.00-1.08), while higher self esteem scores reduced the risks of belonging to the moderate risk stable group ( OR=0.93, 95%CI =0.91-0.96) and the high risk deterioration group ( OR=0.88, 95%CI =0.83-0.94) (all P <0.05). Conclusions The overall trend of clustered health risk behaviors among junior high school students gradually improves, and the self esteem and loneliness are significant correlative factors. Targeted intervention measures should be developed for the junior high school students, with a focus on enhancing their self esteem and alleviating loneliness.

Objective: To investigate the relationship between 24 hour activity behaviors and fine motor development in preschool children, and to simulate the effects of reallocating time among different activity behaviors on fine motor development using isotemporal substitution analysis. Methods: From March to July 2022, a stratified cluster random sampling method was used to recruit 447 preschool children aged 3-6 years (254 boys and 193 girls) from Pingxiang City, Jiangxi Province. The 24 hour activity behaviors in preschool children were measured using ActiGraph wGT3-BT accelerometers and subjective sleep reports. Fine motor development was assessed using the Gesell Developmental Schedules. A component linear regression model was employed to analyze the impact of 24 hour activity behaviors on the development of fine motor activities, and the potential effects of adjusting activity behaviors were simulated through an isochoric substitution model. Results: The daily durations of sedentary behavior (SB) was ( 572.92 ±102.96) min (accounting for 39.79% of 24 h), the duration of light physical activity (LPA) was (131.21± 38.11 ) min ( 9.11% ), the duration of moderate to vigorous physical activity (MVPA) was (65.61±22.21) min (4.56%), and sleep duration was (670.65±57.58) min (46.82%). Sleep composition was positively associated with fine motor development ( β =2.74), while MVPA ( β =-0.84) and SB ( β =-1.93) compositions were negatively associated with fine motor development (all P <0.01). Isochoric substitution analysis showed that sleep had positive effects on the development of fine motor skills when replacing other activity behaviors (all P < 0.05), with the substitution effect for MVPA being the most significant and gradually increasing with the duration of substitution (60 min: β =28.66); sleep replacement of SB and LPA also showed positive effects (60 min: β =4.25, 2.00) (all P < 0.05). On the contrary, the substitution of sleep with MVPA showed negative effects (60 min: β =-7.86), and the substitution of LPA and SB with MVPA also showed negative effects (60 min: β =-5.65, -3.40) (all P <0.05). Conclusions The overall composition of 24 hour activity behaviors is associated with fine motor development in preschool children, with sleep playing a crucial role. Ensuring adequate sleep and optimizing the structure of activity behaviors may effectively promote the development of fine motor skills in preschool children.

Diabetic kidney disease （DKD） is a kidney disease caused by hyperglycemia，which is one of the most common microvascular complications of diabetes. Due to the high incidence of diabetes，the incidence of DKD has also increased year by year，and DKD has become a global public health problem. The pathogenesis of DKD is related to mechanisms such as oxidative stress，inflammation，renal fibrosis，and decreased mitophagy activity，which are developed under a variety of complex mechanisms. In traditional Chinese medicine，it is believed that the incidence of DKD is closely related to damp heat. Therefore，it is necessary to grasp the treatment method of clearing heat and removing dampness in clinical medication. Huangkui Capsules （HKC） have the effect of clearing damp heat，detoxifying， and detumescence. Because of its unique curative effect on DKD，HKC is often used in the treatment of DKD. HKC plays a role in the treatment of DKD with a variety of pharmacokinetic and pharmacodynamic processes. In many laboratory studies，it has been found that the specific mechanisms of HKC in the treatment of DKD include increasing mitophagy，reducing mitochondrial damage，reducing renal fibrosis，controlling inflammatory response，and inhibiting oxidative stress，which can achieve the purpose of reducing renal damage and promoting renal function. Some clinical studies have also verified that the application of HKC alone can exert renal protective function through anti-inflammatory，anti-oxidative stress，anti-renal fibrosis effects，as well as reduction of urinary protein. Since DKD is not a single injury of renal function，it is often accompanied by problems in blood pressure，blood lipids，blood circulation，body immunity， and other aspects. Therefore，the combination of HKC with other drugs can often achieve more comprehensive results，improve the advantages of various drugs，and improve the therapeutic effect. The combination of drugs such as antihypertensive，lipid-lowering， vascular circulation improvement，immunity inhibition，and anti-oxidative stress with HKC has achieved good results. In addition，HKC is often used in combination with other Chinese patent medicines in clinics. The application of HKC in the treatment of DKD has made some progress，but there are still many places worthy of further study，and the research on the mechanism of HKC is not comprehensive enough. The research on its long-term effect and safety in clinical application is relatively lacking，and the drug variety is relatively single when combined with certain drugs. These problems deserve further attention. Finally，it is necessary to pay attention to the promotion and application of HKC in clinical practice so that HKC can be better applied in clinical practice and better solve practical problems for patients.

Diabetic kidney disease （DKD） is a kidney disease caused by hyperglycemia，which is one of the most common microvascular complications of diabetes. Due to the high incidence of diabetes，the incidence of DKD has also increased year by year，and DKD has become a global public health problem. The pathogenesis of DKD is related to mechanisms such as oxidative stress，inflammation，renal fibrosis，and decreased mitophagy activity，which are developed under a variety of complex mechanisms. In traditional Chinese medicine，it is believed that the incidence of DKD is closely related to damp heat. Therefore，it is necessary to grasp the treatment method of clearing heat and removing dampness in clinical medication. Huangkui Capsules （HKC） have the effect of clearing damp heat，detoxifying， and detumescence. Because of its unique curative effect on DKD，HKC is often used in the treatment of DKD. HKC plays a role in the treatment of DKD with a variety of pharmacokinetic and pharmacodynamic processes. In many laboratory studies，it has been found that the specific mechanisms of HKC in the treatment of DKD include increasing mitophagy，reducing mitochondrial damage，reducing renal fibrosis，controlling inflammatory response，and inhibiting oxidative stress，which can achieve the purpose of reducing renal damage and promoting renal function. Some clinical studies have also verified that the application of HKC alone can exert renal protective function through anti-inflammatory，anti-oxidative stress，anti-renal fibrosis effects，as well as reduction of urinary protein. Since DKD is not a single injury of renal function，it is often accompanied by problems in blood pressure，blood lipids，blood circulation，body immunity， and other aspects. Therefore，the combination of HKC with other drugs can often achieve more comprehensive results，improve the advantages of various drugs，and improve the therapeutic effect. The combination of drugs such as antihypertensive，lipid-lowering， vascular circulation improvement，immunity inhibition，and anti-oxidative stress with HKC has achieved good results. In addition，HKC is often used in combination with other Chinese patent medicines in clinics. The application of HKC in the treatment of DKD has made some progress，but there are still many places worthy of further study，and the research on the mechanism of HKC is not comprehensive enough. The research on its long-term effect and safety in clinical application is relatively lacking，and the drug variety is relatively single when combined with certain drugs. These problems deserve further attention. Finally，it is necessary to pay attention to the promotion and application of HKC in clinical practice so that HKC can be better applied in clinical practice and better solve practical problems for patients.

AIM: To investigate the effects of insulin-like growth factor 1(IGF-1)on the secretion of transforming growth factor β2(TGF-β2), matrix metalloproteinase 2(MMP-2)and hypoxia-inducible factor 1α(HIF-1α)in human scleral fibroblasts(HSF)and their mechanism.METHODS: The cells were cultured with IGF-1 and PI3K/AKT pathway inhibitor LY294002, respectively. CCK-8 method was used to detect cell viability and determine the optimal concentration and time of drug action. Cell migration activity was observed by cell scratch method. To determine the effects of IGF-1 on HSF cells and the regulatory role of PI3K/AKT pathway, HSF cells were divided into control group(without drugs), IGF-1(80 μg/L)group, IGF-1+LY294002(80 μg/L+5 mmol/L)group, and LY294002(5 mmol/L)group, and were cultured for 24 h; the protein expression levels of TGF-β2, MMP-2, HIF-1α, PI3K and AKT were detected by Western blot; the fluorescence expression of TGF-β2, MMP-2 and HIF-1α was detected by cellular immunofluorescence.RESULTS: The results of CCK-8 showed that the cell viability of the 80 μg/L IGF-1 group cultured with different concentrations of IGF-1 was the highest(all P<0.05), and the cell viability of the 80 μg/L IGF-1 group at 24 h was the highest under different culture times. Therefore, the concentration of IGF-1 was selected as 80 μg/L for 24 h. The viability of cells cultured with different concentrations of LY294002 gradually decreased from 6 h(all P<0.05). According to the IC50 value, therefore, the concentration of LY294002 was selected as 5 mmol/L for 24 h. The cell scratch results showed that compared with the control group, the cell mobility of 40 μg/L and 80 μg/L IGF-1 groups was increased(all P<0.05). Compared with the control group, cell mobility in the 2.5 and 5 mmol/L LY294002 groups was decreased(all P<0.05). Western blot results showed that compared with the control group, the protein expressions of TGF-β2, MMP-2, HIF-1α, PI3K and AKT in the IGF-1 group were increased, while those in the LY294002 group were decreased(all P<0.05). Compared with the IGF-1 group, the expression levels of TGF-β2, MMP-2, HIF-1α, PI3K and AKT in the IGF-1+LY294002 group were decreased(all P<0.05). The results of cell immunofluorescence showed that compared with the control group, the fluorescence expressions of TGF-β2, MMP-2 and HIF-1α in the IGF-1 group were increased, while those in the LY294002 group were decreased(all P<0.05). Compared with the IGF-1 group, the fluorescence expressions of TGF-β2, MMP-2 and HIF-1α in the IGF-1+LY294002 group were significantly decreased(all P<0.05).CONCLUSION: IGF-1 promoted the proliferation and migration of human HSF. IGF-1 may up-regulate the expression of TGF-β2, MMP-2 and HIF-1α in HSF through the PI3K/AKT signaling pathway, and participate in the occurrence and development of myopia.

BACKGROUND:The immune-related pathogenesis of Alzheimer's disease is still unclear.Exploring the correlation between natural killer cells and cuproptosis mechanism in Alzheimer's disease patients through bioinformatics can provide a new direction for the study of the occurrence and development of Alzheimer's disease. OBJECTIVE:To screen the key genes related to cuproptosis of natural killer cells in peripheral blood of patients with Alzheimer's disease by bioinformatics analysis and verify them in clinical specimens. METHODS:The GEO online database was used to screen the transcriptome differentially expressed genes and natural killer cell related genes in the peripheral blood of patients with Alzheimer's disease,and intersected with the reported cuproptosis factors.Differentially expressed cuproptosis-related genes were obtained.Then RT-qPCR technology was used to verify the relative gene expression levels.The experimental samples were all from peripheral blood of hospitalized patients in the Department of Neurology of Anhui Provincial Hospital from 2021 to 2023,and 30 patients in the disease group and 20 in the control group were included according to the inclusion and exclusion criteria.The protein-protein interaction network was further constructed using the online GeneMANIA website.R language was used for immune infiltration analysis.Transcription factor prediction was conducted based on ENCODE database. RESULTS AND CONCLUSION:(1)The differential expression genes of peripheral blood transcriptome of Alzheimer's disease patients in GSE63060 data set,natural killer cell related genes in GSE168522 data set,and reported cuproptosis genes were used to screen and obtain four differentially expressed cuproptosis-related genes by using online Venn diagram tool,LASSO algorithm,and random forest machine learning methods:ferredoxin 1(FDX1),ATPase Cu2+transporting alpha polypeptide(ATP7A),pyruvate dehydrogenase El subunit beta(PDHB),and dihydrolipoamide succinyltransferase(DLST).(2)Clinical sample experiments showed that FDX1 and ATP7A were up-regulated in peripheral blood of patients with Alzheimer's disease(P<0.001),and were differentially expressed in different genotypes of apolipoprotein E4(P<0.01,P<0.001).The expression of PDHB and DLST in peripheral blood of patients with Alzheimer's disease was down-regulated(P<0.001),and there was no difference in apolipoprotein E4 genotypes(P>0.05).(3)Protein-protein interaction network found that 20 functional proteins were associated with key genes,and immunoinfiltration analysis showed that key genes were significantly associated with 12 immune cells(P<0.05 was considered to be relevant).(4)Bioinformatics analysis and experimental verification results suggest that FDX1,ATP7A,PDHB,and DLST are differentially expressed in Alzheimer's disease,may participate in the occurrence and development of Alzheimer's disease through the cuproptosis mechanism in peripheral blood natural killer cells,and also provide potential targets for the diagnosis and treatment of Alzheimer's disease.

Objective: To investigate the sleep quality in patients with burning mouth syndrome (BMS) and its influencing factors, providing a basis for developing sleep intervention measures to reduce the impact of BMS symptoms. Methods: This study was reviewed and approved by the Medical Ethics Committee, and informed consent was obtained from patients. A total of 150 patients with BMS and 150 healthy volunteers were enrolled as subjects in this study. The Pittsburgh sleep quality index (PSQI) was used to assess the sleep quality of patients with BMS. Visual analog scale (VAS) was used to assess the degree of oral mucosal pain, generalized anxiety disorder 7-item scale (GAD-7) was used to assess the frequency of anxiety symptoms, and the patient health questionnaire depression questionnaire (PHQ-9) was used to assess the frequency of depression symptoms. Univariate analysis was performed to identify potential influencing factors affecting sleep quality in patients with BMS, and multiple linear regression analysis was employed to determine independent risk factors. Results: The PSQI score for patients with BMS was 7.61 ± 4.29, which was significantly higher than that of healthy controls (P = 0.016). In the PSQI subscale analysis, patients with BMS exhibited increased sleep latency, decreased sleep duration, and lower sleep efficiency compared to healthy controls (P<0.05). Patients with BMS and comorbid sleep difficulties had significantly higher scores on GAD-7 and PHQ-9 compared to the patients with BMS without sleep difficulties (P<0.001), but there was no significant difference in pain VAS scores between the two (P = 0.068). Multiple linear regression analysis revealed that longer disease duration (>6 months), the presence of systemic concomitant symptoms (such as headache and mental stress), and higher depression scores were identified as independent risk factors affecting sleep quality in patients with BMS. Conclusion For patients with BMS, long course of illness, presence of headaches, high mental stress, and depressive symptoms may be independent factors affecting their sleep quality.

Background: The immune system plays a critical role in the development and progression of osteoporosis and fractures. However, the causal relationships between antibody immune responses, immune cells, and these bone conditions remain unclear. This study aimed to explore these relationships using Mendelian randomization (MR) analysis. Methods: We collected complete blood count data from patients with fractures and healthy individuals and analyzed their differences. Then, we conducted a 2-sample, 2-step MR analysis to investigate the causal effects of antibody immune responses on osteoporosis and fractures, using inverse-variance weighted (IVW) as the primary method. We also explored whether immune cells mediate the pathway between antibodies and osteoporosis or fractures. Finally, we analyzed the functions and expression levels of key genes involved. Results: Overall, the fracture group exhibited increased white blood cell count, absolute neutrophil count, absolute monocyte count, platelet count, and their respective proportions, while absolute lymphocyte count, absolute eosinophil count, absolute basophil count, red blood cell count, and their proportions were decreased. We identified 44 causal relationships between antibodies and osteoporosis or fractures, with 7 supported by multiple MR methods, and 5 showing odds ratios significantly deviating from 1 in the IVW analysis. Epstein-Barr virus-related antibodies had a notable impact on osteoporosis and fractures. The human leukocyte antigen (HLA) gene family, particularly HLA-DPB1, emerged as a significant risk factor. However, immune cells were not found to mediate these effects. Conclusions This study elucidated the causal relationships between antibody immune responses, immune cells, and osteoporosis or fractures. The HLA gene family plays a crucial role in the interaction between antibodies and these bone conditions, with HLA-DPB1 identified as a key risk gene. Immune cells do not serve as mediators in this process. These findings provide valuable insights for future research.

Background: The immune system plays a critical role in the development and progression of osteoporosis and fractures. However, the causal relationships between antibody immune responses, immune cells, and these bone conditions remain unclear. This study aimed to explore these relationships using Mendelian randomization (MR) analysis. Methods: We collected complete blood count data from patients with fractures and healthy individuals and analyzed their differences. Then, we conducted a 2-sample, 2-step MR analysis to investigate the causal effects of antibody immune responses on osteoporosis and fractures, using inverse-variance weighted (IVW) as the primary method. We also explored whether immune cells mediate the pathway between antibodies and osteoporosis or fractures. Finally, we analyzed the functions and expression levels of key genes involved. Results: Overall, the fracture group exhibited increased white blood cell count, absolute neutrophil count, absolute monocyte count, platelet count, and their respective proportions, while absolute lymphocyte count, absolute eosinophil count, absolute basophil count, red blood cell count, and their proportions were decreased. We identified 44 causal relationships between antibodies and osteoporosis or fractures, with 7 supported by multiple MR methods, and 5 showing odds ratios significantly deviating from 1 in the IVW analysis. Epstein-Barr virus-related antibodies had a notable impact on osteoporosis and fractures. The human leukocyte antigen (HLA) gene family, particularly HLA-DPB1, emerged as a significant risk factor. However, immune cells were not found to mediate these effects. Conclusions This study elucidated the causal relationships between antibody immune responses, immune cells, and osteoporosis or fractures. The HLA gene family plays a crucial role in the interaction between antibodies and these bone conditions, with HLA-DPB1 identified as a key risk gene. Immune cells do not serve as mediators in this process. These findings provide valuable insights for future research.