Objective To investigate mechanism of levetiracetam(LEV)on rats with febrile seizures(FS)based on the dipeptidyl peptidase-4(DPP4)/glucagon-like peptide-1(GLP-1)/gluca-gon-like peptide-1 receptor(GLP-1 R)signaling axis.Methods SD juvenile rats were randomly di-vided into blank control group,model group,low-dose LEV group,medium-dose LEV group and high-dose LEV group,with 10 rats in each group.The behavioral indicators of seizures in rats were observed.Hematoxylin-eosin(HE)staining was used to detect histopathological damage in the hippo-campus.Nissl staining was employed to observe the number of Nissl bodies in hippocampal neurons.Enzyme-linked immunosorbent assay(ELISA)was utilized to measure the levels of tumor necrosis factor-α(TNF-α),interleukin-1β(IL-1β),interleukin-6(IL-6),glutamate(Glu)and γ-aminobu-tyric acid(GABA)in the hippocampus.Western blot was applied to detect the protein expressions of glial fibrillary acidic protein(GFAP),inducible nitric oxide synthase(iNOS),CD86,arginase 1(Arg1),CD206,brain-derived neurotrophic factor(BDNF),DPP4,GLP-1 and GLP-1 R in the hippocampus.Results Compared with the blank control group,the model group showed histopatho-logical changes in the hippocampus,with a decreased number of Nissl bodies.The relative protein expressions of GFAP,BDNF,iNOS,CD86 and DPP4,as well as the levels of TNF-α,IL-1β,IL-6 and Glu in the hippocampus were increased,while the relative protein expressions of Arg1,CD206,GLP-1 and GLP-1R,and the level of GABA were decreased,with statistically significant differences(P＜0.05).Compared with the model group,the seizure latency in the low-dose,medium-dose and high-dose LEV groups was prolonged in a dose-dependent manner,and the incidence of grade 3 to 5 seizures was reduced in a dose-dependent manner.The histopathological damage in the hippo-campus was alleviated,the number of Nissl bodies increased in a dose-dependent manner,the rela-tive protein expressions of GFAP,BDNF,iNOS,CD86 and DPP4,and the levels of TNF-α,IL-1β,IL-6 and Glu were decreased in a dose-dependent manner,while the relative protein expres-sions of Arg1,CD206,GLP-1 and GLP-1 R,and the level of GABA were increased in a dose-de-pendent manner,with statistically significant differences(P＜0.05).Conclusion LEV can effec-tively alleviate seizure attacks and histopathological damage in the hippocampus of FS rats,and re-duce hippocampal inflammatory responses and neurotransmitter imbalance.Its mechanism may be re-lated to the inhibition of DPP4 signaling and the activation of the GLP-1/GLP-1R signaling pathway.

Objective:To improve the risk management process for clinical trial projects using healthcare failure mode and effect analysis(HFMEA), for references for enhancing the risk identification and preventing capabilities of drug clinical trial institutions.Methods:From June to December 2022, this study focused on the project management process of a clinical trial centre in a tertiary public hospital. Following HFMEA procedures, a research team was established. Core processes prone to failure modes in the drug clinical trial project management and their potential failure modes were identified through group discussions, literature analysis, the Delphi method, and decision tree analysis. High-risk failure modes were screened via risk assessment, corresponding improvement measures were formulated and performed, and their effectiveness was validated.Results:The study identified 6 main processes, 17 sub-processes, and 102 potential failure modes. Delphi analysis confirmed 88 failure modes, with 19 having a failure risk priority number(RPN)≥8.00. Decision tree analysis identified 16 high-risk failure modes, involving 5 main processes and 10 sub-processes. Targeted improvements, such as adopting standardized hospital contract templates and setting deadlines for final payment settlement, etc., were implemented. One year post-implementation(January 2024), the RPN for all 16 high-risk failure modes were<8.00.Conclusions:HFMEA could help hospital clinical trial institutions comprehensively and systematically identify high-risk failure modes in the project management process, develop targeted improvement measures, and improve the level of drug clinical trial project management.

Objective:To improve the risk management process for clinical trial projects using healthcare failure mode and effect analysis(HFMEA), for references for enhancing the risk identification and preventing capabilities of drug clinical trial institutions.Methods:From June to December 2022, this study focused on the project management process of a clinical trial centre in a tertiary public hospital. Following HFMEA procedures, a research team was established. Core processes prone to failure modes in the drug clinical trial project management and their potential failure modes were identified through group discussions, literature analysis, the Delphi method, and decision tree analysis. High-risk failure modes were screened via risk assessment, corresponding improvement measures were formulated and performed, and their effectiveness was validated.Results:The study identified 6 main processes, 17 sub-processes, and 102 potential failure modes. Delphi analysis confirmed 88 failure modes, with 19 having a failure risk priority number(RPN)≥8.00. Decision tree analysis identified 16 high-risk failure modes, involving 5 main processes and 10 sub-processes. Targeted improvements, such as adopting standardized hospital contract templates and setting deadlines for final payment settlement, etc., were implemented. One year post-implementation(January 2024), the RPN for all 16 high-risk failure modes were<8.00.Conclusions:HFMEA could help hospital clinical trial institutions comprehensively and systematically identify high-risk failure modes in the project management process, develop targeted improvement measures, and improve the level of drug clinical trial project management.

AIM: To assess the repeatability and agreement of higher-order aberration obtained by adaptive optics visual simulator(VAO)compared with OPD-Scan Ⅲ.METHODS: A cross-sectional study was conducted from August to September 2023, including a total of 204 patients(204 eyes)with myopia whose right eyes were measured. The examinations were performed by the same skilled examiner using both devices separately. The VAO device was used to measure higher order aberrations of orders 3 to 6 at a pupil diameter of 4.5 mm, while both the VAO and OPD-Scan Ⅲ devices were utilized to measure total higher-order aberration(tHOA), spherical aberration(SA), coma aberration(Coma), and trefoil aberration(Trefoil)of the entire eye at pupil diameters ranging from 3 to 6 mm. Furthermore, the repeatability of whole eye aberration measurements obtained with the VAO device was evaluated and the agreement of the two devices was assessed.RESULTS: The whole-eye higher-order aberrations measured by VAO demonstrated excellent repeatability(0.767≤ICC≤0.941, Sw<0.01 μm, TRT<0.1 μm). There was no statistically significant difference in Coma measured by VAO or OPD-Scan Ⅲ for pupil diameters ranging from 4 to 6 mm(P>0.05), while a statistically significant difference was observed in whole-eye tHOA of other pupil diameters(all P<0.05). The agreement of aberration measurements for each order between VAO and OPD-Scan Ⅲ for 3 mm pupil diameters, SA at 4 and 5 mm pupil diameter and Coma at 4 mm pupil diameter showed a 95% limit of agreement(LoA)<0.1, indicating good agreement; however, poor agreement was found for the remaining aberration measurements at different pupil diameters, with a 95%LoA>0.1, and there were significant differences in higher-order aberrations measured by two devices under a pupil diameter of 3 mm(r=0.218-0.317, P<0.01), 4 mm(r=0.406-0.672, P<0.01), 5 mm(r=0.538-0.839, P<0.01 and r=0.030-0.109, P>0.01)and 6 mm(r=0.369-0.766, P<0.01).CONCLUSION: The VAO demonstrates favorable repeatability when assessing whole-eye higher order aberration under pupil diameters of 3-6 mm. However, there is inadequate agreement and interchangeability in whole-eye higher order aberration at 3-6 mm pupil diameter between VAO and OPD-Scan Ⅲ for clinical purposes.

Micro-computed tomography(Micro-CT)is a non-invasive technology that is widely used in animal experiments to assist in the detection of bone,lung,oral,metabolic,middle and inner ear diseases,as well as tumors,and in other animal disease models.The technique can provide diverse scientific and reliable imaging data for animal experiments and has accordingly become an indispensable experimental method in animal experiments.In this review,we introduce the imaging principles of Micro-CT,review its application in the study of animal disease models,summarize the limitations of Micro-CT technology,and consider its future prospects.

Objective:This study aims to analyze the clinical characteristics of elderly patients with lung adenocarcinoma and to construct a predictive model for assessing their survival.Methods:We conducted a retrospective analysis of clinical data sourced from the SEER database for patients aged 60 years or older who were diagnosed with lung adenocarcinoma between 2013 and 2018.Cox regression analysis was employed to identify independent prognostic factors affecting the survival of elderly lung adenocarcinoma patients, leading to the development of a nomogram model.The discriminative ability and calibration of the nomogram were assessed using the C-index and calibration curve.Each patient's total risk score was calculated based on the predictive model, and patients were stratified according to the quartiles of their total risk scores.The Kaplan-Meier method and Log-rank test were utilized to evaluate survival differences among the identified risk groups.Results:Among 38, 852 lung adenocarcinoma patients, 17, 200 were males and 21, 652 were females.Significant differences in survival rates were observed among lung adenocarcinoma patients based on age, gender, marital status, histological grade, TNM stage, tumor size, and the presence of bone, brain, or liver metastases, as well as the type of treatment received, including surgical treatment, radiation therapy, and chemotherapy(all P<0.001).The C-index of the training model was 0.815(95% CI: 0.811-0.819), while the validation model yielded a C-index of 0.810(95% CI: 0.804-0.816).The prediction model demonstrated higher Area Under Curve(AUC)values of 0.746, 0.768, and 0.775 for 1-year, 3-year, and 5-year survival in the modeling dataset, respectively, and 0.747, 0.770, and 0.777 in the validation dataset.Furthermore, the risk stratification model effectively distinguished patients at varying levels of risk( P<0.001). Conclusions:Age, gender, marital status, histological grade, TNM stage, tumor size, and the presence of bone, brain, and liver metastases, along with treatment modalities such as surgery, radiotherapy, and chemotherapy, were identified as independent prognostic factors for elderly patients with lung adenocarcinoma.The risk prediction model developed in this study effectively differentiates between patients at varying levels of risk, which holds significant implications for predicting treatment responses in elderly lung adenocarcinoma patients and advancing the practice of precision medicine.

Background:Colorectal cancer is a common malignant tumor of the digestive system,its incidence rate is increasing and seriously affect human health.Aims:To investigate whether GANT61,an inhibitor of Hedgehog signaling pathway,induces apoptosis of colon cancer cells by regulating autophagy.Methods:Colon cancer cell line SW480 was cultured in vitro and treated with GANT61 of different concentrations(0,10,20,and 40 μmol/L)for 24 h.The cell viability was measured by CCK-8 assay,and the apoptosis rate was determined by flow cytometry.Expressions of the key molecules in Hedgehog/GLI signaling pathway,as well as the proteins related to autophagy and apoptosis were detected by Western blotting and/or qRT-PCR.Then the SW480 cells were treated with combination of GANT61 and chloroquine,an autophagy inhibitor,or rapamycin,an autophagy agonist,the alterations of the apoptosis rates and the related protein expressions were assessed.Results:The viability of SW480 cells decreased and the apoptosis rate increase with the increase of GANT61 concentration.Meanwhile,the mRNA and protein expressions of GLI1,GLI2,cyclin D1(a cell cycle G1/S-specific protein),and BCL-2(an anti-apoptotic protein)were inhibited,and the protein expressions of C-PARP1(an apoptosis-related protein)and BECLIN1,LC3Ⅱ(autophagy-related proteins)were increased.Chloroquine could partially reverse the effect of GANT61 on autophagy activation and cell apoptosis,while rapamycin could promote the pro-apoptotic effect of GANT61.Conclusions:GANT61 can activate autophagy and induce apoptosis in colon cancer cells.

Background:Colorectal cancer is a common malignant tumor of the digestive system,its incidence rate is increasing and seriously affect human health.Aims:To investigate whether GANT61,an inhibitor of Hedgehog signaling pathway,induces apoptosis of colon cancer cells by regulating autophagy.Methods:Colon cancer cell line SW480 was cultured in vitro and treated with GANT61 of different concentrations(0,10,20,and 40 μmol/L)for 24 h.The cell viability was measured by CCK-8 assay,and the apoptosis rate was determined by flow cytometry.Expressions of the key molecules in Hedgehog/GLI signaling pathway,as well as the proteins related to autophagy and apoptosis were detected by Western blotting and/or qRT-PCR.Then the SW480 cells were treated with combination of GANT61 and chloroquine,an autophagy inhibitor,or rapamycin,an autophagy agonist,the alterations of the apoptosis rates and the related protein expressions were assessed.Results:The viability of SW480 cells decreased and the apoptosis rate increase with the increase of GANT61 concentration.Meanwhile,the mRNA and protein expressions of GLI1,GLI2,cyclin D1(a cell cycle G1/S-specific protein),and BCL-2(an anti-apoptotic protein)were inhibited,and the protein expressions of C-PARP1(an apoptosis-related protein)and BECLIN1,LC3Ⅱ(autophagy-related proteins)were increased.Chloroquine could partially reverse the effect of GANT61 on autophagy activation and cell apoptosis,while rapamycin could promote the pro-apoptotic effect of GANT61.Conclusions:GANT61 can activate autophagy and induce apoptosis in colon cancer cells.

Objective:To explore benchmark dose (BMD) estimations of polycyclic aromatic hydrocarbons (PAHs) based on Bayesian kernel machine regression (BKMR) .Methods:A total of 155 adult residents of a coking plant in Shanxi Province who were surveyed in summer (June to August) from 2014 to 2019 were selected as the research objects. Fasting elbow vein blood of the subjects was collected in the morning for automatic analysis and detection of blood routine. Morning urine samples were collected for automatic analysis and detection of urine routine and urine creatinine detection. BKMR model combined with BMD method was used to calculate the acceptable doses of PAHs exposure on red blood cell damage in non-occupational population.Results:The concentration of hydroxylpolycyclic aromatic hydrocarbons (OH-PAHs) in the red blood cells abnormal group ( n=117) was significantly higher than that in the normal group ( n=38) ( P<0.01). In the combined effect of OH-PAHs, 2-hydrol-naphthalene contributed the most, and the posterior inclusion probability (PIP) value was 0.9354. When OH-PAHs ≥ P55 concentration, the joint effect on the risk of red blood cell abnormalities increased as the concentration of the OH-PAHs mixture increased. When OH-PAHs were at P65 and P75 concentrations, respectively, the risk of red blood cell abnormalities in adults were 3.09 and 4.98 times that of OH-PAHs at P50 concentrations, respectively. Compared with high concentration, low concentration of OH-PAHs exposure was more sensitive to red blood cell darmage. The acceptable doses of 8 kinds of OH-PAHs were 1.010 μmol/mol Cr (2-hydrol-naphthalene), 0.743 μmol/mol Cr (1-hydrol-naphthalene), 0.901 μmol/mol Cr (2-hydroxy-fluorene) and 0.775 μmol/mol Cr (1-hydroxy-phenanthrene), 0.737 μmol/mol Cr (1-hydroxy-pyrene), 0.607 μmol/mol Cr (9-hydroxy-fluorene), 0.713 μmol/mol Cr (2-hydroxy-phenanthrene) and 0.628 μmol/mol Cr (3-hydroxybenzo[a] pyrene), respectively. Conclusion:OH-PAHs mixture has positive combined effect on red blood cell damage in non-occupational population, and low concentration of OH-PAHs exposure is more sensitive to red blood cell damage. It is recommended that the exposure dose of PAHs should be controlled within 1 μmol/mol Cr.

Objective:To explore benchmark dose (BMD) estimations of polycyclic aromatic hydrocarbons (PAHs) based on Bayesian kernel machine regression (BKMR) .Methods:A total of 155 adult residents of a coking plant in Shanxi Province who were surveyed in summer (June to August) from 2014 to 2019 were selected as the research objects. Fasting elbow vein blood of the subjects was collected in the morning for automatic analysis and detection of blood routine. Morning urine samples were collected for automatic analysis and detection of urine routine and urine creatinine detection. BKMR model combined with BMD method was used to calculate the acceptable doses of PAHs exposure on red blood cell damage in non-occupational population.Results:The concentration of hydroxylpolycyclic aromatic hydrocarbons (OH-PAHs) in the red blood cells abnormal group ( n=117) was significantly higher than that in the normal group ( n=38) ( P<0.01). In the combined effect of OH-PAHs, 2-hydrol-naphthalene contributed the most, and the posterior inclusion probability (PIP) value was 0.9354. When OH-PAHs ≥ P55 concentration, the joint effect on the risk of red blood cell abnormalities increased as the concentration of the OH-PAHs mixture increased. When OH-PAHs were at P65 and P75 concentrations, respectively, the risk of red blood cell abnormalities in adults were 3.09 and 4.98 times that of OH-PAHs at P50 concentrations, respectively. Compared with high concentration, low concentration of OH-PAHs exposure was more sensitive to red blood cell darmage. The acceptable doses of 8 kinds of OH-PAHs were 1.010 μmol/mol Cr (2-hydrol-naphthalene), 0.743 μmol/mol Cr (1-hydrol-naphthalene), 0.901 μmol/mol Cr (2-hydroxy-fluorene) and 0.775 μmol/mol Cr (1-hydroxy-phenanthrene), 0.737 μmol/mol Cr (1-hydroxy-pyrene), 0.607 μmol/mol Cr (9-hydroxy-fluorene), 0.713 μmol/mol Cr (2-hydroxy-phenanthrene) and 0.628 μmol/mol Cr (3-hydroxybenzo[a] pyrene), respectively. Conclusion:OH-PAHs mixture has positive combined effect on red blood cell damage in non-occupational population, and low concentration of OH-PAHs exposure is more sensitive to red blood cell damage. It is recommended that the exposure dose of PAHs should be controlled within 1 μmol/mol Cr.