BACKGROUND:Our previous studies found that decreased expression of connexin 43 and its Ser368 phosphorylation after myocardial hypothermic ischemia-reperfusion was closely associated with decreased cardiac conduction velocity and reperfusion arrhythmia.OBJECTIVE:To observe the effect of changes in membrane-type matrix metalloproteinase 2,matrix metalloproteinase 2 and collagen type Ⅳ on the expression of connexin 43 and its Ser368 phosphorylation and electrical conduction in the myocardial extracellular matrix after hypothermic ischemia-reperfusion.METHODS:Sixteen Langendorff extracorporeal cardiac perfusion models were successfully established from SD rats and randomly divided into a control group(n=8)and a hypothermic ischemia-reperfusion group(n=8).The control group was balanced perfused with 37 ℃ Krebs-Henseleit solution for 15 minutes and then continued to be perfused with 37 ℃ Krebs-Henseleit solution for 90 minutes.The hypothermic ischemia-reperfusion group was balanced perfused with 37 ℃ Krebs-Henseleit solution for 15 minutes,and then the heart was arrested for 60 minutes by injection of 4 ℃ Thomas solution.During the cardiac arrest,the periphery was protected by 4 ℃ Krebs-Henseleit solution.Half-volume 4 ℃ Thomas solution was reperfused 30 minutes after the arrest.After stopping the arrest,the heart was reperfused with 37 ℃ Krebs-Henseleit solution for 30 minutes.The occurrence of arrhythmias,rebeating time,and the duration of arrhythmias were recorded from the immediate time point to the end of the reperfusion period.Conduction velocity,absolute inhomogeneity,and inhomogeneity index were measured using the Mapping Lab multi-channel electrophysiological mapping system at the time of balanced perfusion for 15 minutes(T1),reperfusion for 15 minutes/continuous perfusion for 90 minutes(T2),and reperfusion for 30 minutes/continuous perfusion for 105 minutes(T3).The relative expression levels of membrane-type matrix metalloproteinase 2,matrix metalloproteinase 2,collagen type Ⅳ,connexin 43,and its Ser368 phosphorylation in ventricular tissue were detected by western blot assay.RESULTS AND CONCLUSION:(1)No arrhythmia occurred in the control group.There were six cases of arrhythmia in the hypothermic ischemia-reperfusion group during reperfusion.Rebeating time and duration of arrhythmias were(25.38+12.02)and(158.67±67.68)seconds,respectively.(2)The conduction sochronal diagrams at T1,T2,and T3 in the control group were uniform and regular in direction,and the conduction velocity at T2 and T3 was not different from that at T1(P＞0.05).The conduction isochronal diagrams at T2 and T3 in the hypothermic ischemia-reperfusion group were uneven and irregular in direction,and the conduction velocity was slower than that at T1(P＜0.01).The conduction velocity at T2 and T3 in the hypothermic ischemia-reperfusion group was slower than that in the control group(P＜0.01).Conduction dispersion was greater in the hypothermic ischemia-reperfusion group than that in the control group at T2 and T3(P＜0.05).(3)Compared with the control group,the protein expressions of membrane-type matrix metalloproteinase 2 and matrix metalloproteinase 2 in the hypothermic ischemia-reperfusion group were increased(P＜0.05 or P＜0.01),and the protein expression levels of type Ⅳ collagen,connexin 43 and its Ser368 phosphorylation were decreased(P＜0.05 or P＜0.01).(4)The results indicate that after hypothermic ischemia-reperfusion,myocardial extracellular matrix remodeling may mediate the downregulation of myocardial connexin 43 and its Ser368 phosphorylation,slowed conduction velocity and increased conduction dispersion,thereby increasing the risk of arrhythmia.

Objective:To establish a three-dimensional U-shaped residual coordinated attention network (URCA-Net) based on enhanced CT images for small bowel polyp detection and analyze its application effectiveness in intelligent detection of small bowel polyps.Methods:Abdominal CT data of patients with small bowel polyps were collected from the Air Force Medical Center between June 2019 and July 2023. All patients underwent bowel preparation followed by thin-slice spiral CT scanning to obtain enhanced CT arterial phase images. The data were randomly divided into training, validation and test sets in an 8∶1∶1 ratio. The URCA-Net deep learning model was used for small bowel polyp segmentation. The training set was used for model parameter training, the validation set for hyperparameter adjustment and monitoring of model generalization performance and the test set for final unbiased evaluation of the model. An early intelligent detection model for small bowel polyps was constructed, and its performance was evaluated. Evaluation metrics included pixel-level metrics for the segmentation task [Dice Similarity Coefficient (DSC)], as well as sensitivity and precision for polyp detection. A two-stage segmentation strategy was adopted: the first stage segmented the small bowel region to remove external interference, and the second stage performed polyp segmentation within the small bowel region.Results:A total of 78 subjects were included in the study, with an average age of (54±7) years. A total of 23 400 scan images were extracted, including 136 hyperplastic polyps, 298 hamartomatous polyps, 14 adenomatous polyps, and 4 cancerous polyps. On the test set, the average DSC for the first stage (small bowel segmentation) and the second stage (polyp segmentation) was 0.790 and 0.314, respectively. In the second stage task (polyp segmentation based on small bowel region), the polyp segmentation DSC increased to 0.701, with a precision of 0.836 (95% CI: 0.700-0.972) and a sensitivity of 0.759 (95% CI: 0.631-0.888) for polyp detection. Conclusion:The URCA-Net deep learning technique demonstrates good auxiliary diagnostic effectiveness in small bowel polyp detection and can provide a reference for screening and detection of small bowel polyps. The model is capable of generating high-quality segmentation results, which could facilitate evaluating polyp lesion morphology and provide support for downstream tasks such as preoperative navigation and risk prediction.

OBJECTIVE To establish a population pharmacokinetic(PopPK)model to predict the PK characteristics of GLS-010 in humans.METHODS Fifty-eight cynomolgus monkeys were used,18 of which were randomly divided into three groups and received a single intravenous infusion of GLS-010 at doses of 2,6,and 18 mg·kg-1,respectively.The rest were randomly assigned to four groups and received multiple intravenous infusions of GLS-010 at doses of 0,5,25,and 100 mg·kg-1,respectively,once a week(quaque week,qw)for five consecutive weeks.Blood samples were collected before and after administration.The concentrations of GLS-010 in the monkey serum were measured using a validated enzyme-linked immunosorbent assay,while those of anti-drug antibodies(ADA)in the cynomolgus monkey serum were determined by ultra-sensitive electrochemiluminescence immunoassay.The PK data on GLS-010 in cynomolgus monkeys was obtained,and the drug-time curves were plotted.A PopPK model was constructed using non-compartmental analysis and evaluated by goodness-of-fit plots and visual predictive checks.The constructed PopPK model was used to predict the PK characteristics in humans,which were finally compared with actual Phase Ⅰ clinical study results for validation.RESULTS The predictive results of the PopPK model were highly consistent with the actual Phase Ⅰ clinical study results.The model was able to predict the human PK characteristics under various dosing regimens,including 1 mg·kg-1 quaque 2 weeks(q2w),4 mg·kg-1(q2w),240 mg(q2w),240 mg(q3w),and 10 mg·kg-1(q2w).The predicted maximum plasma concentrations(Cmax)were 24.8,99.1,85.0,85.0,and 247.8 mg·L-1,respectively,and the AUC0-336h was 4 902.0,20 060.0,17 147.7,22 145.7(AUC0-504h),and 50 817.6 mg·h·L-1,respectively.The safety risks for the corresponding dosing regimens were 47.3,11.6,13.5,10.5,and 4.6,respectively.The predicted receptor occupancy at steady state(ROss)at Cmax,average plasma concentration(Cavg),and minimum plasma concentration(Cmin)were 38.8％,72.7％,69.4％,64.1％and 87.2％,29.1％,63.8％,60.0％,49.8％and 82.1％,21.9％,55.5％,51.3％,36.3％and 76.7％,respectively.CONCLUSION The PopPK model can effectively predict the human PK characteristics under different dosing regimens with high consistency with actual Phase Ⅰ clinical study results,which can serve as an important reference for selection of safe and effective doses for first-in-human research.

OBJECTIVE To establish a population pharmacokinetic(PopPK)model to predict the PK characteristics of GLS-010 in humans.METHODS Fifty-eight cynomolgus monkeys were used,18 of which were randomly divided into three groups and received a single intravenous infusion of GLS-010 at doses of 2,6,and 18 mg·kg-1,respectively.The rest were randomly assigned to four groups and received multiple intravenous infusions of GLS-010 at doses of 0,5,25,and 100 mg·kg-1,respectively,once a week(quaque week,qw)for five consecutive weeks.Blood samples were collected before and after administration.The concentrations of GLS-010 in the monkey serum were measured using a validated enzyme-linked immunosorbent assay,while those of anti-drug antibodies(ADA)in the cynomolgus monkey serum were determined by ultra-sensitive electrochemiluminescence immunoassay.The PK data on GLS-010 in cynomolgus monkeys was obtained,and the drug-time curves were plotted.A PopPK model was constructed using non-compartmental analysis and evaluated by goodness-of-fit plots and visual predictive checks.The constructed PopPK model was used to predict the PK characteristics in humans,which were finally compared with actual Phase Ⅰ clinical study results for validation.RESULTS The predictive results of the PopPK model were highly consistent with the actual Phase Ⅰ clinical study results.The model was able to predict the human PK characteristics under various dosing regimens,including 1 mg·kg-1 quaque 2 weeks(q2w),4 mg·kg-1(q2w),240 mg(q2w),240 mg(q3w),and 10 mg·kg-1(q2w).The predicted maximum plasma concentrations(Cmax)were 24.8,99.1,85.0,85.0,and 247.8 mg·L-1,respectively,and the AUC0-336h was 4 902.0,20 060.0,17 147.7,22 145.7(AUC0-504h),and 50 817.6 mg·h·L-1,respectively.The safety risks for the corresponding dosing regimens were 47.3,11.6,13.5,10.5,and 4.6,respectively.The predicted receptor occupancy at steady state(ROss)at Cmax,average plasma concentration(Cavg),and minimum plasma concentration(Cmin)were 38.8％,72.7％,69.4％,64.1％and 87.2％,29.1％,63.8％,60.0％,49.8％and 82.1％,21.9％,55.5％,51.3％,36.3％and 76.7％,respectively.CONCLUSION The PopPK model can effectively predict the human PK characteristics under different dosing regimens with high consistency with actual Phase Ⅰ clinical study results,which can serve as an important reference for selection of safe and effective doses for first-in-human research.

BACKGROUND:Our previous studies found that decreased expression of connexin 43 and its Ser368 phosphorylation after myocardial hypothermic ischemia-reperfusion was closely associated with decreased cardiac conduction velocity and reperfusion arrhythmia.OBJECTIVE:To observe the effect of changes in membrane-type matrix metalloproteinase 2,matrix metalloproteinase 2 and collagen type Ⅳ on the expression of connexin 43 and its Ser368 phosphorylation and electrical conduction in the myocardial extracellular matrix after hypothermic ischemia-reperfusion.METHODS:Sixteen Langendorff extracorporeal cardiac perfusion models were successfully established from SD rats and randomly divided into a control group(n=8)and a hypothermic ischemia-reperfusion group(n=8).The control group was balanced perfused with 37 ℃ Krebs-Henseleit solution for 15 minutes and then continued to be perfused with 37 ℃ Krebs-Henseleit solution for 90 minutes.The hypothermic ischemia-reperfusion group was balanced perfused with 37 ℃ Krebs-Henseleit solution for 15 minutes,and then the heart was arrested for 60 minutes by injection of 4 ℃ Thomas solution.During the cardiac arrest,the periphery was protected by 4 ℃ Krebs-Henseleit solution.Half-volume 4 ℃ Thomas solution was reperfused 30 minutes after the arrest.After stopping the arrest,the heart was reperfused with 37 ℃ Krebs-Henseleit solution for 30 minutes.The occurrence of arrhythmias,rebeating time,and the duration of arrhythmias were recorded from the immediate time point to the end of the reperfusion period.Conduction velocity,absolute inhomogeneity,and inhomogeneity index were measured using the Mapping Lab multi-channel electrophysiological mapping system at the time of balanced perfusion for 15 minutes(T1),reperfusion for 15 minutes/continuous perfusion for 90 minutes(T2),and reperfusion for 30 minutes/continuous perfusion for 105 minutes(T3).The relative expression levels of membrane-type matrix metalloproteinase 2,matrix metalloproteinase 2,collagen type Ⅳ,connexin 43,and its Ser368 phosphorylation in ventricular tissue were detected by western blot assay.RESULTS AND CONCLUSION:(1)No arrhythmia occurred in the control group.There were six cases of arrhythmia in the hypothermic ischemia-reperfusion group during reperfusion.Rebeating time and duration of arrhythmias were(25.38+12.02)and(158.67±67.68)seconds,respectively.(2)The conduction sochronal diagrams at T1,T2,and T3 in the control group were uniform and regular in direction,and the conduction velocity at T2 and T3 was not different from that at T1(P＞0.05).The conduction isochronal diagrams at T2 and T3 in the hypothermic ischemia-reperfusion group were uneven and irregular in direction,and the conduction velocity was slower than that at T1(P＜0.01).The conduction velocity at T2 and T3 in the hypothermic ischemia-reperfusion group was slower than that in the control group(P＜0.01).Conduction dispersion was greater in the hypothermic ischemia-reperfusion group than that in the control group at T2 and T3(P＜0.05).(3)Compared with the control group,the protein expressions of membrane-type matrix metalloproteinase 2 and matrix metalloproteinase 2 in the hypothermic ischemia-reperfusion group were increased(P＜0.05 or P＜0.01),and the protein expression levels of type Ⅳ collagen,connexin 43 and its Ser368 phosphorylation were decreased(P＜0.05 or P＜0.01).(4)The results indicate that after hypothermic ischemia-reperfusion,myocardial extracellular matrix remodeling may mediate the downregulation of myocardial connexin 43 and its Ser368 phosphorylation,slowed conduction velocity and increased conduction dispersion,thereby increasing the risk of arrhythmia.

Objective:To establish a three-dimensional U-shaped residual coordinated attention network (URCA-Net) based on enhanced CT images for small bowel polyp detection and analyze its application effectiveness in intelligent detection of small bowel polyps.Methods:Abdominal CT data of patients with small bowel polyps were collected from the Air Force Medical Center between June 2019 and July 2023. All patients underwent bowel preparation followed by thin-slice spiral CT scanning to obtain enhanced CT arterial phase images. The data were randomly divided into training, validation and test sets in an 8∶1∶1 ratio. The URCA-Net deep learning model was used for small bowel polyp segmentation. The training set was used for model parameter training, the validation set for hyperparameter adjustment and monitoring of model generalization performance and the test set for final unbiased evaluation of the model. An early intelligent detection model for small bowel polyps was constructed, and its performance was evaluated. Evaluation metrics included pixel-level metrics for the segmentation task [Dice Similarity Coefficient (DSC)], as well as sensitivity and precision for polyp detection. A two-stage segmentation strategy was adopted: the first stage segmented the small bowel region to remove external interference, and the second stage performed polyp segmentation within the small bowel region.Results:A total of 78 subjects were included in the study, with an average age of (54±7) years. A total of 23 400 scan images were extracted, including 136 hyperplastic polyps, 298 hamartomatous polyps, 14 adenomatous polyps, and 4 cancerous polyps. On the test set, the average DSC for the first stage (small bowel segmentation) and the second stage (polyp segmentation) was 0.790 and 0.314, respectively. In the second stage task (polyp segmentation based on small bowel region), the polyp segmentation DSC increased to 0.701, with a precision of 0.836 (95% CI: 0.700-0.972) and a sensitivity of 0.759 (95% CI: 0.631-0.888) for polyp detection. Conclusion:The URCA-Net deep learning technique demonstrates good auxiliary diagnostic effectiveness in small bowel polyp detection and can provide a reference for screening and detection of small bowel polyps. The model is capable of generating high-quality segmentation results, which could facilitate evaluating polyp lesion morphology and provide support for downstream tasks such as preoperative navigation and risk prediction.

Objective To address the national requirements for high-quality development of public hospitals issued by the National Health Commission(NHC),this study establishes a knowledge-value-oriented performance management system tailored to dental specialty characteristics,aiming to synergistically enhance disciplinary advancement and operational efficiency.Methods Guided by policies such as Guidelines on Strengthening Operational Management in Public Hospitals,we integrated resources in oral and maxillofacial surgery through data-driven decision-making and multidimensional investigations.A"2-3-3"performance manage-ment model was developed,featuring dual objectives(public welfare and economic efficiency),a three-tier allocation mechanism(hospital-department-individual),and triple support strategies(key disciplines,young talents,and under-resourced projects).Im-plementation involved organizational restructuring,business-finance integration,and digital transformation.Results Post-reform outcomes demonstrated a 14％year-on-year increase in outpatient volume and a 9％growth in bed-to-surgery ratio.Both medical quality indicators and revenue and expenditure structures were optimized,achieving better equilibrium between public welfare and economic sustainability.Conclusion This model replaces the egalitarian distribution approach with a value-driven incentive mech-anism,effectively promoting disciplinary specialization and talent engagement.It provides a replicable framework for performance reform in dental specialty hospitals,aligning with the NHC's policy orientation on refined public hospital management.

Objective To address the national requirements for high-quality development of public hospitals issued by the National Health Commission(NHC),this study establishes a knowledge-value-oriented performance management system tailored to dental specialty characteristics,aiming to synergistically enhance disciplinary advancement and operational efficiency.Methods Guided by policies such as Guidelines on Strengthening Operational Management in Public Hospitals,we integrated resources in oral and maxillofacial surgery through data-driven decision-making and multidimensional investigations.A"2-3-3"performance manage-ment model was developed,featuring dual objectives(public welfare and economic efficiency),a three-tier allocation mechanism(hospital-department-individual),and triple support strategies(key disciplines,young talents,and under-resourced projects).Im-plementation involved organizational restructuring,business-finance integration,and digital transformation.Results Post-reform outcomes demonstrated a 14％year-on-year increase in outpatient volume and a 9％growth in bed-to-surgery ratio.Both medical quality indicators and revenue and expenditure structures were optimized,achieving better equilibrium between public welfare and economic sustainability.Conclusion This model replaces the egalitarian distribution approach with a value-driven incentive mech-anism,effectively promoting disciplinary specialization and talent engagement.It provides a replicable framework for performance reform in dental specialty hospitals,aligning with the NHC's policy orientation on refined public hospital management.

Objective To analyze the risk factors influencing the occurrence of atherosclerosis in patients with type 2 diabetes, and to construct and evaluate a nomogram prediction model. Methods Multivariate logistic regression was used to analyze the risk factors of atherosclerosis in type 2 diabetes mellitus, and R software was used to build a nomogram prediction model. The accuracy and clinical validity of the model were verified by using H-L fit curve, area under ROC curve and calibration curve. Results The prevalence rate of atherosclerosis was 56.37%. Independent risk factors for atherosclerosis in type 2 diabetes mellitus (P<0.05) were body weight (OR=1.42，P<0.05), glycated serum protein (OR=1.35, P<0.05), lactate dehydrogenase (OR=1.17, P<0.05), alkaline phosphatase (OR=0.79, P<0.05), hyperlipidemia (OR=2.30, P<0.05), stroke (OR=4.20, P<0.05), coronary heart disease (OR=64.54, P<0.05), lower extremity artery disease (OR=24.52, P<0.05), and other endocrine diseases (OR=1.65 , P<0.05). The area under ROC curve was 0.91, the slope of the calibration curve was close to 1, and the H-L fit curve χ²=3.11. The internal verification result of the constructed nomogram prediction model was P=0.93. External verification of patients in the test set showed that the area under ROC curve was 0.91, indicating good differentiation and accuracy of the model. Conclusion The prediction model established by using the risk factors screened in this study has a high accuracy and differentiation, and medical staff can take effective prevention measures according to the individual factors of patients.

Alzheimer's disease (AD) is the first degenerative disease of the nervous system, but no drugs have been found to reverse AD progression. Starting from 2 major pathogenesis of AD, namely amyloid beta (Aβ) cascade and Tau protein, this study systematically reviews anti-Aβ or Tau protein AD new drugs that have entered clinical research; this study also expounds their clinical trial findings and mechanisms, and analyzes the reasons for their success or failure to provide a theoretical basis for AD drug exploitation.