Objective:To predict the risk of cryptogenic stroke (CS) patients with right-to-left shunt (RLS) by machine learning, and provide potential solutions for accurate and efficient prediction of CS.Methods:A retrospective analysis of clinical data on 289 subjects with positive RLS detected by contrast-enhanced transcranial Doppler tests (c-TCD) treated in the Department of Neurology at Laoshan Campus, the Affiliated Hospital of Qingdao University, from January 2018 to September 2023, including demographic information, medical history, laboratory test indicators, diagnosis, and treatment.The dataset was randomly divided into a training set and a testing set by the machine learning function train_test_split(), with a ratio of 8∶2.Risk prediction models for CS in RLS subjects were constructed by algorithms such as Logistic regression, decision trees, random forests, extreme gradient boosting, artificial neural networks, gradient boosting, extra trees, and adaptive Boosting.The model performance was evaluated by receiver operating characteristic curves (ROC), area under curve (AUC), confusion matrix, precision, recall, accuracy, F1 score, calibration curves, and decision curve analysis.The optimal model was subjected to interpretability analysis by feature importance and SHAP values.The t-test, Mann-Whitney U test and χ2 test were used for data analysis by SPSS 25.0 software.Delong test was used to compare the differences in AUC between the two models. Results:In 289 RLS subjects, there were 166 cases of CS (57.5%) and 123 cases of non-CS (42.5%).The statistical analysis results showed that blood biochemical indicators such as D-dimer, mean platelet volume, and fibrinogen in CS patients were higher than those in non-CS patients (all P<0.01).There were no statistically significant differences in variables between the training and testing sets(all P>0.05).Random forest model achieved the highest AUC (0.885), precision (0.806), recall (0.879), accuracy (0.810), and F1 score (0.841) for CS risk prediction in the testing set.The calibration curve showed that the random forest model was closest to the reference line, and the decision curve analysis indicated that it had a greater net benefit.The interpretability analysis revealed that high-risk factors included mean platelet volume, D-dimer, international normalized ratio, body mass index, and age. Conclusion:The random forest-based prediction tool exhibits excellent performance, demonstrating high accuracy in predicting CS risk in RLS population.

Objective:To assess the association between diabetes mellitus and the risk of sudden cardiac death (SCD), and to identify potential contributing factors.Methods:This meta-analysis was an updated version of the original study Diabetes mellitus and the risk of sudden cardiac death： a systematic review and meta-analysis of prospective studies. The original review included all eligible case-control and cohort studies published in PubMed and Embase up to 2017 that investigated the association between diabetes and SCD risk. In this updated study, newly published studies were added, including those available in PubMed, Embase, China National Knowledge Infrastructure (CNKI), and WANFANG MED ONLINE up to December 3, 2023. Search terms included "diabetes""glucose""sudden cardiac death" "cardiac arrest" and their Chinese equivalent. The primary outcome was the risk of SCD, while factors such as country, ethnicity, skin color, follow-up duration, left ventricular ejection fraction (LVEF), baseline comorbidities, and other relevant variables were analyzed as potential influencing factors. Relative risk ( RR) was used as the summary measure. A random-effects model was used when significant heterogeneity was detected, otherwise a fixed-effects model was used. Cochran′s Q test was used for subgroup analysis to assess the influence of factors such as region, baseline diseases, LVEF, and ethnicity (based on skin color) on the outcomes. Results:A total of 32 cohort/case-control studies with a combined sample size of 3 252 954 individuals were included. The meta-analysis showed that the risk of SCD in patients with diabetes was double that of non-diabetics ( RR=2.00, 95% CI: 1.83-2.19, P<0.001). In Asian populations, the risk of SCD in diabetic patients was 1.78 times that of non-diabetic individuals ( RR=1.78, 95% CI: 1.51-2.10), 2.05 times that of in European populations ( RR=2.05, 95% CI: 1.79-2.34), and 2.12 times that of in American populations ( RR=2.12, 95% CI: 1.82-2.47), with no statistically significant heterogeneity between regions ( P=0.287). Among individuals without other baseline comorbidities, the risk of SCD was 2.12 times higher in diabetic patients than in those without diabetes ( RR=2.12, 95% CI: 1.89-2.38). In patients with baseline coronary heart disease, the risk was 1.75 times that of non-diabetics ( RR=1.75, 95% CI: 1.45-2.11). In those with baseline heart failure, the risk was 1.92 times that of non-diabetics ( RR=1.92, 95% CI: 1.51-2.43). In patients with baseline atrial fibrillation, the risk was 4.00 times that of non-diabetic individuals ( RR=4.00, 95% CI: 1.38-11.56). In patients undergoing hemodialysis due to renal failure, the risk was 1.76 times that of non-diabetic individuals ( RR=1.76, 95% CI: 1.25-2.48), with no statistically significant heterogeneity between groups ( P=0.262). In cardiac patients with LVEF>50%, the risk of SCD in diabetic patients was 2.08 times that of non-diabetic individuals ( RR=2.08, 95% CI: 1.57-2.75), and in those with LVEF<50%, the risk was 1.69 times that of non-diabetic individuals ( RR=1.69, 95% CI: 1.30-2.18), with no statistically significant heterogeneity between groups ( P=0.277). In yellow-skinned populations, the risk of SCD in diabetic patients was 1.80 times that of healthy individuals ( RR=1.80, 95% CI: 1.73-1.87), and in white-skinned populations, it was 2.18 times that of healthy individuals ( RR=2.18, 95% CI: 1.88-2.54), with statistically significant heterogeneity between groups ( P=0.014). Conclusions:Diabetes mellitus significantly increased the risk of SCD, and this effect may be more pronounced in white-skinned populations, while region, baseline comorbidities, and LVEF had no further effect.

Objective To explore the effects of modulating the Hippo-YAP/TAZ pathway using Huashi Runzao Prescription(HRP)on the apoptosis and salivary secretion function of submandibular gland cells in a naive non-obese diabetic(NOD/Ltj)mouse model of Sj?gren's syndrome(SS).Methods Eight-week-old female BALB/c mice were selected as the blank group.Eight-week-old female NOD/Ltj were randomly divided into the model,HRP-L,HRP-M,HRP-H,and hydroxychloroquine sulphate(HCQ)groups.After eight weeks of drug administration,the water consumption and salivary flow rate of each group were recorded.The histopathological damage of the submandibular gland in each group was determined using hematoxylin and eosin staining,the apoptosis rate of the submandibular gland was determined using TUNEL staining,and AQP5,Bax,Bcl-2,beclin-1,YAP,p-YAP,and TAZ expressions in submandibular gland tissues were determined using immunohistochemistry and Western blotting.Results Compared with the blank group,the Hippo-YAP/TAZ pathway was inhibited in the submandibular gland tissues of the model group,lymphocyte infiltration increased,water consumption increased,salivary flow rate decreased,AQP5 expression decreased,and submandibular gland cells apoptosis rate increased(P<0.05).Compared with all other administered groups,in the HRP-M group,the Hippo-YAZ/TAZ pathway was significantly activated,lymphocyte infiltration in submandibular gland tissues was reduced,water consumption was reduced,the salivary flow rate and AQP5 expression were increased,and the apoptosis rate of submandibular gland cells was reduced(P<0.05).Conclusion HRP reduced the pathological damage and apoptosis of submandibular gland cells in SS model mice.It improved the overall secretory function of submandibular gland tissues,which may be related to Hippo pathway activation and downregulating YAP/TAZ expression.

Objective To explore the effects of modulating the Hippo-YAP/TAZ pathway using Huashi Runzao Prescription(HRP)on the apoptosis and salivary secretion function of submandibular gland cells in a naive non-obese diabetic(NOD/Ltj)mouse model of Sj?gren's syndrome(SS).Methods Eight-week-old female BALB/c mice were selected as the blank group.Eight-week-old female NOD/Ltj were randomly divided into the model,HRP-L,HRP-M,HRP-H,and hydroxychloroquine sulphate(HCQ)groups.After eight weeks of drug administration,the water consumption and salivary flow rate of each group were recorded.The histopathological damage of the submandibular gland in each group was determined using hematoxylin and eosin staining,the apoptosis rate of the submandibular gland was determined using TUNEL staining,and AQP5,Bax,Bcl-2,beclin-1,YAP,p-YAP,and TAZ expressions in submandibular gland tissues were determined using immunohistochemistry and Western blotting.Results Compared with the blank group,the Hippo-YAP/TAZ pathway was inhibited in the submandibular gland tissues of the model group,lymphocyte infiltration increased,water consumption increased,salivary flow rate decreased,AQP5 expression decreased,and submandibular gland cells apoptosis rate increased(P<0.05).Compared with all other administered groups,in the HRP-M group,the Hippo-YAZ/TAZ pathway was significantly activated,lymphocyte infiltration in submandibular gland tissues was reduced,water consumption was reduced,the salivary flow rate and AQP5 expression were increased,and the apoptosis rate of submandibular gland cells was reduced(P<0.05).Conclusion HRP reduced the pathological damage and apoptosis of submandibular gland cells in SS model mice.It improved the overall secretory function of submandibular gland tissues,which may be related to Hippo pathway activation and downregulating YAP/TAZ expression.

Objective To explore the effects of modulating the Hippo-YAP/TAZ pathway using Huashi Runzao Prescription(HRP)on the apoptosis and salivary secretion function of submandibular gland cells in a naive non-obese diabetic(NOD/Ltj)mouse model of Sj?gren's syndrome(SS).Methods Eight-week-old female BALB/c mice were selected as the blank group.Eight-week-old female NOD/Ltj were randomly divided into the model,HRP-L,HRP-M,HRP-H,and hydroxychloroquine sulphate(HCQ)groups.After eight weeks of drug administration,the water consumption and salivary flow rate of each group were recorded.The histopathological damage of the submandibular gland in each group was determined using hematoxylin and eosin staining,the apoptosis rate of the submandibular gland was determined using TUNEL staining,and AQP5,Bax,Bcl-2,beclin-1,YAP,p-YAP,and TAZ expressions in submandibular gland tissues were determined using immunohistochemistry and Western blotting.Results Compared with the blank group,the Hippo-YAP/TAZ pathway was inhibited in the submandibular gland tissues of the model group,lymphocyte infiltration increased,water consumption increased,salivary flow rate decreased,AQP5 expression decreased,and submandibular gland cells apoptosis rate increased(P<0.05).Compared with all other administered groups,in the HRP-M group,the Hippo-YAZ/TAZ pathway was significantly activated,lymphocyte infiltration in submandibular gland tissues was reduced,water consumption was reduced,the salivary flow rate and AQP5 expression were increased,and the apoptosis rate of submandibular gland cells was reduced(P<0.05).Conclusion HRP reduced the pathological damage and apoptosis of submandibular gland cells in SS model mice.It improved the overall secretory function of submandibular gland tissues,which may be related to Hippo pathway activation and downregulating YAP/TAZ expression.

Objective To explore the effects of modulating the Hippo-YAP/TAZ pathway using Huashi Runzao Prescription(HRP)on the apoptosis and salivary secretion function of submandibular gland cells in a naive non-obese diabetic(NOD/Ltj)mouse model of Sj?gren's syndrome(SS).Methods Eight-week-old female BALB/c mice were selected as the blank group.Eight-week-old female NOD/Ltj were randomly divided into the model,HRP-L,HRP-M,HRP-H,and hydroxychloroquine sulphate(HCQ)groups.After eight weeks of drug administration,the water consumption and salivary flow rate of each group were recorded.The histopathological damage of the submandibular gland in each group was determined using hematoxylin and eosin staining,the apoptosis rate of the submandibular gland was determined using TUNEL staining,and AQP5,Bax,Bcl-2,beclin-1,YAP,p-YAP,and TAZ expressions in submandibular gland tissues were determined using immunohistochemistry and Western blotting.Results Compared with the blank group,the Hippo-YAP/TAZ pathway was inhibited in the submandibular gland tissues of the model group,lymphocyte infiltration increased,water consumption increased,salivary flow rate decreased,AQP5 expression decreased,and submandibular gland cells apoptosis rate increased(P<0.05).Compared with all other administered groups,in the HRP-M group,the Hippo-YAZ/TAZ pathway was significantly activated,lymphocyte infiltration in submandibular gland tissues was reduced,water consumption was reduced,the salivary flow rate and AQP5 expression were increased,and the apoptosis rate of submandibular gland cells was reduced(P<0.05).Conclusion HRP reduced the pathological damage and apoptosis of submandibular gland cells in SS model mice.It improved the overall secretory function of submandibular gland tissues,which may be related to Hippo pathway activation and downregulating YAP/TAZ expression.

Objective To explore the effects of modulating the Hippo-YAP/TAZ pathway using Huashi Runzao Prescription(HRP)on the apoptosis and salivary secretion function of submandibular gland cells in a naive non-obese diabetic(NOD/Ltj)mouse model of Sj?gren's syndrome(SS).Methods Eight-week-old female BALB/c mice were selected as the blank group.Eight-week-old female NOD/Ltj were randomly divided into the model,HRP-L,HRP-M,HRP-H,and hydroxychloroquine sulphate(HCQ)groups.After eight weeks of drug administration,the water consumption and salivary flow rate of each group were recorded.The histopathological damage of the submandibular gland in each group was determined using hematoxylin and eosin staining,the apoptosis rate of the submandibular gland was determined using TUNEL staining,and AQP5,Bax,Bcl-2,beclin-1,YAP,p-YAP,and TAZ expressions in submandibular gland tissues were determined using immunohistochemistry and Western blotting.Results Compared with the blank group,the Hippo-YAP/TAZ pathway was inhibited in the submandibular gland tissues of the model group,lymphocyte infiltration increased,water consumption increased,salivary flow rate decreased,AQP5 expression decreased,and submandibular gland cells apoptosis rate increased(P<0.05).Compared with all other administered groups,in the HRP-M group,the Hippo-YAZ/TAZ pathway was significantly activated,lymphocyte infiltration in submandibular gland tissues was reduced,water consumption was reduced,the salivary flow rate and AQP5 expression were increased,and the apoptosis rate of submandibular gland cells was reduced(P<0.05).Conclusion HRP reduced the pathological damage and apoptosis of submandibular gland cells in SS model mice.It improved the overall secretory function of submandibular gland tissues,which may be related to Hippo pathway activation and downregulating YAP/TAZ expression.

Objective To explore the effects of modulating the Hippo-YAP/TAZ pathway using Huashi Runzao Prescription(HRP)on the apoptosis and salivary secretion function of submandibular gland cells in a naive non-obese diabetic(NOD/Ltj)mouse model of Sj?gren's syndrome(SS).Methods Eight-week-old female BALB/c mice were selected as the blank group.Eight-week-old female NOD/Ltj were randomly divided into the model,HRP-L,HRP-M,HRP-H,and hydroxychloroquine sulphate(HCQ)groups.After eight weeks of drug administration,the water consumption and salivary flow rate of each group were recorded.The histopathological damage of the submandibular gland in each group was determined using hematoxylin and eosin staining,the apoptosis rate of the submandibular gland was determined using TUNEL staining,and AQP5,Bax,Bcl-2,beclin-1,YAP,p-YAP,and TAZ expressions in submandibular gland tissues were determined using immunohistochemistry and Western blotting.Results Compared with the blank group,the Hippo-YAP/TAZ pathway was inhibited in the submandibular gland tissues of the model group,lymphocyte infiltration increased,water consumption increased,salivary flow rate decreased,AQP5 expression decreased,and submandibular gland cells apoptosis rate increased(P<0.05).Compared with all other administered groups,in the HRP-M group,the Hippo-YAZ/TAZ pathway was significantly activated,lymphocyte infiltration in submandibular gland tissues was reduced,water consumption was reduced,the salivary flow rate and AQP5 expression were increased,and the apoptosis rate of submandibular gland cells was reduced(P<0.05).Conclusion HRP reduced the pathological damage and apoptosis of submandibular gland cells in SS model mice.It improved the overall secretory function of submandibular gland tissues,which may be related to Hippo pathway activation and downregulating YAP/TAZ expression.

Objective To explore the effects of modulating the Hippo-YAP/TAZ pathway using Huashi Runzao Prescription(HRP)on the apoptosis and salivary secretion function of submandibular gland cells in a naive non-obese diabetic(NOD/Ltj)mouse model of Sj?gren's syndrome(SS).Methods Eight-week-old female BALB/c mice were selected as the blank group.Eight-week-old female NOD/Ltj were randomly divided into the model,HRP-L,HRP-M,HRP-H,and hydroxychloroquine sulphate(HCQ)groups.After eight weeks of drug administration,the water consumption and salivary flow rate of each group were recorded.The histopathological damage of the submandibular gland in each group was determined using hematoxylin and eosin staining,the apoptosis rate of the submandibular gland was determined using TUNEL staining,and AQP5,Bax,Bcl-2,beclin-1,YAP,p-YAP,and TAZ expressions in submandibular gland tissues were determined using immunohistochemistry and Western blotting.Results Compared with the blank group,the Hippo-YAP/TAZ pathway was inhibited in the submandibular gland tissues of the model group,lymphocyte infiltration increased,water consumption increased,salivary flow rate decreased,AQP5 expression decreased,and submandibular gland cells apoptosis rate increased(P<0.05).Compared with all other administered groups,in the HRP-M group,the Hippo-YAZ/TAZ pathway was significantly activated,lymphocyte infiltration in submandibular gland tissues was reduced,water consumption was reduced,the salivary flow rate and AQP5 expression were increased,and the apoptosis rate of submandibular gland cells was reduced(P<0.05).Conclusion HRP reduced the pathological damage and apoptosis of submandibular gland cells in SS model mice.It improved the overall secretory function of submandibular gland tissues,which may be related to Hippo pathway activation and downregulating YAP/TAZ expression.

Objective To explore the effects of modulating the Hippo-YAP/TAZ pathway using Huashi Runzao Prescription(HRP)on the apoptosis and salivary secretion function of submandibular gland cells in a naive non-obese diabetic(NOD/Ltj)mouse model of Sj?gren's syndrome(SS).Methods Eight-week-old female BALB/c mice were selected as the blank group.Eight-week-old female NOD/Ltj were randomly divided into the model,HRP-L,HRP-M,HRP-H,and hydroxychloroquine sulphate(HCQ)groups.After eight weeks of drug administration,the water consumption and salivary flow rate of each group were recorded.The histopathological damage of the submandibular gland in each group was determined using hematoxylin and eosin staining,the apoptosis rate of the submandibular gland was determined using TUNEL staining,and AQP5,Bax,Bcl-2,beclin-1,YAP,p-YAP,and TAZ expressions in submandibular gland tissues were determined using immunohistochemistry and Western blotting.Results Compared with the blank group,the Hippo-YAP/TAZ pathway was inhibited in the submandibular gland tissues of the model group,lymphocyte infiltration increased,water consumption increased,salivary flow rate decreased,AQP5 expression decreased,and submandibular gland cells apoptosis rate increased(P<0.05).Compared with all other administered groups,in the HRP-M group,the Hippo-YAZ/TAZ pathway was significantly activated,lymphocyte infiltration in submandibular gland tissues was reduced,water consumption was reduced,the salivary flow rate and AQP5 expression were increased,and the apoptosis rate of submandibular gland cells was reduced(P<0.05).Conclusion HRP reduced the pathological damage and apoptosis of submandibular gland cells in SS model mice.It improved the overall secretory function of submandibular gland tissues,which may be related to Hippo pathway activation and downregulating YAP/TAZ expression.