Background/Aims: Liver transplantation (LT) following total hepatectomy is a life-saving treatment for hepatocellular carcinoma (HCC). The HCC recurrence after LT hinders the effectiveness of the procedure. The objective of this study is to develop a pre-operative risk stratification model based on a liquid biopsy. Methods: We conducted a comprehensive multi-omics study of 260 HCC patients from three centers, including clinical data, low-coverage whole-genome sequencing of cell-free DNA (cfDNA) from plasma, as well as whole-exome, single-nucleus RNA, and spatial transcriptomics from matched tumor and non-tumor tissues. Results: We identified cfDNA-derived copy number alteration (CNA) signatures associated with post-transplant recurrence. By integrating cfDNA-derived CNA profiles with single-cell transcriptomic data, we traced recurrence-associated cfDNA to a distinct subpopulation of malignant cells within the primary tumor. These cells were embedded in a pro-metastatic microenvironment of specialized endothelial subtypes and cancer-associated fibroblasts. Notably, most recurrence-associated lesions were detectable in cfDNA prior to liver transplantation (LT). Building on these insights, we developed the ZJU Criteria based on CNA fragments and tumor markers, a pre-LT risk prediction tool that integrates conventional clinical factors with cfDNA-derived CNA signatures, and validated it using internal and independent external cohorts. Conclusion Our findings suggest that post-transplant recurrence commonly originates from advanced subclones that emerge late during tumor evolution. The ZJU Criteria provides an accurate, non-invasive strategy that significantly improves pre-LT risk stratification and clinical decision-making for patients with HCC.

Objective By comparing the prevalence and mortality of dementia among rural people in Xi'an in 1997 and 2014 to clarify the epidemiological changes of dementia among rural people in the city over 17 years.Methods In 1997 and 2014,people aged 55 and above in villages in Xi'an were selected by random cluster sampling method,and face-to-face questionnaire survey was conducted by combining centralized and home visits.Dementia and its subtypes were diagnosed by"the three-step method";the changes of dementia prevalence and mortality were compared between the two surveys.Results The prevalence of dementia among rural residents aged 55 and above in Xi'an was 3.49％in 1997,with age-gender standardized prevalence of 2.08％.In 2014,the prevalence of dementia was 4.25％,with age-gender standardized prevalence of 2.78％.Over the 17 years,the prevalence of dementia increased by 1.79 times(OR=1.79,95％CI:1.20-2.65,P=0.004),with a 1.9-fold increase in females and a 1.67-fold increase in males.The mortality of dementia patients was 61.76‰ and age-gender standardized mortality was 60.20‰ in 1997,while the mortality was 35.71‰ and age-gender standardized mortality was 34.18‰ in 2014.The mortality of dementia decreased by 33％over the 17 years(HR=0.33,95％CI:0.15-0.74,P=0.007).Conclusion The prevalence of dementia in rural areas of Xi'an increased significantly over the 17 years,but the mortality rate decreased,and this trend was more obvious in women.

Objective To investigate the relationship between type 2 diabetes mellitus(T2DM)and cognitive decline.Methods Data were obtained from the cognitive impairment cohort of middle-aged and elderly population in rural areas of Xi'an City.The cohort consisted of residents aged 40 years and older in two villages of Huyi District,Xi'an.The baseline survey was completed between October 2014 and March 2015,with two follow-up visits in 2016 and 2018.The present study was conducted on cognitively normal people at baseline.Individual characteristics,lifestyle,and medical history were collected;physical and biochemical examinations were completed.According to medical history of T2DM and fasting blood glucose,the study population was divided into non-T2DM group,pre-existing T2DM group,and new-onset T2DM group.The Mini-Mental State Examination(MMSE)was used to assess global cognitive function.Participants with a drop of≥2 points in MMSE score from baseline after 4 years were defined as having cognitive decline.Chi-square test and multivariate Logistic regression analysis were employed to analyze the effect of T2DM status on the risk of cognitive decline.Results A total of 1 350 subjects completed the follow-up.In the follow-up population,1 096(81.2％)were free of T2DM,158(11.7％)already had T2DM at baseline,and 96(7.1％)developed new-onset T2DM during the follow-up.Cognitive decline was observed in 230 individuals after 4 years,representing 17.0％of the study population.The new-onset T2DM group had the highest 4-year incidence of cognitive decline(non-T2DM group vs.pre-existing T2DM group vs.new-onset T2DM group:15.7％vs.20.9％vs.26.0％,P=0.014),and the incidence of cognitive decline in the newly-onset T2DM group was significantly higher than that in the non-T2DM group(P=0.009).Multivariate Logistic regression analysis showed that the new-onset T2DM group had an increased risk of cognitive decline compared with the non-T2DM group within 4 years(OR=1.726,95％CI:1.029-2.896,P=0.039).However,no significant difference in 4-year risk of cognitive decline in the pre-existing T2DM group was observed(OR=1.402,95％CI:0.890-2.210,P=0.145).Conclusion Through the 4-year follow-up study of cognitively normal adults aged 40 and above in rural Xi'an,it was found that new-onset T2DM patients face a significantly elevated risk of cognitive decline,suggesting that cognitive decline may occur in the early stage of T2DM.

Objective To explore the relationship between carotid atherosclerosis(CAS)and cognitive impairment in the stroke high-risk population aged 40 years and above in the rural area of Xi'an City and determine whether CAS is a risk factor for cognitive impairment.Methods In this study,stroke high-risk population found in the Community and Rural Population Stroke High-risk Group Screening and Intervention Project carried out in Huyi District,Xi'an City,from October 2014 to March 2015 were selected as the research subjects.Color Doppler ultrasound was used to evaluate CAS,and CAS was defined as:carotid intima-media thickness(CIMT)≥1.0 mm,or carotid arteries(including common carotid artery,carotid sinus,internal carotid artery,and external carotid artery)have atherosclerotic plaques,or carotid stenosis.Mini-Mental State Examination(MMSE)was used to assess cognitive function.The MMSE score lower than the cut-off value(illiteracy ≤17,primary school ≤ 20 points,and junior high school and above education level ≤24 points)is defined as cognitive impairment.The study population was grouped according to the presence of CAS or cognitive impairment;univariate difference test and bivariate logistic regression were used to analyze the relationship between CAS and cognitive impairment.Results A total of 451 subjects were included in the analysis.The average age of the subjects was(58.7±9.83)years old,and 44.3％were female.Among them,329 cases(72.9％)had CAS and 57 cases(12.6％)met the diagnostic criteria for cognitive impairment.The prevalence of cognitive impairment in CAS group was significantly higher than that in non-CAS group(14.6％vs.7.4％,P=0.041).Multivariate logistic regression analysis showed that cognitive impairment was significantly correlated with age(OR=1.121,95％CI:1.056-1.189,P＜0.001),but not with CAS(OR=1.008,95％CI:0.202-5.170,P=0.992).Conclusion No significant association between CAS and cognitive impairment was found in high stroke risk group aged 40 and above in rural areas of Xi'an.

Objective To analyze the relationship between apolipoprotein E(APOE)genotype and cognitive impairment among individuals aged 40 and above in rural Xi'an and to explore the potential influence of education on this relationship.Methods All permanent residents aged 40 and above from two villages in Huyi District,Xi'an City,were selected as research subjects,employing a cross-sectional survey approach.The Mini-Mental State Examination(MMSE)was utilized to assess overall cognitive function,with MMSE scores below the threshold values(illiterate ≤17,primary school ≤20,junior high and above ≤24)considered as cognitive impairment.Fasting elbow venous blood was drawn in the morning,and the APOE genotype was determined.The population was divided into low-education(LE,≤9 years)and high-education(HE,＞9 years)groups based on educational level.Univariate and multivariate analyses were applied to explore the association between APOE genotype and cognitive impairment,as well as MMSE scores in both the total and stratified populations.Results Out of the 1 692 participants,there were 263 APOE ε4 allele carriers(E2/4,E3/4,E4/4)(15.3％),and 205 individuals met the criteria for cognitive impairment(12.1％).Multivariate Logistic regression and linear regression analyses revealed that in both the total population and the LE population,compared to APOE ε4 allele non-carriers(E2/2,E2/3,E3/3),APOE ε4 allele carriers exhibited a higher risk of cognitive impairments(total population:OR=1.509,95％CI:1.030-2.211,P=0.035;LE:OR=1.604,95％CI:1.080-2.381,P=0.019),and their MMSE scores were lower(total population:β=-0.053,95％CI:-0.983--0.162,P=0.006;LE:β=-0.052,95％CI:-1.052--0.124,P=0.013).However,in the HE population,there was no statistically significant difference in the prevalence of cognitive impairment(OR=1.883,95％CI:0.254-13.980,P=0.536)and MMSE scores(β=0.001,95％CI:-0.635-0.642,P=0.992)between APOE ε4 allele carriers and non-carriers.Conclusion The APOE ε4 allele was associated with an increased risk of cognitive impairment in individuals aged 40 and above in rural areas of Xi'an,while HE attainment may offer protective effects against cognitive impairment in APOE ε4 allele carriers.

Objective To develop a risk predictive model of cognitive decline in a prospective cohort study in rural area of Xi'an and compare the predictive performance with that of the classical CAIDE model.Methods The cohort was established between October 2014 and March 2015 in two selected villages in rural Xi'an.Mini-Mental State Examination(MMSE)was applied to assess global cognition at baseline and 4-year follow-up,and cognitive decline was defined as a drop of ≥4 points in MMSE after 4-year follow-up.Participants were randomly split into training set and validation set in a ratio of 7∶3.The Logistic regression analysis was used to develop the predictive model,and the area under the receiver operating characteristic(ROC)curve was applied to assess the performance of the risk model.Results Occurrence of cognitive decline after 4-year follow-up was 4.15％.Future cognitive decline was significantly predicted by age,low education and stroke(AUC in training set=0.73,95％CI:0.63-0.79;AUC in valid data=0.77,95％CI:0.67-0.87),while the classical CAIDE model did not predict the risk of cognitive decline well(AUC=0.68,95％CI:0.61-0.75).The results differed after stratification by APOE genotype,and showed a better predictive value of both our model(AUC=0.87,95％CI:0.78-0.96)and CAIDE model(AUC=0.89,95％CI:0.81-0.98)in APOE ε4 carriers.Conclusion The predictive model was developed based on age,educational level and stroke,and it predicted relatively well 4-year cognitive decline as compared with traditional CAIDE model,especially in APOE ε4 carriers.However,the model should be validated after longer follow-up and further improved to increase its predictive value.

Objective By comparing the prevalence and mortality of dementia among rural people in Xi'an in 1997 and 2014 to clarify the epidemiological changes of dementia among rural people in the city over 17 years.Methods In 1997 and 2014,people aged 55 and above in villages in Xi'an were selected by random cluster sampling method,and face-to-face questionnaire survey was conducted by combining centralized and home visits.Dementia and its subtypes were diagnosed by"the three-step method";the changes of dementia prevalence and mortality were compared between the two surveys.Results The prevalence of dementia among rural residents aged 55 and above in Xi'an was 3.49％in 1997,with age-gender standardized prevalence of 2.08％.In 2014,the prevalence of dementia was 4.25％,with age-gender standardized prevalence of 2.78％.Over the 17 years,the prevalence of dementia increased by 1.79 times(OR=1.79,95％CI:1.20-2.65,P=0.004),with a 1.9-fold increase in females and a 1.67-fold increase in males.The mortality of dementia patients was 61.76‰ and age-gender standardized mortality was 60.20‰ in 1997,while the mortality was 35.71‰ and age-gender standardized mortality was 34.18‰ in 2014.The mortality of dementia decreased by 33％over the 17 years(HR=0.33,95％CI:0.15-0.74,P=0.007).Conclusion The prevalence of dementia in rural areas of Xi'an increased significantly over the 17 years,but the mortality rate decreased,and this trend was more obvious in women.

Objective To investigate the relationship between type 2 diabetes mellitus(T2DM)and cognitive decline.Methods Data were obtained from the cognitive impairment cohort of middle-aged and elderly population in rural areas of Xi'an City.The cohort consisted of residents aged 40 years and older in two villages of Huyi District,Xi'an.The baseline survey was completed between October 2014 and March 2015,with two follow-up visits in 2016 and 2018.The present study was conducted on cognitively normal people at baseline.Individual characteristics,lifestyle,and medical history were collected;physical and biochemical examinations were completed.According to medical history of T2DM and fasting blood glucose,the study population was divided into non-T2DM group,pre-existing T2DM group,and new-onset T2DM group.The Mini-Mental State Examination(MMSE)was used to assess global cognitive function.Participants with a drop of≥2 points in MMSE score from baseline after 4 years were defined as having cognitive decline.Chi-square test and multivariate Logistic regression analysis were employed to analyze the effect of T2DM status on the risk of cognitive decline.Results A total of 1 350 subjects completed the follow-up.In the follow-up population,1 096(81.2％)were free of T2DM,158(11.7％)already had T2DM at baseline,and 96(7.1％)developed new-onset T2DM during the follow-up.Cognitive decline was observed in 230 individuals after 4 years,representing 17.0％of the study population.The new-onset T2DM group had the highest 4-year incidence of cognitive decline(non-T2DM group vs.pre-existing T2DM group vs.new-onset T2DM group:15.7％vs.20.9％vs.26.0％,P=0.014),and the incidence of cognitive decline in the newly-onset T2DM group was significantly higher than that in the non-T2DM group(P=0.009).Multivariate Logistic regression analysis showed that the new-onset T2DM group had an increased risk of cognitive decline compared with the non-T2DM group within 4 years(OR=1.726,95％CI:1.029-2.896,P=0.039).However,no significant difference in 4-year risk of cognitive decline in the pre-existing T2DM group was observed(OR=1.402,95％CI:0.890-2.210,P=0.145).Conclusion Through the 4-year follow-up study of cognitively normal adults aged 40 and above in rural Xi'an,it was found that new-onset T2DM patients face a significantly elevated risk of cognitive decline,suggesting that cognitive decline may occur in the early stage of T2DM.

Objective To explore the relationship between carotid atherosclerosis(CAS)and cognitive impairment in the stroke high-risk population aged 40 years and above in the rural area of Xi'an City and determine whether CAS is a risk factor for cognitive impairment.Methods In this study,stroke high-risk population found in the Community and Rural Population Stroke High-risk Group Screening and Intervention Project carried out in Huyi District,Xi'an City,from October 2014 to March 2015 were selected as the research subjects.Color Doppler ultrasound was used to evaluate CAS,and CAS was defined as:carotid intima-media thickness(CIMT)≥1.0 mm,or carotid arteries(including common carotid artery,carotid sinus,internal carotid artery,and external carotid artery)have atherosclerotic plaques,or carotid stenosis.Mini-Mental State Examination(MMSE)was used to assess cognitive function.The MMSE score lower than the cut-off value(illiteracy ≤17,primary school ≤ 20 points,and junior high school and above education level ≤24 points)is defined as cognitive impairment.The study population was grouped according to the presence of CAS or cognitive impairment;univariate difference test and bivariate logistic regression were used to analyze the relationship between CAS and cognitive impairment.Results A total of 451 subjects were included in the analysis.The average age of the subjects was(58.7±9.83)years old,and 44.3％were female.Among them,329 cases(72.9％)had CAS and 57 cases(12.6％)met the diagnostic criteria for cognitive impairment.The prevalence of cognitive impairment in CAS group was significantly higher than that in non-CAS group(14.6％vs.7.4％,P=0.041).Multivariate logistic regression analysis showed that cognitive impairment was significantly correlated with age(OR=1.121,95％CI:1.056-1.189,P＜0.001),but not with CAS(OR=1.008,95％CI:0.202-5.170,P=0.992).Conclusion No significant association between CAS and cognitive impairment was found in high stroke risk group aged 40 and above in rural areas of Xi'an.

Objective To analyze the relationship between apolipoprotein E(APOE)genotype and cognitive impairment among individuals aged 40 and above in rural Xi'an and to explore the potential influence of education on this relationship.Methods All permanent residents aged 40 and above from two villages in Huyi District,Xi'an City,were selected as research subjects,employing a cross-sectional survey approach.The Mini-Mental State Examination(MMSE)was utilized to assess overall cognitive function,with MMSE scores below the threshold values(illiterate ≤17,primary school ≤20,junior high and above ≤24)considered as cognitive impairment.Fasting elbow venous blood was drawn in the morning,and the APOE genotype was determined.The population was divided into low-education(LE,≤9 years)and high-education(HE,＞9 years)groups based on educational level.Univariate and multivariate analyses were applied to explore the association between APOE genotype and cognitive impairment,as well as MMSE scores in both the total and stratified populations.Results Out of the 1 692 participants,there were 263 APOE ε4 allele carriers(E2/4,E3/4,E4/4)(15.3％),and 205 individuals met the criteria for cognitive impairment(12.1％).Multivariate Logistic regression and linear regression analyses revealed that in both the total population and the LE population,compared to APOE ε4 allele non-carriers(E2/2,E2/3,E3/3),APOE ε4 allele carriers exhibited a higher risk of cognitive impairments(total population:OR=1.509,95％CI:1.030-2.211,P=0.035;LE:OR=1.604,95％CI:1.080-2.381,P=0.019),and their MMSE scores were lower(total population:β=-0.053,95％CI:-0.983--0.162,P=0.006;LE:β=-0.052,95％CI:-1.052--0.124,P=0.013).However,in the HE population,there was no statistically significant difference in the prevalence of cognitive impairment(OR=1.883,95％CI:0.254-13.980,P=0.536)and MMSE scores(β=0.001,95％CI:-0.635-0.642,P=0.992)between APOE ε4 allele carriers and non-carriers.Conclusion The APOE ε4 allele was associated with an increased risk of cognitive impairment in individuals aged 40 and above in rural areas of Xi'an,while HE attainment may offer protective effects against cognitive impairment in APOE ε4 allele carriers.