ObjectiveTo systematically evaluate the association between serum indirect bilirubin （IBIL） levels and the risk of stroke incidence in patients with cardiovascular-kidney-metabolic （CKM） syndrome stages 0-3. MethodsA total of 48 301 participants with CKM syndrome stages 0-3 were included， during which 2 904 stroke events were recorded. A prospective cohort study design was employed. Cox proportional hazards regression models were used to analyze the relationship between IBIL and stroke risk， and restricted cubic spline （RCS） regression was applied to examine the dose-response relationship. Threshold effect analysis was conducted to identify potential inflection points in nonlinear relationships. ResultsMultivariable Cox regression analysis showed that in the overall population， each 1 μmol/L increase in IBIL level was associated with approximately a 1.2% reduction in stroke risk （HR = 0.988， 95% CI： 0.979-0.996， P < 0.05）. A significant interaction was observed between IBIL and CKM stages in relation to stroke risk （P_interaction < 0.05）. In individuals with stages 0–2 of CKM syndrome， higher IBIL levels showed a significant inverse association with stroke risk （P_trend < 0.05）； however， no such association was observed in stage 3 patients. RCS regression and threshold effect analysis further revealed a nonlinear relationship between IBIL levels and stroke risk in stage 3 CKM patients （P_{log-likelihood ratio} < 0.05）. When serum IBIL exceeded 10.980 μmol/L， each 1 μmol/L increase was associated with approximately 5.7% increase in stroke risk （HR = 1.057， 95% CI： 1.009–1.107， P < 0.05）. ConclusionThe correlation between serum IBIL and stroke varies across different stages of CKM syndrome， showing a significant negative association in individuals at stages \0–2， while in stage 3 patients， it exhibits a threshold effect with an inflection point at 10.980 μmol/L.

Objective To investigate the correlation of the cumulative exposure of body mass index(BMI)with epicardial adipose tissue(EAT)volume.Methods Based on the Kailuan study cohort,subjects were divided into Q1,Q2 and Q3 according to the cumula-tive BMI exposure level.The generalized linear regression model was used to analyze the correlation between different cumulative BMI exposure levels and EAT volume.According to the median of EAT volume(115.83 cm3),EAT volume was defined as increased EAT volume when EAT volume was higher than or equal to the median EAT volume.Logistic regression model was used to analyze the correlation between different cumulative BMI exposure levels and increased EAT volume.Results With the increased of cumu-lative BMI exposure level.The EAT volume increased gradually and the risk of increased EAT volume was significantly increased.Conclusion The level of cumulative BMI exposure is significantly correlated with EAT volume.High levels of cumulative BMI exposure lead to an increased risk of increased EAT volume.

Objective To investigate the association between the variability of remnant cholesterol inflammatory index(RCII),a novel composite biomarker,and the risk of stroke,in order to provide a theoretical basis for stroke prevention.Methods A prospective cohort study was conducted on 38 659 Kailuan individuals who took annual physical examinations in 2006,2008,and 2010.These subjects were grouped based on the quartiles of RCII variability,which was represented by standard deviation(SD)and average real variability(ARV),and were followed up every 2 years,with the occurrence of stroke(including ischemic and hemorrhagic strokes),death,or the end of follow-up on December 31,2022 as the endpoints.Kaplan-Meier method was used to calculate the cumulative incidence rate of endpoint events across different groups,and log-rank test was used to compare the difference of cumulative incidence of endpoint events in each group.Multivariate Cox proportional hazards regression model was adopted to analyze the association between RCII variability and risk of stroke.Results Among the 38 659 participants,a total of 2 539 strokes occurred during a mean follow-up period of 11.22±2.26 years.After adjusting confounding factors,when the participants were grouped by the quartiles of RCII-SD,the hazard ratio(HR)for stroke was 1.034(95%CI:0.917～1.167,P=0.584),1.146(95%CI:1.018～1.290,P=0.025),and 1.209(95%CI:1.066～1.370,P=0.003),respectively in the Q2,Q3,and Q4 groups,when compared with the Q1 group(Ptrend<0.05).When they were grouped by the quartiles of RCII-ARV,the HR for stroke was 1.008(95%CI:0.894～1.136,P=0.901),1.109(95%CI:0.986～1.248,P=0.085),and 1.152(95%CI:1.018～1.303,P=0.025),respectively,in the Q2,Q3,and Q4 groups,when compared with the Q1 group.Furthermore,both sensitivity and stratified analyses yielded similar results.Conclusion RCII variability is significantly associated with stroke,and the risk of stroke is gradually increasing with increment of the variability.Countermeasures Relevant authorities can focus on reducing RCII variability as a central objective by establishing regular monitoring mechanism,strengthening lifestyle interventions,and standardizing dietary,exercise,and weight management in order to suppress the index fluctuations.The principle of stable lipid-lowering in medication and optimization of therapeutic regimens with stable efficacy should be emphasized to prevent the risk of additional vascular damage.

Objective:To investigate the influence of diabetes mellitus (DM) and high-sen-sitivity C-reactive protein (Hs-CRP) on the risk of digestive system malignancy.Methods:The pro-spective cohort study was conducted. The clinical data of 93 928 participants who participated health examination in 9 hospitals at Tangshan, including Kailuan General Hospital Affiliated to North China University of Science and Technology et al, in 2006 were selected. According to the presence or absence of DM and the level of Hs-CRP, all participants were divided into 4 groups, including the DM(-)CRP(-) group defined as absence of DM and Hs-CRP ≤3 mg/L, the DM(-)CRP(+) group defined as absence of DM and Hs-CRP>3 mg/L, the DM(+)CRP(-) group defined as presence of DM and Hs-CRP ≤3 mg/L, and the DM(+)CRP(+) group defined as presence of DM and Hs-CRP >3 mg/L. The data of participants were collected by a fixed team of physicians. The first physical examination in 2006 was taken as the starting point for follow-up. The end event of follow-up was defined as the occurrence of digestive system malignancy or death, and the follow-up was up to December 31, 2021. Observation indicators: (1) comparison of clinical data among the 4 groups of participants; (2) the incidence and cumulative incidence rate of digestive system malignancy in participants; (3) influence of DM and Hs-CRP level on the risk of digestive system malignancy; (4) the combined influence of DM and Hs-CRP level on the risk of digestive system malignancy; (5) sensitivity analysis. Comparison of measurement data with normal distribution among multiple groups was conducted using the one-way analysis of variance. For pairwise comparison, least significant difference test was used for homogeneity of variance, and Dunnett′s T3 test was used for heterogeneity of variance. Comparison of measurement data with skewed distribution among multiple groups was conducted using the Kruskal-Wallis rank sum test, and Dunn-Bonferroni test was used for pairwise comparison. Comparison of count data among multiple groups was conducted using the chi-square test, and Bonferroni test was used among multiple comparisons. The Kaplan-Meier method was used to plot cumulative incidence curve, and Log-rank test was used for cumulative incidence rate analysis. The Cox proportional risk model was used for multivariate analysis. All models were adjusted for relevant confounders. Results:(1) Comparison of clinical data among the 4 groups of participants. Of the 93 928 participants, there were 70 743 cases in the DM(-)CRP(-) group, 14 644 cases in the DM(-)CRP(+) group, 6 425 cases in the DM(+)CRP(-) group, and 2 116 cases in the DM(+)CRP(+) group. There were significant differences in gender, age, fasting blood glucose, Hs-CRP, triglyceride, alanine aminotransferase, body mass index, marrital status, smoking, drinking, high school degree or above, physical exercise, high salt diet, high fat diet, positive hepatitis B virus surface antigen, fatty liver, liver cirrhosis, gallstone, taking hypoglycemic drugs, taking lipid-lowering drugs among the 4 groups of participants ( P<0.05). (2) The incidence and cumulative incidence rate of digestive system malignancy in participants. At the end-up of follow-up, 2 008 cases developed digestive system malignancy in the 93 928 participants, including 717 cases of colorectal cancer, 456 cases of liver cancer, 396 cases of gastric cancer, 195 cases of esophageal cancer, 144 cases of pancreatic cancer, 65 cases of gallbladder cancer or extrahepatic cholangiocarcinoma, 35 cases of small bowel cancer. The cumulative incidence rates of digestive system malignancy were 2.19%, 2.42%, 2.86%, 3.59% in participants of the DM(-)CRP(-) group, DM(-)CRP(+) group, DM(+)CRP(-) group, DM(+)CRP(+) group, respectively, showing a significant difference among the 4 groups ( χ2=31.72, P<0.05). (3) Influence of DM and Hs-CRP level on the risk of digestive system malignancy. After adjusting for the confounding factors of the participants, results of multivariate analysis showed that DM and Hs-CRP >3 mg/L were independent influencing factors for the incidence of digestive system malignancy ( hazard ratio=1.32, 1.19, 95% confidence interval as 1.13-1.56, 1.06-1.33, P<0.05). Futher analysis showed that there was a significant difference in interaction between DM and Hs-CRP >3 mg/L ( P<0.05). (4) The combined influence of DM and Hs-CRP level on the risk of digestive system malign-ancy. After adjusting for confounding factors, results of multivariate analysis showed that using the DM(-)CRP(-) group as the control group, the risk of incidence of digestive system malignancy increased in the DM(-)CRP(+) group, DM(+)CRP(-) group, and DM(+)CRP(+) group, respectively ( hazard ratio=1.14, 1.23, 1.79, 95% confidence interval as 1.01-1.29, 1.02-1.48, 1.38-2.31, P<0.05). In the site-specific analysis of digestive system malignancy, using the DM(-)CRP(-) group as the control group, the risk of incidence of liver cancer increased in the DM(-)CRP(+) group ( hazard ratio=1.37, 95% confidence interval as 1.07-1.75, P<0.05), the risk of incidence of liver cancer and pancrea-tic cancer increased in the DM(+)CRP(-) group ( hazard ratio=1.60, 1.74, 95% confidence interval as 1.16-2.21, 1.00-3.02, P<0.05), the risk of incidence of small bowel cancer, pancreatic cancer and colorectal cancer increased in the DM(+)CRP(+) group ( hazard ratio=5.05, 2.31, 2.23, 95% confidence interval as 1.57-16.21, 1.00-5.31, 1.54-3.24, P<0.05). (5) Sensitivity analysis. After adjusting for confounding factors of excluding 3 types of participants (103 cases of digestive system malignancy within 1 year of follow-up, 2 370 cases of taking glucose-lowering drugs, and 915 cases of taking lipid-lowering drugs), results of multivariate analysis showed that using the DM(-)CRP(-) group as the control group, the risk of incidence of digestive system malignancy increased in the DM(+)CRP(-) group, and DM(+)CRP(+) group, respectively ( hazard ratioexcluding cases of digestive system malignancy within 1 year of follow-up=1.26, 1.66, 95% confidence interval as 1.04-1.52, 1.26-2.18, P<0.05; hazard ratioexcluding cases taking glucose-lowering drugs=1.23, 1.75, 95% confidence interval as 1.02-1.49, 1.31-2.33, P<0.05; hazard ratioexcluding cases taking lipid-lowering drugs=1.24, 1.80, 95% confidence interval as 1.03-1.49, 1.39-2.34, P<0.05). Conclusions:DM and Hs-CRP >3 mg/L are independent influencing factors for the incidence of digestive system malignancy. There is an interation and synergistic effect between DM and Hs-CRP to promote the incidence of digestive system malignancy.

Objective:To explore the impact of metabolic syndrome in conjunction with hyperuricemia on the risk of new-onset cardiovascular disease.Methods:This study was a prospective cohort study. From June 2006 to October 2007, employees of Kailuan Group in Tangshan City, Hebei Province were selected as the research subjects. Participants were divided into four groups based on the presence or absence of metabolic syndrome and hyperuricemia. The groups include the normal group, pure hyperuricemia group, pure metabolic syndrome group, and the metabolic syndrome combined with hyperuricemia group. Four groups of participants were followed up, the primary endpoint was the occurrence of a first-ever cardiovascular disease event, including stroke and myocardial infarction. The cumulative incidence rates of cardiovascular disease in different groups during the continuous follow-up period were calculated using the Kaplan-Meier method, and the differences in cumulative incidence rates among groups were compared using the log-rank test. Multivariate Cox regression analysis was used to analyze the effect of hyperuricemia combined with metabolic syndrome on the risk of cardiovascular disease. The likelihood ratio test was used to analyze whether there was a multiplicative interaction and additive interaction between hyperuricemia and metabolic syndrome.Results:A total of 82 780 individuals were included, aged (51.5±12.6) years, and 68 622 (82.90%) were males, with a median follow-up of 14.97 years. Kaplan-Meier survival curve analysis showed that the cumulative incidence of cardiovascular disease was the highest in the metabolic syndrome combined with hyperuricemia group (log-rank P<0.001). Multivariate Cox regression analysis indicated that after adjusting for various confounding factors, the HR value and 95% CI of cardiovascular disease in the metabolic syndrome combined with hyperuricemia group were 1.24 (1.12-1.38) compared with the normal group, which were higher than those in the pure hyperuricemia group and the pure metabolic syndrome group alone. The effect of metabolic syndrome combined with hyperuricemia on the risk of cardiovascular disease demonstrated an additive effect (relative excess risk of interaction: 0.18(0.11-0.25), attributable proportion due to interaction: 0.14(0.09-0.19)). Conclusions:The combination of hyperuricemia and metabolic syndrome is an independent risk factor for cardiovascular disease. Compared to pure metabolic syndrome or hyperuricemia alone, the impact of metabolic syndrome combined with hyperuricemia on cardiovascular disease is more significant.

Objectives:This study aims to investigate the relationship between neutrophil to high-density lipoprotein cholesterol ratio(NHR)and incidence of cardiovascular disease(CVD)among individuals with metabolic associated fatty liver disease(MAFLD).Methods:We conducted a prospective cohort study utilizing health check-up data from 2006 to 2007 at Kailuan General Hospital and its 10 affiliated hospitals.The study population consisted of employees and retirees diagnosed with MAFLD,excluding those with incomplete neutrophil and high-density lipoprotein cholesterol data or a history of heart failure,myocardial infarction,cerebral hemorrhage,or cerebral infarction.CVD was defined as the presence of heart failure,myocardial infarction,cerebral hemorrhage,or cerebral infarction.Annual follow-ups were conducted from 2006,new-onset CVD cases identified through discharge records from the 11 Kailuan Group hospitals and records from municipal social insurance agencies,the final follow up date was December 31,2022.NHR was calculated as the ratio of neutrophil to high-density lipoprotein cholesterol,and the MAFLD cohort(n=28 952)was stratified into four groups by NHR quartiles:Q1 group(NHR<1.97,n=7 241),Q2 group(1.97≤NHR<2.57,n=7 235),Q3 group(2.57≤NHR<3.36,n=7 240),and Q4 group(NHR≥3.36,n=7 236).The Kaplan-Meier method was employed to plot survival curves for new-onset CVD,and the cumulative incidences of CVD across different NHR quartiles groups were determined.Intergroup comparisons were made using the log-rank test,and a multifactorial Cox proportional hazards regression model was used to assess the association between NHR quartiles and the risk of new-onset CVD in the MAFLD population.Results:The average follow-up duration was(14.03±3.99)years,during which 4 666 new CVD cases were recorded among the study population.The number of CVD cases across Q1 group to Q4 group were 1 061,1 167,1 186 and 1 252,respectively,with an overall incidence density of 11.5 cases per 1 000 person-years.The incidence densities for Q1 group to Q4 group were 10.4,11.4,11.7 and 12.5 cases per 1 000 person-years,respectively.The multifactorial Cox proportional hazards regression analysis revealed that higher NHR quartiles were associated with an increased relative risk of new-onset CVD(Q2 group:HR=1.13,95%CI:1.04-1.23;Q3 group:HR=1.15,95%CI:1.05-1.25;Q4 group:HR=1.22,95%CI:1.12-1.33).Conclusions:The risk of new-onset cardiovascular disease in individuals with MAFLD escalates with increasing NHR.

Objective:To explore the relationship between long-term blood pressure variability and arteriosclerosis in women with a history of hypertensive disorders in pregnancy (HDP).Methods:This study was a retrospective cohort study. Data were obtained from the Kailuan Research Database. Women with a history of HDP who delivered between January 1990 and December 2020 and completed brachial-ankle pulse wave velocity (baPWV) measurement in the postpartum period were enrolled. Baseline data were obtained from the first post-delivery health examination, while the outcome measure was the baPWV recorded during the last follow-up visit, synchronized with blood pressure measurements. Based on long-term blood pressure variability, the enrolled study subjects were divided into the first, second, and third tertile groups in ascending order using the tertile method, and intergroup differences in clinical characteristics were compared. Multivariable logistic regression was performed to evaluate the impact of long-term blood pressure variability levels on arteriosclerosis risk in women with a history of HDP. Sensitivity analyses excluded individuals with multiple deliveries to validate the robustness of findings. Subgroup analyses were conducted based on delivery age (<40 vs. ≥40 years) and blood pressure measurement frequency (3 vs. >3 times) to explore the potential impact of different population characteristics on the study results.Results:A total of 421 study subjects were enrolled, aged (36.07±6.05) years, with a baPWV value of (1 376.80±238.18) cm/s. Long-term blood pressure variability was 4.66 (3.41, 6.50) mmHg (1 mmHg=0.133 kPa). The first, second and third quartile group included 140, 141 and 140 individuals, respectively. In the total population, the incidence of arteriosclerosis was 40.4% (170/421). The incidence rates in the first, second, and third tertile groups were 34.3% (48/140), 39.0% (55/141), and 47.9% (67/140), respectively. Multivariate logistic regression analysis showed that increased long-term blood pressure variability was an independent risk factor for arteriosclerosis in women with a history of HDP ( OR=1.702, 95% CI 1.018-2.844, P=0.043). The results of sensitivity analyses were consistent with that of the primary analysis ( OR=1.758, 95% CI 1.044-2.959, P=0.034). Subgroup analyses further indicated that in the subgroups with delivery age <40 years ( OR=2.116, 95% CI 1.153-3.885, P=0.016) and blood pressure measurement frequency >3 times ( OR=1.894, 95% CI 1.069-3.355, P=0.029), the association between long-term blood pressure variability and arterial stiffness risk was more significant. Conclusions:For women with a history of HDP, elevated long-term blood pressure variability may increase the risk of arteriosclerosis, and this effect is more pronounced in younger women (delivery age <40 years) and those with high-frequency blood pressure measurements (>3 times). Enhanced monitoring and management of blood pressure variability in this population are crucial to improving long-term cardiovascular health outcomes.

Objective To investigate the correlation of the cumulative exposure of body mass index(BMI)with epicardial adipose tissue(EAT)volume.Methods Based on the Kailuan study cohort,subjects were divided into Q1,Q2 and Q3 according to the cumula-tive BMI exposure level.The generalized linear regression model was used to analyze the correlation between different cumulative BMI exposure levels and EAT volume.According to the median of EAT volume(115.83 cm3),EAT volume was defined as increased EAT volume when EAT volume was higher than or equal to the median EAT volume.Logistic regression model was used to analyze the correlation between different cumulative BMI exposure levels and increased EAT volume.Results With the increased of cumu-lative BMI exposure level.The EAT volume increased gradually and the risk of increased EAT volume was significantly increased.Conclusion The level of cumulative BMI exposure is significantly correlated with EAT volume.High levels of cumulative BMI exposure lead to an increased risk of increased EAT volume.

Objectives:This study aims to investigate the relationship between neutrophil to high-density lipoprotein cholesterol ratio(NHR)and incidence of cardiovascular disease(CVD)among individuals with metabolic associated fatty liver disease(MAFLD).Methods:We conducted a prospective cohort study utilizing health check-up data from 2006 to 2007 at Kailuan General Hospital and its 10 affiliated hospitals.The study population consisted of employees and retirees diagnosed with MAFLD,excluding those with incomplete neutrophil and high-density lipoprotein cholesterol data or a history of heart failure,myocardial infarction,cerebral hemorrhage,or cerebral infarction.CVD was defined as the presence of heart failure,myocardial infarction,cerebral hemorrhage,or cerebral infarction.Annual follow-ups were conducted from 2006,new-onset CVD cases identified through discharge records from the 11 Kailuan Group hospitals and records from municipal social insurance agencies,the final follow up date was December 31,2022.NHR was calculated as the ratio of neutrophil to high-density lipoprotein cholesterol,and the MAFLD cohort(n=28 952)was stratified into four groups by NHR quartiles:Q1 group(NHR<1.97,n=7 241),Q2 group(1.97≤NHR<2.57,n=7 235),Q3 group(2.57≤NHR<3.36,n=7 240),and Q4 group(NHR≥3.36,n=7 236).The Kaplan-Meier method was employed to plot survival curves for new-onset CVD,and the cumulative incidences of CVD across different NHR quartiles groups were determined.Intergroup comparisons were made using the log-rank test,and a multifactorial Cox proportional hazards regression model was used to assess the association between NHR quartiles and the risk of new-onset CVD in the MAFLD population.Results:The average follow-up duration was(14.03±3.99)years,during which 4 666 new CVD cases were recorded among the study population.The number of CVD cases across Q1 group to Q4 group were 1 061,1 167,1 186 and 1 252,respectively,with an overall incidence density of 11.5 cases per 1 000 person-years.The incidence densities for Q1 group to Q4 group were 10.4,11.4,11.7 and 12.5 cases per 1 000 person-years,respectively.The multifactorial Cox proportional hazards regression analysis revealed that higher NHR quartiles were associated with an increased relative risk of new-onset CVD(Q2 group:HR=1.13,95%CI:1.04-1.23;Q3 group:HR=1.15,95%CI:1.05-1.25;Q4 group:HR=1.22,95%CI:1.12-1.33).Conclusions:The risk of new-onset cardiovascular disease in individuals with MAFLD escalates with increasing NHR.