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.

ObjectiveTo investigate the association between metabolic associated fatty liver disease （MAFLD） and the risk of atherosclerotic cardiovascular disease （ASCVD）， and to provide data support for the prevention and treatment of such metabolic-associated diseases in clinical practice. MethodsAn observation cohort was established for the workers of Kailuan who underwent physical examination for the first time from June 2006 to October 2007 and had complete liver assessment data， without the history of malignant tumor， MAFLD or ASCVD. According to the presence or absence of MAFLD， the patients were divided into non-MAFLD group with 67 565 patients and MAFLD group with 29 004 patients， and according to the presence or absence of ASCVD， the patients were divided into non-ASCVD group with 69 141 patients and ASCVD group with 481 patients. The group t-test or the Wilcoxon rank-sum test was used for comparison of continuous data between the two groups. The χ² test was used for comparison of categorical data between the two groups. The life-table method was used to calculate the cumulative incidence rates of new-onset ASCVD and MAFLD； the Kaplan-Meier method was used to plot the survival curves of the cumulative incidence rates of ASCVD in the MAFLD group and the non-MAFLD group and the cumulative incidence rates of MAFLD in the ASCVD group and the non-ASCVD group， and the log-rank test was used for comparison of cumulative incidence rates between two groups. A multivariate Cox proportional-hazards regression model analysis was used to investigate the impact of MAFLD on the risk of ASCVD and the impact of ASCVD on the risk of MAFLD. ResultsCompared with the non-MAFLD group， the MAFLD group had significantly higher levels of body mass index （BMI）， waist circumference， systolic blood pressure （SBP）， diastolic blood pressure （DBP）， resting heart rate， alanine aminotransferase， uric acid （UA）， fasting blood glucose （FBG）， triglyceride （TG）， total cholesterol， low-density lipoprotein cholesterol， and high sensitivity C-reactive protein （hs-CRP）， as well as significanty lower levels of estimated glomerular filtration rate （eGFR） and high-density lipoprotein cholesterol （all P <0.05）. Compared with the non-ASCVD group， the ASCVD group had significantly higher levels of BMI， waist circumference， SBP， DBP， UA， FBG， TG， and hs-CRP and a significantly lower level of eGFR （all P<0.05）. The incidence rate of new-onset ASCVD continued to increase over time in the MAFLD group and the non-MAFLD group， while the incidence rate of new-onset MAFLD firstly increased and then remained stable over time in the ASCVD group and the non-ASCVD group. There were 4 263 cases （14.70%） of new-osnet ASCVD in the MAFLD group， with an incidence density of 12.90 per 1 000 person-years， while there were 6 529 cases （9.66%） of new-osnet ASCVD in the non-MAFLD group， with an incidence density of 8.24 per 1 000 person-years， and there were significant differences in the incidence density and cumulative incidence rate of ASCVD between the two groups （χ²=519.09 and 531.80， both P<0.05）. There were 148 cases （30.77%） of new-onset MAFLD in the ASCVD group， with an incidence density of 40.10 per 1 000 person-years， while there were 32 194 cases （46.56%） of new-onset MAFLD in the non-ASCVD group， with an incidence density of 57.59 per 1 000 person-years， and there were significant differences in the incidence density and cumulative incidence rate of MAFLD between the two groups （χ²=19.29 and 30.78， both P<0.05）. The corrected multivariate Cox proportional-hazards regression model analysis showed that MAFLD was a risk factor for new-onset ASCVD （hazard ratio ［HR］=1.11， 95% confidence interval ［CI］： 1.06 — 1.16， P<0.001）， while ASCVD was a protective factor against new-onset MAFLD （HR=0.72， 95%CI： 0.61 — 0.85， P<0.001）. ConclusionThere is a significant association between MAFLD and ASCVD， with an increase in the risk of ASCVD in the MAFLD population and a reduction in the risk of MAFLD in the ASCVD population.

ObjectiveTo investigate the association between cumulative atherogenic index of plasma （cumAIP） and the risk of new-onset nonalcoholic fatty liver disease （NAFLD） in young and middle-aged individuals. MethodsA prospective cohort study was conducted among the young and middle-aged individuals （aged 18 to <60 years） in the Kailuan study cohort who underwent physical examination in Kailuan General Hospital and its 10 affiliated hospitals in June 2006 to October 2010， and after screening based on the inclusion and exclusion criteria， 33 987 individuals were included in the observation cohort. The individuals were divided into Q1， Q2， Q3， and Q4 groups based on the quantiles of cumAIP. The Kaplan-Meier method was used to calculate the cumulative incidence rate of new-onset NAFLD in the four groups， while the log-rank test was used for comparison between groups. A multivariate Cox regression analysis was used to obtain the hazard ratio （HR） and 95% confidence interval （CI） of the risk of new-onset NAFLD in the four groups. A one-way analysis of variance was used for comparison of normally distributed continuous data between multiple groups， and the Kruskal-Wallis H test was used for comparison of non-normally distributed continuous data between multiple groups； the chi-square test was used for comparison of categorical variables between groups. ResultsThe mean follow-up was 10.89±2.54 years， and there were 6 011 cases of new-onset NAFLD， including 995 cases in the Q1 group， 1 366 in the Q2 group， 1661 in the Q3 group， and 1 989 in the Q4 group， with an incidence density of 11.37， 16.02， 19.97， and 24.91 per thousand person-years. The log-rank test showed that there was a significant difference in cumulative incidence rate between the four groups （P<0.001）. With the presence or absence of NAFLD as the dependent variable and the quantiles of different exposure levels to cumAIP as the independent variable， the multivariate Cox regression model analysis showed that compared with the Q1 group， the Q2， Q3， and Q4 groups had an HR of 1.30 （95%CI： 1.20 — 1.41）， 1.52 （95%CI： 1.41 — 1.65）， and 1.79 （95%CI： 1.64 — 1.95）， respectively， for new-onset NAFLD， with a P_trend value of <0.001. With the presence or absence of new-onset NAFLD as the dependent variable and the cumulative exposure to AIP for 0， 2， 4， and 6 years as the independent variable， the Cox regression analysis showed that compared with cumulative exposure to AIP for 0 years， cumulative exposure to AIP for 2， 4， and 6 years had an HR of 1.24 （95%CI： 1.15 — 1.35）， 1.51 （95%CI： 1.40 — 1.64）， and 1.70 （95%CI： 1.56 — 1.84）， respectively， with a P_trend value of <0.001. A sensitivity analysis was performed after exclusion of the individuals with new-onset NAFLD within 2 years， the individuals who experienced atherosclerotic cardiovascular disease events during follow-up， and the individuals taking antihypertensive， hypoglycemic， and lipid-lowering drugs， and the results were similar to those of the main analysis. Considering the competitive relationship between all-cause death and outcome events， a competing risk analysis of death was performed， which showed that the results of risk analysis were similar to those of the main analysis. ConclusionA high level of cumAIP exposure can increase the risk of new-onset NAFLD in young and middle-aged individuals.

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.

Aim To investigate the effect of cumulative non-high density lipoprotein cholesterol/high density lip-oprotein cholesterol(non-HDLC/HDLC)exposure on atherosclerotic cardiovascular disease(ASCVD).Methods A prospective cohort study was conducted.A total of 50 777 employees of Kailuan Group who participated in three physical examinations in 2006-2007,2008-2009 and 2010-2011 were selected as the study subjects.Groups were divided into Q1,Q2,Q3 and Q4 according to the cumulative non-HDLC/HDLC exposure quartiles.Kaplan-Meier curve was used to calculate the cumulative incidence of ASCVD in different cumulative non-HDLC/HDLC groups,and Log-rank test was used to compare the differences among groups.Cox proportional risk model was used to analyze the effect of cumulative non-HDLC/HDLC exposure on ASCVD.Results The average follow-up was(10.19±2.21)years,and 5 003 new cases of ASCVD occurred.The cumulative incidence of ASCVD in groups Q1 to Q4 was 6.49％,8.71％,10.86％and 14.85％,respectively(Log-rank P＜0.01).Multivariate Cox regression analysis showed that compared with group Q1,the HR(95％CI)of ASCVD in groups Q2,Q3 and Q4 were 1.13(1.03～1.24),1.18(1.07～1.29),1.22(1.12～1.34),respectively;the HR(95％CI)of myocardial infarction were 1.15(0.87～1.53),1.44(1.10～1.88),1.67(1.29～2.17),respectively;the HR(95％CI)of revascularization were 1.21(0.99～1.49),1.31(1.07～1.60)and 1.49(1.22～1.81),respectively;the HR(95％CI)of ischemic stroke were 1.17(1.03～1.32),1.17(1.04～1.33)and 1.21(1.06～1.37),respectively;but the above association was not found when heart failure and atrial fibrillation were used as the outcome events.The restricted cubic spline showed that cumulative non-HDLC/HDLC values were line-arly associated with the risk of ASCVD.Conclusion Cumulative non-HDLC/HDLC exposure was positively associated with the risk of ASCVD.

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 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:To investigate the correlation between resting heart rate(RHR)and atherosclerotic cardiovascular disease(ASCVD)and all-cause death in young and middle-aged people.Methods:A prospective cohort study was conducted enrolling 72 642 young and middle-aged participants(aged<60 years),who participated in the medical examination of the Kailuan Study from June 2006 to October 2007.According to the quartile of the RHR level,the participants were divided into Q1 group(<67 beats/min,n=14 381),Q2 group(67-70 beats/min,n=15 815),Q3 group(71-75 beats/min,n=15 876),Q4 group(76-80 beats/min,n=13 933)and Q5 group(>80 beats/min,n=12 637).Cox proportional hazard regression model was used to analyze the effect of RHR on ASCVD and all-cause death.The dose-response relationship between RHR and the risk of ASCVD and all-cause death was investigated using a restricted cubic spline regression model.Results:During a mean follow-up of(10.0±4.85)years,2 898 patients(3.99%)developed ASCVD.Multivariate Cox regression analysis showed that after adjusting for confounding factors,the risk of RHR and ASCVD in group Q5 increased by 20%compared with group Q1(HR=1.20,95%CI:1.06-1.35,P<0.05).There was no significant risk in groups Q2 to Q4 compared to Q1 group(all P>0.05).In addition,the risk of ASCVD increased by 4%for every 10 beats/min increase in RHR(HR=1.04,95%CI:1.01-1.07,P=0.009).During the follow-up period of(10.2±4.82)years,all-cause death occurred in 2 175 participants(2.99%).The results showed that compared with Q1 group,the risk of all-cause death in Q3 to Q5 groups increased by 33%(HR=1.33,95%CI:1.15-1.54,P<0.001),33%(HR=1.33,95%CI:1.14-1.54,P<0.001),and 78%(HR=1.78,95%CI:1.54-2.05,P<0.001)respectively,and there was no statistical significance between group Q2 and group Q1.The risk of all-cause death increased by 15%for every 10 beats/min increase in RHR(HR=1.15,95%CI:1.11-1.19,P<0.001).Restricted cubic spline analysis showed that RHR was linearly correlated with risk of ASCVD(Poverall=0.022,Pnon-linear=0.617),and the risk of ASCVD increased significantly with RHR>72 beats/min.RHR was linearly associated with the risk of all-cause death(Poverall<0.001,Pnon-linear=0.212),and the risk of all-cause death was significantly increased with RHR>72 betas/min.Conclusions:Higher RHR is associated with an increased risk of ASCVD and all-cause mortality in young and middle-aged individuals.

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.