A large study of metabolomics reveals common and distinct metabolic biomarkers for type 2 diabetes, coronary heart disease, and stroke.

We aimed at examining the shared and unique associations of metabolites with multiple cardiometabolic diseases (CMD), i.e. type 2 diabetes (T2D), coronary heart disease (CHD) and stroke. In this study, a total of 168 plasma metabolites were measured by targeted high-throughput nuclear magnetic resonance spectroscopy among 98,162 participants free of T2D, CHD, and stroke at baseline. Cox proportional hazard models estimated hazard ratios for one SD increase in metabolite concentration levels, and false discovery rate (at 10%) was used to correct for multiple comparisons. Over 12.1 years of follow-up on average, 3,463 T2D, 6,186 CHD, and 1,892 stroke events were recorded. Most lipoprotein metabolites were associated with risks of T2D and CHD but not with the risk of stroke, with stronger associations for T2D than for CHD. Phospholipids within intermediate-density lipoprotein or large low-density lipoprotein particles showed positive associations with CHD and inverse associations with T2D. Metabolites indicating very small very low-density lipoprotein, histidine, creatinine, albumin, and glycoprotein acetyls were associated with risks of all three conditions. This large-scale metabolomics study revealed common and distinct metabolic biomarkers for T2D, CHD and stroke, providing instrumental information to possibly implement precision medicine for preventing and treating these conditions.

Handgrip strength is associated with risks of new-onset stroke and heart disease: results from 3 prospective cohorts.

BACKGROUND: Stroke and heart disease are two major contributors to the global disease burden. We aimed to evaluate and compare the roles of different handgrip strength (HGS) expressions in predicting stroke and heart disease in three nationally representative cohorts. METHODS: This longitudinal study used data from the Health and Retirement Study (HRS), the Survey of Health, Ageing, and Retirement in Europe (SHARE), and the China Health and Retirement Longitudinal Study (CHARLS). The Cox proportional hazard model was applied to analyze the relationship between HGS and stroke and heart disease, and Harrell's C index was used to assess the predictive abilities of different HGS expressions. RESULTS: A total of 4,407 participants suffered from stroke and 9,509 from heart disease during follow-up. Compared with the highest quartile, participants in the lowest quartile of dominant HGS, absolute HGS and relative HGS possessed a significantly higher risk of new-onset stroke in Europe, America, and China (all P < 0.05). After adding HGS to office-based risk factors, there were minimal or no differences in the increases of Harrell's C indexes among three HGS expressions. In contrast, the modest association between HGS and heart disease was only seen in SHARE and HRS, but not in CHARLS. CONCLUSION: Our findings support that HGS can be used as an independent predictor of stroke in middle-aged and older European, American and Chinese populations, and the predictive ability of HGS may not depend on how it is expressed. The relationship between HGS and heart disease calls for further validation.

Associations of handgrip strength with morbidity and all-cause mortality of cardiometabolic multimorbidity.

BACKGROUND: Cardiometabolic multimorbidity (CM) is an increasing public health and clinical concern. However, predictors for the development and prognosis of CM are poorly understood. The aims of this study were to investigate the relation between handgrip strength (HGS) and the risk of CM and to examine the association of HGS with all-cause mortality risk among patients with CM. METHODS: This prospective cohort study involved 493,774 participants from the UK Biobank. CM was defined as the simultaneous occurrence of two or more of the following conditions: type 2 diabetes, stroke, and coronary heart disease (CHD). Cox proportional hazards models were performed to estimate hazard ratios (HRs) and 95% confidence intervals (95% CIs). RESULTS: During a median follow-up of 12.1 years, 4701 incident CM cases were documented among participants with none cardiometabolic disease at baseline. Compared with the fourth quartile (Q4), the multivariable adjusted HR (95% CI) value of Q1 of HGS for developing CM was 1.46 (1.34-1.60). In participants with one cardiometabolic disease at baseline, participants in Q1 of HGS also possessed higher risk of CM than those in Q4, with HRs (95% CIs) being 1.35 (1.23-1.49) in patients with type 2 diabetes, 1.23 (1.04-1.46) in patients with stroke, and 1.23 (1.11-1.36) in patients with CHD. For participants with CM at recruitment, HGS was also associated with the risk of all-cause mortality (Q1 vs. Q4 HR: 1.57, 95% CI: 1.36-1.80). CONCLUSIONS: Our study provided novel evidence that HGS could be an independent predictor of morbidity and all-cause mortality of CM.

Waist-to-height ratio, waist circumference, body mass index, waist divided by height0.5 and the risk of cardiometabolic multimorbidity: A national longitudinal cohort study.

BACKGROUND AND AIMS: Cardiometabolic multimorbidity (CM) is an increasing public health burden. This study aimed to evaluate the association of waist-to-height ratio (WHtR), waist circumference (WC), waist divided by height0.5 (WHT.5R) and body mass index (BMI) with the risk of CM. METHODS AND RESULTS: We used data from the China Health and Retirement Longitudinal Study (CHARLS). A total of 10,521 participants aged 45 years and over were recruited, including 8807 individuals with 0 cardiometabolic diseases at baseline (stage I) and 1714 individuals with 1 cardiometabolic disease at baseline (stage II). CM was defined as self-reporting of two or more of the following conditions: stroke, diabetes and heart disease. Logistic regression was conducted to estimate the odds ratios (ORs) and 95% confidence intervals (CIs). The net reclassification index (NRI) and integrated discrimination improvement (IDI) were used to evaluate the incremental predictive value beyond conventional factors. In stage I, an increased risk of CM was observed among participants with WHtR ≥0.5 (OR: 1.76, 95% CI: 1.05-2.97), WC ≥ 90 cm (men) + WC ≥ 80 cm (women) (OR: 2.06, 95% CI: 1.29-3.27), WHT.5R ≥ 6.54 cm0.5 (OR: 1.81, 95% CI: 1.16-2.83) or BMI ≥24 kg/m2 (OR: 1.48, 95% CI: 0.98-2.24). Furthermore, the NRI and IDI of WHtR, WC and WHT.5R were all higher than those of BMI. In stage II, the adjusted ORs (95% CIs) of WHtR, WC, WHT.5R and BMI were 2.04 (1.24-3.35), 1.89 (1.29-2.77), 1.86 (1.24-2.78) and 1.47 (1.06-2.04), respectively. In addition, WC exhibited the highest NRI and IDI. CONCLUSION: WHtR, WC, WHT.5R and BMI are independent predictors of CM in the middle-aged and older Chinese population. WHtR, WC and WHT.5R show better abilities in predicting CM than BMI.

Longitudinal Follow-Up Studies on the Bidirectional Association between ADL/IADL Disability and Multimorbidity: Results from Two National Sample Cohorts of Middle-Aged and Elderly Adults.

BACKGROUND AND OBJECTIVES: Few studies have investigated the bidirectional relationship between disability and multimorbidity, which are common conditions among the older population. Based on the data from the China Health and Retirement Longitudinal Study (CHARLS) and the Survey of Health, Ageing and Retirement in Europe (SHARE), we aimed to investigate the bidirectional relationship between disability and multimorbidity. METHODS: The activities of daily living (ADLs) and the instrumental activities of daily living (IADLs) scales were used to measure disability. In stage I, we used multinomial logistic regression to assess the longitudinal association between ADL/IADL disability and follow-up multimorbidity. In stage II, binary logistic regression was used to evaluate the multimorbidity effect on future disability. RESULTS: Compared with those free of disability, people with disability possessed ascending risks for developing an increasing number of diseases. For ADL disability, the odds ratio (OR) (95% confidence interval [CI]) values of developing ≥4 diseases were 4.10 (2.58, 6.51) and 6.59 (4.54, 9.56) in CHARLS and SHARE; for IADL disability, the OR (95% CI) values were 2.55 (1.69, 3.84) and 4.85 (3.51, 6.70) in CHARLS and SHARE. Meanwhile, the number of diseases at baseline was associated, in a dose-response manner, with future disability. Compared with those without chronic diseases, participants carrying ≥4 diseases had OR (95% CI) values of 4.82 (3.73, 6.21)/4.66 (3.65, 5.95) in CHARLS and 3.19 (2.59, 3.94)/3.28 (2.71, 3.98) in SHARE for developing ADL/IADL disability. CONCLUSION: The consistent findings across 2 national longitudinal studies supported a strong bidirectional association between disability and multimorbidity among middle-aged and elderly adults. Thus, tailored interventions should be taken to prevent the mutual development of disability and multimorbidity.

Role of handgrip strength in predicting new-onset diabetes: findings from the survey of health, ageing and retirement in Europe.

BACKGROUND: Diabetes is a major concern for the global health burden. This study aimed to investigate the relationship between handgrip strength (HGS) and the risk of new-onset diabetes and to compare the predictive abilities between relative HGS and dominant HGS. METHODS: This longitudinal study used data from the Survey of Health, Ageing and Retirement in Europe (SHARE), including 66,100 European participants aged 50 years or older free of diabetes at baseline. The Cox proportional hazard model was used to analyze the relationship between HGS and diabetes, and the Harrell's C index, net reclassification index (NRI), and integrated discrimination improvement (IDI) were calculated to evaluate the predictive abilities of different HGS expressions. RESULTS: There were 5,661 diabetes events occurred during follow-up. Compared with individuals with lowest quartiles, the hazard ratios (95 % confidence intervals) of the 2nd-4th quartiles were 0.88 (0.81-0.94), 0.82 (0.76-0.89) and 0.85 (0.78-0.93) for dominant HGS, and 0.95 (0.88-1.02), 0.82 (0.76-0.89) and 0.60 (0.54-0.67) for relative HGS. After adding dominant HGS to an office-based risk score (including age, gender, body mass index, smoking, and hypertension), the incremental values of the Harrell's C index, NRI, IDI of relative HGS were all slightly higher than those of dominant HGS in both training and validation sets. CONCLUSIONS: Our findings supported that HGS was an independent predictor of new-onset diabetes in the middle-aged and older European population. Moreover, relative HGS exhibited a slightly higher predictive ability than dominant HGS.

Automated evaluation of liver fibrosis in thioacetamide, carbon tetrachloride, and bile duct ligation rodent models using second-harmonic generation/two-photon excited fluorescence microscopy.

Animal models provide a useful platform for developing and testing new drugs to treat liver fibrosis. Accordingly, we developed a novel automated system to evaluate liver fibrosis in rodent models. This system uses second-harmonic generation (SHG)/two-photon excited fluorescence (TPEF) microscopy to assess a total of four mouse and rat models, using chemical treatment with either thioacetamide (TAA) or carbon tetrachloride (CCl4), and a surgical method, bile duct ligation (BDL). The results obtained by the new technique were compared with that using Ishak fibrosis scores and two currently used quantitative methods for determining liver fibrosis: the collagen proportionate area (CPA) and measurement of hydroxyproline (HYP) content. We show that 11 shared morphological parameters faithfully recapitulate Ishak fibrosis scores in the models, with high area under the receiver operating characteristic (ROC) curve (AUC) performance. The AUC values of 11 shared parameters were greater than that of the CPA (TAA: 0.758-0.922 vs 0.752-0.908; BDL: 0.874-0.989 vs 0.678-0.966) in the TAA mice and BDL rat models and similar to that of the CPA in the TAA rat and CCl4 mouse models. Similarly, based on the trends in these parameters at different time points, 9, 10, 7, and 2 model-specific parameters were selected for the TAA rats, TAA mice, CCl4 mice, and BDL rats, respectively. These parameters identified differences among the time points in the four models, with high AUC accuracy, and the corresponding AUC values of these parameters were greater compared with those of the CPA in the TAA rat and mouse models (rats: 0.769-0.894 vs 0.64-0.799; mice: 0.87-0.93 vs 0.739-0.836) and similar to those of the CPA in the CCl4 mouse and BDL rat models. Similarly, the AUC values of 11 shared parameters and model-specific parameters were greater than those of HYP in the TAA rats, TAA mice, and CCl4 mouse models and were similar to those of HYP in the BDL rat models. The automated evaluation system, combined with 11 shared parameters and model-specific parameters, could specifically, accurately, and quantitatively stage liver fibrosis in animal models.

[Geographical distribution of MTHFR and MTRR gene polymorphisms among the Han women in Zhengzhou city].

OBJECTIVE: To explore the genotype distribution of 5,10-methylenetetrahydrofolate reductase (MTHFR) and 5-methyltetrahydrofolate-homocysteine methyltransferase reductase (MTRR) among Chinese Han women in Zhengzhou. 
 METHODS: A total of 1 253 women were recruited from Zhengzhou city. The genotype of MTHFR C677T, A1298C and MTRR A66G was detected to analyze the distribution of gene polymorphisms and to compare them with the published data from other Han women.
 RESULTS: The frequency of the MTHFR 1298CC genotypes (1.3%) in Zhengzhou was lower than that in Xiangtan (4.8%), Yanbian (3.8%), Zhenjiang (3.5%), Jingzhou (3.2%), Kunming (2.7%), Deyang (6.3%), Huizhou (7.2%) and Wulumuqi (3.4%) (all P<0.05). The difference in allele frequency was significant compared with that in Yantai, Yanbian, Wulumuqi, Zhenjiang, Jingzhou, Kunming, Dezhou, Xiangtan or Huizhou (all P<0.05). The frequency of the MTRR 66GG genotypes (5.4%) in Zhengzhou was lower than that in Deyang (8.2%) (P<0.01) and allele frequency between them was significant difference (P<0.05). 
 CONCLUSION: The gene polymorphism of MTHFR A1298C and MTRR A66G among the Han women in Zhengzhou is statistically different from that in some regions of China.

Preserved Ratio Impaired Spirometry, Metabolomics, and the Risk of Type 2 Diabetes.

CONTEXT: Whether baseline preserved ratio impaired spirometry (PRISm) is associated with the risk of developing type 2 diabetes (T2D) and if this association could be mediated by circulating metabolites remains to be elucidated. OBJECTIVE: To measure the prospective association of PRISm with T2D and potential metabolic mediators thereof. METHODS: This study used data from the UK Biobank and included 72 683 individuals without diabetes at baseline. PRISm was defined as the predicted forced expiratory volume in 1 second (FEV1) <80% and the FEV1/forced vital capacity ratio ≥0.70. Cox proportional hazards modeling was performed to assess the longitudinal relation between baseline PRISm and incident T2D. Mediation analysis was used to explore the mediation effects of circulating metabolites in the path from PRISm to T2D. RESULTS: During a median follow-up of 12.06 years, 2513 participants developed T2D. Individuals who had PRISm (N = 8394) were 47% (95% CI, 33%-63%) more likely to develop T2D compared with those who had normal spirometry (N = 64 289). A total of 121 metabolites showed statistically significant mediation effects in the path from PRISm to T2D (false discovery rate <0.05). Glycoprotein acetyls, cholesteryl esters in large high-density lipoprotein (HDL), degree of unsaturation, cholesterol in large HDL, and cholesteryl esters in very large HDL were the top 5 metabolic markers, with mediation proportions (95% CI) being 11.91% (8.76%-16.58%), 11.04% (7.34%-15.55%), 10.36% (7.34%-14.71%), 9.87% (6.78%-14.09%), and 9.51% (6.33%-14.05%), respectively. A total of 11 principal components that explained 95% variance of the metabolic signatures accounted for 25.47% (20.83%-32.19%) of the relation between PRISm and T2D. CONCLUSIONS: Our study revealed the association of PRISm with T2D risk and the potential roles of circulating metabolites in mediating this association.

Preserved Ratio Impaired Spirometry and Risks of Macrovascular, Microvascular Complications and Mortality Among Individuals With Type 2 Diabetes.

BACKGROUND: The prospective associations of preserved ratio impaired spirometry (PRISm) with new-onset macrovascular and microvascular complications and mortality among individuals with type 2 diabetes (T2D) and whether PRISm enhances the prediction ability of an established office-based risk score remain to be elucidated. RESEARCH QUESTION: Can PRISm be used as a predictor of poor prognosis in individuals with T2D? STUDY DESIGN AND METHODS: We included 20,047 study participants with T2D and complete data on spirometry at recruitment from the UK Biobank cohort. Multivariable Cox proportional hazards models were used to assess the associations of baseline PRISm (FEV1 to FVC ratio, ≥ 0.70; FEV1, < 80% predicted) with subsequent risks of incident stroke (any type), ischemic stroke, myocardial infarction, unstable angina, coronary heart disease, diabetic retinopathy, diabetic kidney disease, all-cause mortality, cardiovascular mortality, and respiratory mortality. RESULTS: For this cohort analysis, 4,521 patients (22.55% of participants with T2D) showed comorbid PRISm at baseline. Over a median follow-up of 11.52 to 11.87 years, patients with T2D with PRISm at baseline showed higher risks than those with normal spirometry findings of various T2D complications developing and mortality; the adjusted hazard ratios for PRISm were 1.413 (95% CI, 1.187-1.681) for stroke (any type), 1.382 (95% CI, 1.129-1.690) for ischemic stroke, 1.253 (95% CI, 1.045-1.503) for myocardial infarction, 1.206 (95% CI, 1.086-1.339) for coronary heart disease, 1.311 (95% CI, 1.141-1.506) for diabetic retinopathy, 1.384 (95% CI, 1.190-1.610) for diabetic kidney disease, 1.337 (95% CI, 1.213-1.474) for all-cause mortality, 1.597 (95% CI, 1.296-1.967) for cardiovascular mortality, and 1.559 (95% CI, 1.189-2.044) for respiratory mortality, respectively. The addition of PRISm significantly improved the reclassification ability, based on the net reclassification index, of an office-based risk score by 15.53% (95% CI, 10.14%-19.63%) to 33.60% (95% CI, 20.90%-45.79%). INTERPRETATION: Individuals with T2D with comorbid PRISm, accounting for a considerable proportion of the population with T2D, showed significantly increased risks of adverse macrovascular and microvascular complications and mortality.

[Methylenetetrahydrofolate reductase and methionine synthase reductase gene polymorphisms in ethnic Han women from Linyi].

OBJECTIVE: To explore the distribution of genetic polymorphisms of methylenetetrahydrofolate reductase (MTHFR) 677C/T, 1298A/C and methionine synthase reductase (MTRR) 66A/G among ethnic Han females from Linyi, and to correlate it with serum level of homocysteine (Hcy). METHODS: A cross-sectional study was carried out. Oral epithelial cell samples were collected from 825 subjects. MTHFR and MTRR gene polymorphisms were determined with a Taqman-Minor Groove Binder (MGB) method. Distribution of gene polymorphisms was analyzed and compared with others regions of China including Weifang, Zhengzhou, Deyang and Hainan. A biochemical assay was also carried out to determine the total Hcy in plasma of 281 subjects. The reductase activity of MTHFR was classified into decreased and stable groups according to genetic polymorphism of MTHFR. Correlation between MTHFR groups and total Hcy level were also explored. RESULTS: (1) The frequencies of MTHFR677CC, CT and TT genotypes of the selected subjects were 16.7%, 48.3% and 35.0%, respectively. The frequencies of MTHFR 1298AA, AC and CC genotypes were 76.0%, 21.6% and 2.4%, respectively. And those of MTRR 66AA, AG and GG genotypes were 54.7%, 39.4% and 5.9%, respectively. For the selected subjects, their frequency of MTHFR 677TT genotype was higher than that of Deyang and Hainan (P< 0.01), whilst the frequency of MTHFR 1298CC genotype was lower than that of Deyang and Hainan (P < 0.01), and the frequency of MTRR 66 GG genotype was lower than that of Hainan (P< 0.01). (2) The Hcy level for those with decreased MTHFR activity was significantly higher than those with stable MTHFR activity (P< 0.05). CONCLUSION: MTHFR gene 677C/T, 1298A/C and MTRR 66A/G polymorphisms in ethnic Han women from Linyi have differed significantly from other regions of China. Decreased MTHFR activity caused by genetic polymorphisms is a risk factor for raised Hcy level.

[Study of genetic susceptibility in 198 children with asthma].

OBJECTIVE: To analyze the frequency distribution of single nucleotide polymorphisms (SNPs) of four asthma-related gene loci (ACE I/D; ADRB2 Arg16Gly; TNF-α G-308A; MS4A2 Glu237Gly) in 198 asthmatic children, and to investigate its association with genetic susceptibility to childhood asthma and some clinical phenotypes of asthma. METHODS: Polymerase chain reaction product electrophoresis identification and real-time quantitative PCR detecting system were used to determine the frequency distributions of the SNPs of the four asthma-related gene loci in 198 asthmatic children and 110 healthy controls. The serum total IgE (TIgE) levels and blood eosinophil proportion (%EOS) of the asthmatic children were measured. Different genotypes at the four asthma-related gene loci were compared in terms of TIgE and %EOS. RESULTS: The genotype DD of angiotensin-converting enzyme (ACE) had a significantly higher frequency in the asthmatic children than in the healthy controls (χ2= 30.667, P<0.01), and the frequency of D allele was also significantly higher in the asthmatic children than in the healthy controls (χ2=7.151, P<0.01). No correlation was found between the polymorphism of each gene locus and serum TIgE level and %EOS (P>0.05). CONCLUSIONS: Genotype DD of ACE is related to genetic susceptibility to childhood asthma and may be the risk factor for childhood asthma.

Role of Pulmonary Function in Predicting New-Onset Cardiometabolic Diseases and Cardiometabolic Multimorbidity.

BACKGROUND: Although pulmonary function has been studied in relationship to individual cardiometabolic diseases, uncertainty persists about the difference in risk magnitudes of pulmonary function for these diseases and its association with cardiometabolic multimorbidity (CM). RESEARCH QUESTION: Does pulmonary function have different risk magnitudes for cardiometabolic diseases and CM? STUDY DESIGN AND METHODS: This study used data from the UK Biobank, including 357,433 individuals with no cardiometabolic diseases at baseline (stage I) and 35,034 individuals with one cardiometabolic disease at baseline (stage II). Pulmonary function was measured by FVC or FEV1. We defined CM as the coexistence of at least two cardiometabolic diseases: type 2 diabetes (T2D), coronary heart disease (CHD), and stroke. Multinomial logistic regression models and Cox proportional hazards models were performed to estimate ORs or hazard ratios (HRs) and their 95% CIs for the longitudinal relationship between baseline pulmonary function and incident cardiometabolic outcomes. RESULTS: In stage I, FVC showed the most pronounced associations with new-onset CM and T2D among the four mutually exclusive end points. Compared with the lowest quartile (quartile 1), the adjusted ORs of quartile 4 of FVC were 0.525 (95% CI, 0.468-0.589) for CM, 0.534 (95% CI, 0.498-0.572) for T2D alone, 0.817 (95% CI, 0.751-0.888) for stroke alone, and 0.800 (95% CI, 0.764-0.837) for CHD alone. In stage II, FVC also was associated with the risk of CM in patients with T2D (HR of quartile 4, 0.727; 95% CI, 0.649-0.814), patients with CHD (HR, 0.635; 95% CI, 0.555-0.727), and patients who experienced stroke (HR, 0.783, 95% CI, 0.642-0.955). Similar results were observed for FEV1 in both stages. INTERPRETATION: This study revealed the different risk associations of pulmonary function with individual cardiometabolic diseases and CM. Tailor-made screening and monitoring through pulmonary function may be applicable for the precise prevention and control of these conditions.

Role of depression in the development of cardiometabolic multimorbidity: Findings from the UK Biobank study.

BACKGROUND: Depression has been acknowledged as a risk factor for cardiometabolic diseases, but its role in the development of cardiometabolic multimorbidity (CM) remains unclear. We aimed to prospectively investigate how depression affected the development of CM based on the UK Biobank study. METHODS: We included 459,747 participants with none or one prior cardiometabolic disease. Depression was assessed by the clinical diagnosis and Patient Health Questionnaire (PHQ-2). CM was defined as the coexistence of two or more conditions of type 2 diabetes, stroke, and coronary heart disease (CHD). Multistate models were used to examine the role of depression in the transitions from baseline to single cardiometabolic diseases and subsequently to CM. RESULTS: During a median follow-up of 12.07 years, we documented 3413 incident CM cases among initially disease-free participants and 7461 cases among participants with one prior cardiometabolic disease, respectively. The hazard of developing CM associated with depression was higher among disease-free individuals than that among individuals with one cardiometabolic disease (HR, 95 % CI: 1.68, 1.54-1.83 vs 1.28, 1.20-1.35). Moreover, depression was significantly associated with all transitions from baseline to diabetes (HR, 95 % CI: 1.43, 1.37-1.50), stroke (1.28, 1.20-1.38), and CHD (1.35, 1.31-1.40). After the onset of these cardiometabolic diseases, the HR values (95 % CIs) of progression to CM were 1.26 (1.09-1.46) for diabetes, 1.43 (1.16-1.76) for stroke, and 1.23 (1.08-1.40) for CHD. CONCLUSIONS: Depression was an independent risk factor for CM, and adversely influenced the whole progression from disease-free status to CM.

Metabolomics on vascular events and death after acute ischemic stroke: A prospective matched nested case-control study.

BACKGROUND AND AIMS: Ischemic stroke is a major contributor to global mortality and disability. Metabolomics represents a powerful tool for discovering biomarkers of ischemic stroke due to its ability to detect metabolites small enough to cross the blood-brain barrier. The aim of this study is to identify potential metabolic biomarkers for predicting 1-year vascular events and death after acute ischemic stroke (AIS). METHODS: We adopted a nested case-control design from a multicenter prospective cohort study. A total of 143 AIS patients with 1-year vascular events/death and 143 sex-, age- and center-matched patients without 1-year vascular events/death were selected, and further divided into the discovery set (n = 140) and validation set (n = 146). We then performed untargeted metabolomics analysis by liquid chromatography coupled to mass spectrometry. RESULTS: Metabolomics analyses could predict 1-year vascular events and death after AIS using pattern recognition methods. Eight metabolites (e.g., LysoPC(18:1)) were identified as potential biomarkers of AIS prognosis. Four of them (e.g., PS(O-18:0/0:0)) were found to be significantly decreased in patients with early vascular events/death. Adding these metabolic biomarkers to traditional factors resulted in a great improvement of the predictive utility for 1-year vascular events/death, with net reclassification index and integrated discrimination improvement being 0.9143 (p < 0.0001) and 0.1906 (p < 0.0001) in the discovery cohort, and 0.9041 (p < 0.0001) and 0.1896 (p < 0.0001) in the validation cohort. CONCLUSIONS: This study found several metabolic biomarkers for 1-year vascular events and death after AIS, providing opportunities for the construction of prognostic models and the discovery of novel therapeutic targets.

Role of depressive symptoms in cardiometabolic diseases and subsequent transitions to all-cause mortality: an application of multistate models in a prospective cohort study.

BACKGROUND AND PURPOSE: The role of depression in the development and outcome of cardiometabolic diseases remains to be clarified. We aimed to examine the extent to which depressive symptoms affect the transitions from healthy to diabetes, stroke, heart disease and subsequent all-cause mortality in a middle-aged and elderly European population. METHODS: A total of 78 212 individuals aged ≥50 years from the Survey of Health Ageing and Retirement in Europe were included. Participants with any baseline cardiometabolic diseases including diabetes, stroke and heart disease were excluded. Depressive symptoms were measured by the Euro-Depression scale at baseline. Participants were followed up to determine the occurrence of cardiometabolic diseases and all-cause mortality. We used multistate models to estimate the transition-specific HRs and 95% CIs after adjustment of confounders. RESULTS: During 500 711 person-years of follow-up, 4742 participants developed diabetes, 2173 had stroke, 5487 developed heart disease and 7182 died. Depressive symptoms were significantly associated with transitions from healthy to diabetes (HR: 1.12, 95% CI: 1.05 to 1.20), stroke (HR: 1.31, 95% CI: 1.18 to 1.44), heart disease (HR: 1.26, 95% CI: 1.18 to 1.34) and all-cause mortality (HR: 1.41, 95% CI: 1.34 to 1.49). After cardiometabolic diseases, depressive symptoms were associated with the increased risk of all-cause mortality in patients with diabetes (HR: 1.54, 95% CI: 1.25 to 1.89), patients who had stroke (HR: 1.29, 95% CI: 1.03 to 1.61) and patients with heart disease (HR: 1.21, 95% CI: 1.02 to 1.44). CONCLUSIONS: Depressive symptoms increase the risk of diabetes, stroke and heart disease, and affect the risk of mortality after the onset of these cardiometabolic conditions. Screening and treatment of depressive symptoms may have profound implications for the prevention and prognosis of cardiometabolic diseases.

Identification of a DNA methylome profile of esophageal squamous cell carcinoma and potential plasma epigenetic biomarkers for early diagnosis.

DNA methylation is a critical epigenetic mechanism involved in key cellular processes. Its deregulation has been linked to many human cancers including esophageal squamous cell carcinoma (ESCC). This study was designed to explore the whole methylation status of ESCC and to identify potential plasma biomarkers for early diagnosis. We used Infinium Methylation 450k array to analyze ESCC tissues (n = 4), paired normal surrounding tissues (n = 4) and normal mucosa from healthy individuals (n = 4), and combined these with gene expression data from the GEO database. One hundred and sixty eight genes had differentially methylated CpG sites in their promoter region and a gene expression pattern inverse to the direction of change in DNA methylation. These genes were involved in several cancer-related pathways. Three genes were validated in additional 42 ESCC tissues and paired normal surrounding tissues. The methylation frequency of EPB41L3, GPX3, and COL14A1 were higher in tumor tissues than in normal surrounding tissues (P < 0.017). The higher methylation frequency of EPB41l3 was correlated with large tumor size (P = 0.044) and advanced pT tumor stage (P = 0.001). The higher methylation frequency of GPX3 and COL14A1 were correlated with advanced pN tumor stage (P = 0.001 and P < 0.001). The methylation of EPB41L3, GPX3, and COL14A1 genes were only found in ESCC patients' plasma, but not in normal individuals upon testing 42 ESCC patients and 50 healthy individuals. Diagnostic sensitivity was increased when methylation of any of the 3 genes were counted (64.3% sensitivity and 100% specificity). These differentially methylated genes in plasma may be used as biomarkers for early diagnosis of ESCC.