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Background and ObjectivesBoth genetic and environmental factors contribute to stroke risk. We sought to identify novel metabolites associated with incident stroke in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) cohort and determine whether they reflected genetic or environmental variation.MethodsThis was a stroke case–cohort observational study nested in REGARDS. Cases were defined as incident stroke and metabolomic profiles were compared to a randomly selected control cohort. In baseline plasma samples, 162 metabolites were measured using liquid chromatography–tandem mass spectrometry. Cox proportional hazards models were adjusted for age, sex, race, and age by race in the base model. Fully adjusted models included traditional stroke risk factors. Mediation analyses conducted for these stroke risk factors used the metabolite as mediator. Genome-wide associations with the leading candidate metabolites were calculated using array data. Replication analyses in the Jackson Heart Study (JHS) were conducted using random effects meta-analysis.ResultsThere were 2,043 participants who were followed over an average period of 7.1 years, including 1,075 stroke cases and 968 random controls. Nine metabolites were associated with stroke in the base model, 8 of which were measured and remained significant in meta-analysis with JHS. In the fully adjusted model in REGARDS, guanosine (hazard ratio [HR] 1.34, 95% CI 1.18–1.53;p= 7.26 × 10−6) and pseudouridine (HR 1.28, 95% CI 1.13–1.45;p= 1.03 × 10−4) were associated with incident ischemic stroke following Bonferroni adjustment. Guanosine also partially mediated the relationship between hypertension and stroke (17.6%) and pseudouridine did not mediate any risk factor. Genome-wide association analysis identified loci rs34631560 and rs34631560 associated with pseudouridine, but these did not explain the association of pseudouridine with stroke.DiscussionGuanosine and pseudouridine are nucleosides associated with incident ischemic stroke independently of other risk factors. Genetic and mediation analyses suggest that environmental exposures rather than genetic variation link nucleoside levels to stroke risk.Classification of EvidenceThis study provides Class II evidence that guanosine and pseudouridine are associated with incident stroke.

Introduction: Several diet patterns have previously been associated with incident stroke risk in the REasons for Geographic And Racial Differences in Stroke (REGARDS) study. We used metabolomics to assess biological state changes that could link diet exposures to stroke risk. Hypothesis: Metabolites linked to stroke risk are correlated with adherence to unhealthy and protective dietary patterns. Methods: Using liquid chromatography-tandem mass spectrometry, we analyzed 162 metabolites in baseline plasma samples from REGARDS subjects with or without incident stroke (n = 2,249). Survey-weighted Cox models adjusted for age, race, and sex identified metabolites associated with incident ischemic stroke. Candidate metabolites were correlated with diet patterns using linear regression. Results: Correlations between stroke-associated metabolites and diet patterns linked to higher (Southern diet) or lower (Mediterranean and plant-based diets) stroke risk were consistent with known effects on stroke risk conferred by each metabolite and diet pattern. Notably, the “harmful” nucleoside guanosine was positively correlated with Southern diet (β = 0.11, FDR = 4.7x10 -3 ) and negatively with Mediterranean (β = -0.11, FDR = 3.2x10 -2 ) and plant-based diets (β = -0.13, FDR = 1.6x10 -4 ). In contrast, the “protective” indole-3-propanoic acid, derived from tryptophan metabolism by gut microbiota, was negatively correlated with Southern diet (β = -0.23, FDR = 3.0x10 -6 ) but positively with Mediterranean (β = 0.15, FDR = 6.1x10 -3 ) and plant-based diets (β = 0.23, FDR = 1.5x10 -5 ). Inverse odds ratio weighting mediation analyses showed that guanosine levels partly mediated the protective effect of a plant-based diet (indirect effect hazard ratio [HR] = 0.94, 95% CI = 0.86-0.99) and Mediterranean diet (indirect effect HR = 0.94, 95% CI = 0.85-0.99) on stroke risk. We also examined associations between stroke-linked metabolites and 265 specific food items, finding that unhealthy intakes were positively correlated with harmful metabolites and vice versa. Conclusion: Metabolites relevant to ischemic stroke risk correlate with broader diet patterns and specific food exposures. Metabolome perturbations might link dietary intake and the gut microbiota to stroke risk.

Introduction: Haemodynamics in sepsis is complex. Clinical variables such as heart rate, blood pressure and capillary refill time have been demonstrated to be misleading in their accuracy. Measurements of central blood flow such as cardiac output provide haemodynamic information, which may be different from the assumed underlying physiology. Aim: To evaluate the Right Ventricular Output (RVO) and Left Ventricular Output (LVO) in neonates diagnosed with late onset sepsis, with the help of functional echocardiography (FnECHO). Materials and Methods: This prospective cohort study was conducted at a tertiary care neonatal unit of Western India from March 2015 to November 2015. All infants admitted in the NICU with suspected late onset sepsis underwent FnECHO within 12 hours of onset of clinical signs, before initiation of inotropic support. Right Ventricular Output and LVO were recorded. Infants with positive culture results were included in the final analysis. Infants with early onset or culture negative sepsis, perinatal asphyxia, congenital heart disease, major congenital malformations and genetic syndromes were excluded from the study. Descriptive statistics were used to analyse data. Unpaired t-test was used for comparison of means of two independent groups. Results: Thirty one infants were analysed, of which two-thirds were preterm. Majority of patients (24, 77.4%) in the study group had gram-negative sepsis. Mean (±SD) RVO and LVO of the infants with late onset sepsis were 313 mL/kg/minute (±110.4) and 347 mL/kg/minute (±139.9) respectively, which were higher than normal values. The higher values of RVO and LVO were seen in patients with gram-negative sepsis (338 and 378 mL/kg/minute respectively), while remaining in the normal range in patients with gram-positive sepsis (225 and 240 mL/ kg/minute respectively). Conclusion: Neonates with late onset sepsis showed high RVO and LVO as demonstrated by FnECHO. The higher cardiac output values were predominantly seen in patients with gram-negative sepsis as compared to those with gram-positive sepsis.

Table reporting multivariable logistic regression model evaluating association between steroid use and sepsis events stratified by Morisky Adherence Scale and propensity scores. (PDF 181 kb)

Table reporting piecewise Cox regression model evaluating association between steroid use and first infection events stratified by follow-up time stratified by time in study. (PDF 198 kb)