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There is growing evidence that Alzheimer disease (AD) is a pervasive metabolic disorder with dysregulation in multiple biochemical pathways underlying its pathogenesis. Understanding how perturbations in metabolism are related to AD is critical to identifying novel targets for disease-modifying therapies. In this study, we test whether AD pathogenesis is associated with dysregulation in brain transmethylation and polyamine pathways. We first performed targeted and quantitative metabolomics assays using capillary electrophoresis-mass spectrometry (CE-MS) on brain samples from three groups in the Baltimore Longitudinal Study of Aging (BLSA) (AD: n = 17; Asymptomatic AD [ASY]: n = 13; Control [CN]: n = 13) (overall 37.2% female; mean age at death 86.118 ± 9.842 years) in regions both vulnerable and resistant to AD pathology. Using linear mixed-effects models within two primary brain regions (inferior temporal gyrus [ITG] and middle frontal gyrus [MFG]), we tested associations between brain tissue concentrations of 26 metabolites and the following primary outcomes: group differences, Consortium to Establish a Registry for Alzheimer's Disease (CERAD) (neuritic plaque burden), and Braak (neurofibrillary pathology) scores. We found significant alterations in concentrations of metabolites in AD relative to CN samples, as well as associations with severity of both CERAD and Braak, mainly in the ITG. These metabolites represented biochemical reactions in the (1) methionine cycle (choline: lower in AD, p = 0.003; S-adenosyl methionine: higher in AD, p = 0.005); (2) transsulfuration and glutathione synthesis (cysteine: higher in AD, p < 0.001; reduced glutathione [GSH]: higher in AD, p < 0.001); (3) polyamine synthesis/catabolism (spermidine: higher in AD, p = 0.004); (4) urea cycle (N-acetyl glutamate: lower in AD, p < 0.001); (5) glutamate-aspartate metabolism (N-acetyl aspartate: lower in AD, p = 0.002); and (6) neurotransmitter metabolism (gamma-amino-butyric acid: lower in AD, p < 0.001). Utilizing three Gene Expression Omnibus (GEO) datasets, we then examined mRNA expression levels of 71 genes encoding enzymes regulating key reactions within these pathways in the entorhinal cortex (ERC; AD: n = 25; CN: n = 52) and hippocampus (AD: n = 29; CN: n = 56). Complementing our metabolomics results, our transcriptomics analyses also revealed significant alterations in gene expression levels of key enzymatic regulators of biochemical reactions linked to transmethylation and polyamine metabolism. Our study has limitations: our metabolomics assays measured only a small proportion of all metabolites participating in the pathways we examined. Our study is also cross-sectional, limiting our ability to directly test how AD progression may impact changes in metabolite concentrations or differential-gene expression. Additionally, the relatively small number of brain tissue samples may have limited our power to detect alterations in all pathway-specific metabolites and their genetic regulators. In this study, we observed broad dysregulation of transmethylation and polyamine synthesis/catabolism, including abnormalities in neurotransmitter signaling, urea cycle, aspartate-glutamate metabolism, and glutathione synthesis. Our results implicate alterations in cellular methylation potential and increased flux in the transmethylation pathways, increased demand on antioxidant defense mechanisms, perturbations in intermediate metabolism in the urea cycle and aspartate-glutamate pathways disrupting mitochondrial bioenergetics, increased polyamine biosynthesis and breakdown, as well as abnormalities in neurotransmitter metabolism that are related to AD.

Although chronic obstructive pulmonary disease has been related to heart failure, the relationship between the restrictive spirometry pattern (forced vital capacity [FVC] < 80% predicted with preserved forced expiratory volume in 1 second [FEV ]/FVC ratio) and heart failure is poorly understood. To determine whether having a restrictive spirometry pattern is associated with incident heart failure hospitalization. Community-dwelling African Americans from the Jackson Heart Study (total n = 5,306; analyzed n = 4,210 with spirometry and heart failure outcome data) were grouped by restrictive spirometry (FEV /FVC ≥ 0.70, FVC < 80%; n = 840), airflow obstruction (FEV /FVC < 0.70; n = 341), and normal spirometry (FEV /FVC ≥ 0.70, FVC ≥ 80%; n = 3,029) at the time of baseline examination in 2000-2004. We assessed relationships of echocardiographic parameters and biomarkers with spirometry patterns using regression models. Incident heart failure was defined as an adjudicated hospitalization for heart failure after January 1, 2005 in subjects with no self-reported heart failure history. We used multivariable-adjusted Poisson regression models and Cox proportional hazards models, with death treated as a competing risk in the Cox models, to test associations between spirometry patterns and incident heart failure. We also modeled the association of FVC% predicted with heart failure hospitalization risk using a restricted cubic spline after excluding subjects with airflow obstruction. At the time of baseline spirometry, participants with restrictive spirometry had a median age of 57.2 years (interquartile range, 47.8-64.1); 38.1% were male. Compared with normal spirometry, restrictive spirometry was associated with a higher transmitral early (E) wave velocity to atrial (A) wave velocity ratio, higher pulmonary artery systolic pressure, and higher endothelin levels. After a median follow-up time of 8.0 years, 8.0% of subjects with restrictive spirometry (n = 67) had developed incident heart failure, compared with 3.8% of those with normal spirometry (n = 115) and 10.6% of those with airflow obstruction (n = 36). After risk adjustment, both a restrictive pattern (hazard ratio [HR], 1.5; 95% confidence interval [CI], 1.1-2.0) and airflow obstruction (HR, 1.7; 95% CI, 1.1-2.5) were associated with increased rates of incident heart failure hospitalization compared with normal spirometry. Using flexible modeling, the lowest hazards of heart failure hospitalization were observed around FVC 90-100%, with lower FVC% values associated with an increased incidence of heart failure. Both a restrictive pattern on spirometry and airflow obstruction identify African Americans with impaired lung health at risk for heart failure.

[This corrects the article DOI: 10.1371/journal.pmed.1003012.].[This corrects the article DOI: 10.1371/journal.pmed.1003012.].

Statistical models to predict incident diabetes are often based on limited variables. Here we pursued two main goals: 1) investigate the relative performance of a machine learning method such as Random Forests (RF) for detecting incident diabetes in a high-dimensional setting defined by a large set of observational data, and 2) uncover potential predictors of diabetes. The Jackson Heart Study collected data at baseline and in two follow-up visits from 5,301 African Americans. We excluded those with baseline diabetes and no follow-up, leaving 3,633 individuals for analyses. Over a mean 8-year follow-up, 584 participants developed diabetes. The full RF model evaluated 93 variables including demographic, anthropometric, blood biomarker, medical history, and echocardiogram data. We also used RF metrics of variable importance to rank variables according to their contribution to diabetes prediction. We implemented other models based on logistic regression and RF where features were preselected. The RF full model performance was similar (AUC = 0.82) to those more parsimonious models. The top-ranked variables according to RF included hemoglobin A1C, fasting plasma glucose, waist circumference, adiponectin, c-reactive protein, triglycerides, leptin, left ventricular mass, high-density lipoprotein cholesterol, and aldosterone. This work shows the potential of RF for incident diabetes prediction while dealing with high-dimensional data.

Emerging data suggest that neck circumference (NC) is associated with cardiometabolic risk factors. Limited research is available regarding the association between NC and cardiovascular outcomes in African Americans. Using data from the Jackson Heart Study, we included participants with recorded NC measurements at baseline (2000-2004). Baseline characteristics for the included population were summarized by tertiles of NC. We then calculated age- and sex-adjusted cumulative incidence of clinical cardiovascular outcomes and performed Cox proportional-hazards with stepwise models. Overall, 5,290 participants were categorized into tertiles of baseline NC defined as ≤37 cm (n = 2179), 38-40 cm (n = 1552), and >40 cm (n = 1559). After adjusting for age and sex, increasing NC was associated with increased risk of heart failure (HF) hospitalization (cumulative incidence = 13.4% [99% CI, 10.7-16.7] in the largest NC tertile vs 6.5% [99% CI, 4.7-8.8] in the smallest NC tertile), but not mortality, stroke, myocardial infarction, or coronary heart disease (all P ≥ .1). Following full risk adjustment, there was a nominal increase in the risk of HF hospitalization with increasing NC, but this was not statistically significant (hazard ratio per 1-cm increase, 1.04 [99% CI, 0.99-1.10], P = .06). In this large cohort of African American individuals, a larger NC was associated with increased risk for HF hospitalization following adjustment for age and sex, but this risk was not statistically significant after adjusting for other clinical variables. Although NC is not independently associated with increased risk for cardiovascular events, it may offer prognostic information particularly related to HF hospitalization.

•Low normal ejection fraction (LNEF), which is frequently encountered in clinical practice, is associated with higher risk of incident heart failure (HF) hospitalization in a community-based cohort of African-Americans.•Those with LNEF and diastolic dysfunction may have a particularly higher risk of incident HF hospitalization.•LNEF is associated with a higher risk for incident HF and may be a sign of reducing EF, particularly in African-Americans with LNEF and diastolic dysfunction.•Further longitudinal study in African-Americans is warranted to determine if HF therapies are effective at preventing HF in this group. There is no clear consensus on a lower cutoff value for normal left ventricular ejection fraction (EF) and the prognostic implications of low normal EF (LNEF) are poorly understood, particularly in Blacks. Therefore, we investigated the association of LNEF and incident heart failure (HF) in a community-based cohort of Blacks. We studied 3,669 participants (mean age 54 years, 63% women) of the Jackson Heart Study without prevalent HF or coronary heart disease (CHD). Participants were divided into three groups: (1) Reduced EF (<50%), (2) LNEF (≥50%, <55%), and (3) Normal EF (≥55%). There were 197 cases of incident HF hospitalizations over a median follow-up of 10 years (interquartile range 9.4 to 10). After adjustment for conventional risk factors and incident CHD, the LNEF group had a higher rate of incident HF hospitalization than the Normal EF group (HR 1.58, 95% CI 1.04 to 2.38, p<0.05). Furthermore, this relation remained statistically significant after additionally adjusting for LV mass index but was not significant after adjusting for LV diastolic dysfunction grade. In participants with LNEF with incident HF, 63% developed HF with reduced EF and 37% developed HF with preserved EF. In conclusion, LNEF is associated with higher risk of incident HF hospitalization in comparison with normal EF in a community-based cohort of Blacks. In those with LNEF who went on to develop HF, most cases were HF with reduced EF. These findings suggest that strategies are needed for risk stratification and management to improve outcomes in patients with LNEF.

Introduction. The purpose of this trial was to evaluate the effect of pterostilbene on metabolic parameters. Methods. A prospective, randomized, double-blind, and placebo-controlled study that enrolled 80 patients with a total cholesterol ≥200 mg/dL and/or LDL ≥ 100 mg/dL. Subjects were divided into four groups: (1) pterostilbene 125 mg twice daily; (2) pterostilbene 50 mg twice daily; (3) pterostilbene 50 mg + grape extract (GE) 100 mg twice daily; (4) matching placebo twice daily for 6–8 weeks. Endpoints included lipids, blood pressure, and weight. Linear mixed models were used to examine and compare changes in parameters over time. Models were adjusted for age, gender, and race. Results. LDL increased with pterostilbene monotherapy (17.1 mg/dL; P = 0.001 ) which was not seen with GE combination ( P = 0.47 ). Presence of a baseline cholesterol medication appeared to attenuate LDL effects. Both systolic (−7.8 mmHg; P < 0.01 ) and diastolic blood pressure (−7.3 mmHg; P < 0.001 ) were reduced with high dose pterostilbene. Patients not on cholesterol medication ( n = 51 ) exhibited minor weight loss with pterostilbene (−0.62 kg/m2; P = 0.012 ). Conclusion. Pterostilbene increases LDL and reduces blood pressure in adults. This trial is registered with Clinicaltrials.gov NCT01267227.

Abstract Background Information on outcomes of methicillin-susceptible and -resistant Staphylococcus aureus (MSSA and MRSA, respectively) bacteremia, particularly readmission, is scarce and requires further research to inform optimal patient care. Methods We performed a retrospective analysis using the 2014 Nationwide Readmissions Database, capturing 49.3% of US hospitalizations. We identified MSSA and MRSA bacteremia using International Classification of Diseases, Ninth Revision, Clinical Modification among patients aged ≥18 years. Thirty-day readmission, mortality, length of stay, and costs were assessed using Cox proportional hazards regression, logistic regression, Poisson regression, and generalized linear model with gamma distribution and log link, respectively. Results Of 92 089 (standard error [SE], 1905) patients with S. aureus bacteremia, 48.5% (SE, 0.4%) had MRSA bacteremia. Thirty-day readmission rate was 22% (SE, 0.3) overall with no difference between MRSA and MSSA, but MRSA bacteremia had more readmission for bacteremia recurrence (hazard ratio, 1.17 [95% confidence interval {CI}, 1.02–1.34]), higher in-hospital mortality (odds ratio, 1.15 [95% CI, 1.07–1.23]), and longer hospitalization (incidence rate ratio, 1.09 [95% CI, 1.06–1.11]). Readmission with bacteremia recurrence was particularly more common among patients with endocarditis, immunocompromising comorbidities, and drug abuse. The cost of readmission was $12 425 (SE, $174) per case overall, and $19 186 (SE, $623) in those with bacteremia recurrence. Conclusions Thirty-day readmission after S. aureus bacteremia is common and costly. MRSA bacteremia is associated with readmission for bacteremia recurrence, increased mortality, and longer hospitalization. Efforts should continue to optimize patient care, particularly for those with risk factors, to decrease readmission and associated morbidity and mortality in patients with S. aureus bacteremia. Thirty-day readmission after having Staphylococcus aureus bacteremia is common and costly. Methicillin-resistant S. aureus bacteremia is associated with readmission for recurrent bacteremia, mortality, and longer hospitalization. Identifying high-risk patients for readmission may help optimize care for S. aureus bacteremia.

Evidence from existing cohort studies supports the prediction of incident coronary heart disease and stroke using 10-year cardiovascular disease (CVD) risk scores and the American Heart Association/American Stroke Association's cardiovascular health (CVH) metric. We included all Jackson Heart Study participants with complete scoring information at the baseline study visit (2000-2004) who had no history of stroke (n = 4,140). We used Kaplan-Meier methods to calculate the cumulative incidence of stroke and used Cox models to estimate hazard ratios and 95% CIs for stroke according to CVD risk and CVH score. We compared the discrimination of the 2 models according to the Harrell c index and plotted predicted vs observed stroke risk calibration plots for each of the 2 models. The median age of the African American participants was 54.5 years, and 65% were female. The cumulative incidence of stroke increased across worsening categories of CVD risk and CVH. A 1-unit increase in CVD risk increased the hazard of stroke (1.07, 1.06-1.08), whereas each 1-unit increase in CVH corresponded to a decreased hazard of stroke (0.76, 0.69-0.83). As evidenced by the c statistics, the CVH model was less discriminating than the CVD risk model (0.59 [0.55-0.64] vs 0.79 [0.76-0.83]). Both scores were associated with incident stroke in a dose-response fashion; however, the CVD risk model was more discriminating than the CVH model. The CVH score may still be preferable for its simplicity in application to broad patient populations and public health efforts.

The role of brain cholesterol metabolism in Alzheimer’s disease (AD) remains unclear. Peripheral and brain cholesterol levels are largely independent due to the impermeability of the blood brain barrier (BBB), highlighting the importance of studying the role of brain cholesterol homeostasis in AD. We first tested whether metabolite markers of brain cholesterol biosynthesis and catabolism were altered in AD and associated with AD pathology using linear mixed-effects models in two brain autopsy samples from the Baltimore Longitudinal Study of Aging (BLSA) and the Religious Orders Study (ROS). We next tested whether genetic regulators of brain cholesterol biosynthesis and catabolism were altered in AD using the ANOVA test in publicly available brain tissue transcriptomic datasets. Finally, using regional brain transcriptomic data, we performed genome-scale metabolic network modeling to assess alterations in cholesterol biosynthesis and catabolism reactions in AD. We show that AD is associated with pervasive abnormalities in cholesterol biosynthesis and catabolism. Using transcriptomic data from Parkinson’s disease (PD) brain tissue samples, we found that gene expression alterations identified in AD were not observed in PD, suggesting that these changes may be specific to AD. Our results suggest that reduced de novo cholesterol biosynthesis may occur in response to impaired enzymatic cholesterol catabolism and efflux to maintain brain cholesterol levels in AD. This is accompanied by the accumulation of nonenzymatically generated cytotoxic oxysterols. Our results set the stage for experimental studies to address whether abnormalities in cholesterol metabolism are plausible therapeutic targets in AD.