Blood-informative transcripts define nine common axes of peripheral blood gene expression.

We describe a novel approach to capturing the covariance structure of peripheral blood gene expression that relies on the identification of highly conserved Axes of variation. Starting with a comparison of microarray transcriptome profiles for a new dataset of 189 healthy adult participants in the Emory-Georgia Tech Center for Health Discovery and Well-Being (CHDWB) cohort, with a previously published study of 208 adult Moroccans, we identify nine Axes each with between 99 and 1,028 strongly co-regulated transcripts in common. Each axis is enriched for gene ontology categories related to sub-classes of blood and immune function, including T-cell and B-cell physiology and innate, adaptive, and anti-viral responses. Conservation of the Axes is demonstrated in each of five additional population-based gene expression profiling studies, one of which is robustly associated with Body Mass Index in the CHDWB as well as Finnish and Australian cohorts. Furthermore, ten tightly co-regulated genes can be used to define each Axis as "Blood Informative Transcripts" (BITs), generating scores that define an individual with respect to the represented immune activity and blood physiology. We show that environmental factors, including lifestyle differences in Morocco and infection leading to active or latent tuberculosis, significantly impact specific axes, but that there is also significant heritability for the Axis scores. In the context of personalized medicine, reanalysis of the longitudinal profile of one individual during and after infection with two respiratory viruses demonstrates that specific axes also characterize clinical incidents. This mode of analysis suggests the view that, rather than unique subsets of genes marking each class of disease, differential expression reflects movement along the major normal Axes in response to environmental and genetic stimuli.

Vitamin D status is independently associated with plasma glutathione and cysteine thiol/disulphide redox status in adults.

OBJECTIVE: Redox status and inflammation are important in the pathophysiology of numerous chronic diseases. Epidemiological studies have linked vitamin D status to a number of chronic diseases. We aimed to examine the relationships between serum 25-hydroxyvitamin D [25(OH)D] and circulating thiol/disulphide redox status and biomarkers of inflammation. DESIGN: This was a cross-sectional study of N = 693 adults (449 females, 244 males) in an apparently healthy, working cohort in Atlanta, GA. Plasma glutathione (GSH), cysteine (Cys) and their associated disulphides were determined with high-performance liquid chromatography, and their redox potentials (Eh GSSG and Eh CySS) were calculated using the Nernst equation. Serum inflammatory markers included interleukin-6 (IL-6), interleukin-8 (IL-8) and tumour necrosis factor-α, assayed on a multiplex platform, and C-reactive protein (CRP), assayed commercially. Relationships were assessed with multiple linear regression analyses. RESULTS: Serum 25(OH)D was positively associated with plasma GSH (ß ± SE: 0·002 ± 0·0004) and negatively associated with plasma Eh GSSG (ß ± SE: -0·06 ± 0·01) and Cys (ß ± SE: -0·01 ± 0·003) (P < 0·001 for all); statistical significance remained after adjusting for age, gender, race, percentage body fat and traditional cardiovascular risk factors (P = 0·01-0·02). The inverse relationship between serum 25(OH)D and CRP was confounded by percentage body fat, and full adjustment for covariates attenuated serum 25(OH)D relationships with other inflammatory markers to nonstatistical significance. CONCLUSIONS: Serum 25(OH)D concentrations were independently associated with major plasma thiol/disulphide redox systems, suggesting that vitamin D status may be involved in redox-mediated pathophysiology.

Genetic risk prediction in a small cohort of healthy adults in Atlanta.

Compared with single markers, polygenic scores that evaluate the joint effects of multiple trait-associated variants are more effective in explaining the variance of traits and risk of diseases. In total, 182 CHDWB (Emory-Georgia Tech Center for Health Discovery and Well Being study) adults were genotyped to investigate the common variant contributions to three traits (height, BMI, serum triglycerides) and three diseases (coronary artery disease (CAD), type 2 diabetes (T2D) and asthma). Association was contrasted between weighted and simple allelic sum polygenic scores with quantitative traits, and with the Framingham risk scores for CAD and T2D. Although the cohort size is two or three orders of magnitude smaller than typical discovery cohorts, we were able to detect significant associations and to explain up to 5% of the traits by the genetic risk scores, despite a strong influence of outliers. An unexpected finding was that CAD-associated single nucleotide polymorphisms (SNPs) explain a significant amount of the variation for total serum cholesterol. Forward step-wise sequential addition of SNPs into the regression model showed that the top-ranked SNPs explain a large proportion of variance, whereas inclusion of gender and ethnicity also affect the performance of polygenic scores.

Psychosocial factors associated with diet quality in a working adult population.

The associations between specific intra- and inter-personal psychosocial factors and dietary patterns were explored in a healthy, working adult sample of university and health center employees (N = 640) who were enrolled in a prospective predictive health study. Participants had a mean age of 48 (SD = 11) years and were 67% women and 30% minority. Baseline psychosocial measures of perceived stress, depressive symptoms, social support, and family functioning were examined for their relationships with three diet quality indices-AHEI, DASH, and the Mediterranean. Dietary intake was of moderate quality in this high-income, well-educated, psychosocially healthy population. Social support was positively associated with better diet quality for all three indices (p < .01). Further research should focus on socio-environmental factors associated with diet quality.

The role of mitochondrial oxidation in endotoxin-induced liver-dependent swine pulmonary edema.

UNLABELLED: We reported previously studies in an in situ perfused swine preparation demonstrating that endotoxemia induced lung injury required the presence of the liver and that the response was accompanied by oxidative stress. To determine whether lung and liver mitochondrial oxidative stress was important to the response, we compared the effects of equimolar amounts of two antioxidants, n-acetylcysteine, which does not replenish mitochondrial glutathione, and procysteine which does, on endotoxemia induced lung injury in the swine preparation. In a swine perfused liver-lung preparation, we measured physiologic, biochemical and cellular responses of liver and lung to endotoxemia with and without the drugs. Endotoxemia caused oxidation of the mitochondria-specific protein, thioredoxin-2, in both the lungs and the liver. Procysteine reduced thioredoxin-2 oxidation, attenuated hemodynamic, gas exchange, hepatocellular dysfunction, and cytokine responses and prevented lung edema. n-acetylcysteine had more modest effects and did not prevent lung edema. CONCLUSIONS: We conclude that mitochondrial oxidation may be critical to the pathogenesis of endotoxemia-induced liver-dependent lung injury and that choices of antioxidant therapy for such conditions must consider the desired subcellular target in order to be optimally effective.

Developing a synthetic control group using electronic health records: Application to a single-arm lifestyle intervention study.

The electronic health records (EHR) infrastructure offers a tremendous resource for identifying controls who match the characteristics of study participants in a single-arm trial. The objectives are to (1) demonstrate the feasibility of curating a synthetic control group for an existing study cohort through EHR data extraction and (2) evaluate the effect of a lifestyle intervention on selected cardiovascular health metrics. A total of 711 university employees were recruited between 2008 and 2012 to participate in a health partner intervention to improve cardiovascular health and were followed for five years. Data of nearly 8000 eligible subjects were extracted from the EHR to create a synthetic control cohort during the same study period. To minimize confounding, crude comparison, exact matching, propensity score matching, and doubly robust estimation were used to compare the selected cardiovascular health metrics at 1 and 5 years of follow-up. Blood pressure and body mass index improved in the intervention group compared to the EHR synthetic controls. The findings of changes in lipid measurements were somewhat unexpected. When analyzing the subgroup without lipid-lowering medications, the intervention group exhibited better control of cholesterol levels over time than did our synthetic controls. Some measurements in the EHR system may be more robust for synthetic selection than others. EHR synthetic controls can provide an alternative to estimate intervention effects appropriately in single-arm studies for these measurements.

Oxidation of plasma cysteine/cystine redox state in endotoxin-induced lung injury.

Several lines of evidence indicate that perturbations in the extracellular thiol/disulfide redox environment correlate with the progression and severity of acute lung injury (ALI). Cysteine (Cys) and its disulfide Cystine (CySS) constitute the most abundant, low-molecular-weight thiol/disulfide redox couple in the plasma, and Cys homeostasis is adversely affected during the inflammatory response to infection and injury. While much emphasis has been placed on glutathione (GSH) and glutathione disulfide (GSSG), little is known about the regulation of the Cys/CySS couple in ALI. The purpose of the present study was to determine whether endotoxin administration causes a decrease in Cys and/or an oxidation of the plasma Cys/CySS redox state (E(h) Cys/CySS), and to determine whether these changes were associated with changes in plasma E(h) GSH/GSSG. Mice received endotoxin intraperitoneally, and GSH and Cys redox states were measured at time points known to correlate with the progression of endotoxin-induced lung injury. E(h) in mV was calculated using Cys, CySS, GSH, and GSSG values by high-performance liquid chromatography and the Nernst equation. We observed distinct effects of endotoxin on the GSH and Cys redox systems during the acute phase; plasma E(h) Cys/CySS was selectively oxidized early in response to endotoxin, while E(h) GSH/GSSG remained unchanged. Unexpectedly, subsequent oxidation of E(h) GSH/GSSG and E(h) Cys/CySS occurred as a consequence of endotoxin-induced anorexia. Taken together, the results indicate that enhanced oxidation of Cys, altered transport of Cys and CySS, and decreased food intake each contribute to the oxidation of plasma Cys/CySS redox state in endotoxemia.

Comprehensive Multiple eQTL Detection and Its Application to GWAS Interpretation.

Expression QTL (eQTL) detection has emerged as an important tool for unraveling the relationship between genetic risk factors and disease or clinical phenotypes. Most studies are predicated on the assumption that only a single causal variant explains the association signal in each interval. This greatly simplifies the statistical modeling, but is liable to biases in scenarios where multiple local causal-variants are responsible. Here, our primary goal was to address the prevalence of secondary cis-eQTL signals regulating peripheral blood gene expression locally, utilizing two large human cohort studies, each >2500 samples with accompanying whole genome genotypes. The CAGE (Consortium for the Architecture of Gene Expression) dataset is a compendium of Illumina microarray studies, and the Framingham Heart Study is a two-generation Affymetrix dataset. We also describe Bayesian colocalization analysis of the extent of sharing of cis-eQTL detected in both studies as well as with the BIOS RNAseq dataset. Stepwise conditional modeling demonstrates that multiple eQTL signals are present for ∼40% of over 3500 eGenes in both microarray datasets, and that the number of loci with additional signals reduces by approximately two-thirds with each conditioning step. Although <20% of the peak signals across platforms fine map to the same credible interval, the colocalization analysis finds that as many as 50-60% of the primary eQTL are actually shared. Subsequently, colocalization of eQTL signals with GWAS hits detected 1349 genes whose expression in peripheral blood is associated with 591 human phenotype traits or diseases, including enrichment for genes with regulatory functions. At least 10%, and possibly as many as 40%, of eQTL-trait colocalized signals are due to nonprimary cis-eQTL peaks, but just one-quarter of these colocalization signals replicated across the gene expression datasets. Our results are provided as a web-based resource for visualization of multi-site regulation of gene expression and its association with human complex traits and disease states.

Age-related changes in the murine larynx: initial validation of a mouse model.

OBJECTIVES: Changes in voice are commonly associated with aging (presbyphonia). Age-related voice change significantly impairs elderly individuals' ability to communicate meaningfully with others and affects their quality of life. With changing age demographics in our society and increasing emphasis on quality of life, treatment of presbylaryngis is becoming more paramount. METHODS: We used 9 aged and 9 young mice to validate a mouse model for the aging larynx. We stained the larynges with Alcian blue to determine the hyaluronic acid content, trichrome stain to determine the collagen content, and immunohistochemical stain for alpha smooth muscle actin to determine the myofibroblast content. Morphometric measurements were performed for muscle area, muscle thickness, and muscle fiber diameter. RESULTS: Statistically significant differences in the density measurements of hyaluronic acid and collagen reflected decreased hyaluronic acid and increased collagen content in the aging larynx. We found alpha smooth muscle actin-labeled myofibroblasts only in the aged larynges. No statistically significant differences were found in the morphometric measurements. CONCLUSIONS: Aged mice may make a practical model for the age-related changes in the vocal folds that can be used further in studies aiming to correct these changes.

Constraints on eQTL Fine Mapping in the Presence of Multisite Local Regulation of Gene Expression.

Expression quantitative trait locus (eQTL) detection has emerged as an important tool for unraveling of the relationship between genetic risk factors and disease or clinical phenotypes. Most studies use single marker linear regression to discover primary signals, followed by sequential conditional modeling to detect secondary genetic variants affecting gene expression. However, this approach assumes that functional variants are sparsely distributed and that close linkage between them has little impact on estimation of their precise location and the magnitude of effects. We describe a series of simulation studies designed to evaluate the impact of linkage disequilibrium (LD) on the fine mapping of causal variants with typical eQTL effect sizes. In the presence of multisite regulation, even though between 80 and 90% of modeled eSNPs associate with normally distributed traits, up to 10% of all secondary signals could be statistical artifacts, and at least 5% but up to one-quarter of credible intervals of SNPs within r2 > 0.8 of the peak may not even include a causal site. The Bayesian methods eCAVIAR and DAP (Deterministic Approximation of Posteriors) provide only modest improvement in resolution. Given the strong empirical evidence that gene expression is commonly regulated by more than one variant, we conclude that the fine mapping of causal variants needs to be adjusted for multisite influences, as conditional estimates can be highly biased by interference among linked sites, but ultimately experimental verification of individual effects is needed. Presumably similar conclusions apply not just to eQTL mapping, but to multisite influences on fine mapping of most types of quantitative trait.

Potent effects of aerosol compared with intravenous treprostinil on the pulmonary circulation.

Inhaled vasodilator therapy for pulmonary hypertension may decrease the systemic side effects commonly observed with systemic administration. Inhaled medications only reach ventilated areas of the lung, so local vasodilation may improve ventilation-perfusion matching and oxygenation. We compared the effects of intravenous vs. aerosolized treprostinil on pulmonary and systemic hemodynamics in an unanesthetized sheep model of sustained acute pulmonary hypertension. Acute, stable pulmonary hypertension was induced in instrumented unanesthetized sheep by infusing a PGH(2) analog, U-44069. The sheep were then administered identical doses of treprostinil either intravenously or by aerosol. Systemic and pulmonary hemodynamics were recorded during each administration. Both intravenous and aerosol delivery of treprostinil reduced pulmonary vascular resistance and pulmonary arterial pressure, but the effect was significantly greater with aerosol delivery (P < 0.05). Aerosol delivery of treprostinil had minimal effects on systemic hemodynamics, whereas intravenous delivery increased heart rate and cardiac output and decreased left atrial pressure and systemic blood pressure. Aerosol delivery of the prostacyclin analog treprostinil has a greater vasodilatory effect in the lung with minimal alterations in systemic hemodynamics compared with intravenous delivery of the drug. We speculate that this may result from treprostinil stimulated production of vasodilatory mediators from pulmonary epithelium.

Health Care Expenditures for University and Academic Medical Center Employees Enrolled in a Pilot Workplace Health Partner Intervention.

OBJECTIVE: To evaluate the impact of a pilot workplace health partner intervention delivered by a predictive health institute to university and academic medical center employees on per-member, per-month health care expenditures. METHODS: We analyzed the health care claims of participants versus nonparticipants, with a 12-month baseline and 24-month intervention period. Total per-member, per-month expenditures were analyzed using two-part regression models that controlled for sex, age, health benefit plan type, medical member months, and active employment months. RESULTS: Our regression results found no statistical differences in total expenditures at baseline and intervention. Further sensitivity analyses controlling for high cost outliers, comorbidities, and propensity to be in the intervention group confirmed these findings. CONCLUSIONS: We find no difference in health care expenditures attributable to the health partner intervention. The intervention does not seem to have raised expenditures in the short term.

Altered prostanoid production by fibroblasts cultured from the lungs of human subjects with idiopathic pulmonary fibrosis.

BACKGROUND: Prostanoids are known to participate in the process of fibrogenesis. Because lung fibroblasts produce prostanoids and are believed to play a central role in the pathogenesis of idiopathic pulmonary fibrosis (IPF), we hypothesized that fibroblasts (HF) cultured from the lungs of patients with IPF (HF-IPF) have an altered balance between profibrotic (thromboxane [TX]A2) and antifibrotic (prostacyclin [PGI2]) prostaglandins (PGs) when compared with normal human lung fibroblasts (HF-NL). METHODS: We measured inducible cyclooxygenase (COX)-2 gene and protein expression, and a profile of prostanoids at baseline and after IL-1beta stimulation. RESULTS: In both HF-IPF and HF-NL COX-2 expression was undetectable at baseline, but was significantly upregulated by IL-1beta. PGE2 was the predominant COX product in IL-1beta-stimulated cells with no significant difference between HF-IPF and HF-NL (28.35 [9.09-89.09] vs. 17.12 [8.58-29.33] ng/10(6) cells/30 min, respectively; P = 0.25). TXB2 (the stable metabolite of TXA2) production was significantly higher in IL-1beta-stimulated HF-IPF compared to HF-NL (1.92 [1.27-2.57] vs. 0.61 [0.21-1.64] ng/10(6) cells/30 min, respectively; P = 0.007) and the ratio of PGI2 (as measured by its stable metabolite 6-keto-PGF1alpha) to TXB2 was significantly lower at baseline in HF-IPF (0.08 [0.04-0.52] vs. 0.12 [0.11-0.89] in HF-NL; P = 0.028) and with IL-1beta stimulation (0.24 [0.05-1.53] vs. 1.08 [0.51-3.79] in HF-NL; P = 0.09). CONCLUSION: An alteration in the balance of profibrotic and antifibrotic PGs in HF-IPF may play a role in the pathogeneses of IPF.

A Longitudinal Study of Health Improvement in the Atlanta CHDWB Wellness Cohort.

The Center for Health Discovery and Wellbeing (CHDWB) is an academic program designed to evaluate the efficacy of clinical self-knowledge and health partner counseling for development and maintenance of healthy behaviors. This paper reports on the change in health profiles for over 90 traits, measured in 382 participants over three visits in the 12 months following enrolment. Significant changes in the desired direction of improved health are observed for many traits related to cardiovascular health, including BMI, blood pressure, cholesterol, and arterial stiffness, as well as for summary measures of physical and mental health. The changes are most notable for individuals in the upper quartile of baseline risk, many of whom showed a positive correlated response across clinical categories. By contrast, individuals who start with more healthy profiles do not generally show significant improvements and only a modest impact of targeting specific health attributes was observed. Overall, the CHDWB model shows promise as an effective intervention particularly for individuals at high risk for cardiovascular disease.

Infusion of freshly isolated autologous bone marrow derived mononuclear cells prevents endotoxin-induced lung injury in an ex-vivo perfused swine model.

INTRODUCTION: The acute respiratory distress syndrome (ARDS), affects up to 150,000 patients per year in the United States. We and other groups have demonstrated that bone marrow derived mesenchymal stromal stem cells prevent ARDS induced by systemic and local administration of endotoxin (lipopolysaccharide (LPS)) in mice. METHODS: A study was undertaken to determine the effects of the diverse populations of bone marrow derived cells on the pathophysiology of ARDS, using a unique ex-vivo swine preparation, in which only the ventilated lung and the liver are perfused with autologous blood. Six experimental groups were designated as: 1) endotoxin alone, 2) endotoxin + total fresh whole bone marrow nuclear cells (BMC), 3) endotoxin + non-hematopoietic bone marrow cells (CD45 neg), 4) endotoxin + hematopoietic bone marrow cells (CD45 positive), 5) endotoxin + buffy coat and 6) endotoxin + in vitro expanded swine CD45 negative adherent allogeneic bone marrow cells (cultured CD45neg). We measured at different levels the biological consequences of the infusion of the different subsets of cells. The measured parameters were: pulmonary vascular resistance (PVR), gas exchange (PO2), lung edema (lung wet/dry weight), gene expression and serum concentrations of the pro-inflammatory cytokines IL-1ß, TNF-α and IL-6. RESULTS: Infusion of freshly purified autologous total BMCs, as well as non-hematopoietic CD45(-) bone marrow cells significantly reduced endotoxin-induced pulmonary hypertension and hypoxemia and reduced the lung edema. Also, in the groups that received BMCs and cultured CD45neg we observed a decrease in the levels of IL-1ß and TNF-α in plasma. Infusion of hematopoietic CD45(+) bone marrow cells or peripheral blood buffy coat cells did not protect against LPS-induced lung injury. CONCLUSIONS: We conclude that infusion of freshly isolated autologous whole bone marrow cells and the subset of non-hematopoietic cells can suppress the acute humoral and physiologic responses induced by endotoxemia by modulating the inflammatory response, mechanisms that do not involve engraftment or trans-differentiation of the cells. These observations may have important implications for the design of future cell therapies for ARDS.

Whole genome sequencing in support of wellness and health maintenance.

BACKGROUND: Whole genome sequencing is poised to revolutionize personalized medicine, providing the capacity to classify individuals into risk categories for a wide range of diseases. Here we begin to explore how whole genome sequencing (WGS) might be incorporated alongside traditional clinical evaluation as a part of preventive medicine. The present study illustrates novel approaches for integrating genotypic and clinical information for assessment of generalized health risks and to assist individuals in the promotion of wellness and maintenance of good health. METHODS: Whole genome sequences and longitudinal clinical profiles are described for eight middle-aged Caucasian participants (four men and four women) from the Center for Health Discovery and Well Being (CHDWB) at Emory University in Atlanta. We report multivariate genotypic risk assessments derived from common variants reported by genome-wide association studies (GWAS), as well as clinical measures in the domains of immune, metabolic, cardiovascular, musculoskeletal, respiratory, and mental health. RESULTS: Polygenic risk is assessed for each participant for over 100 diseases and reported relative to baseline population prevalence. Two approaches for combining clinical and genetic profiles for the purposes of health assessment are then presented. First we propose conditioning individual disease risk assessments on observed clinical status for type 2 diabetes, coronary artery disease, hypertriglyceridemia and hypertension, and obesity. An approximate 2:1 ratio of concordance between genetic prediction and observed sub-clinical disease is observed. Subsequently, we show how more holistic combination of genetic, clinical and family history data can be achieved by visualizing risk in eight sub-classes of disease. Having identified where their profiles are broadly concordant or discordant, an individual can focus on individual clinical results or genotypes as they develop personalized health action plans in consultation with a health partner or coach. CONCLUSION: The CHDWB will facilitate longitudinal evaluation of wellness-focused medical care based on comprehensive self-knowledge of medical risks.

Fluid flux and clearance in acute lung injury.

Acute lung injury (ALI) and its most severe form, acute respiratory distress syndrome (ARDS), were presciently described nearly two centuries ago by René Laennec, later to be described clinically in the 1950s and 1960s. Substantial advances have been made in understanding the pathogenesis of these forms of permeability pulmonary edema, including Starling forces and cellular transport mechanisms involved in the generation and resolution of this form of lung injury. Functional animal models and clinically applicable case definitions for ALI and ARDS were instrumental in gaining these new insights. Although no specific pharmacological therapies for ALI and ARDS yet exist, outcomes have improved with advancements in respiratory and fluid-based supportive therapies, and methods to prevent the development or exacerbation of lung injury. Newer targeted therapies continue to be tested for efficacy in this condition where mortality rates frequently exceed 30%. In this article, we review the history of the pathophysiology of lung fluid and solute movement and the seminal clinical observations that brought that history to clinical relevance. We review the relevant lung structure and function and the dynamics of edema formation and resolution, and we describe the related clinical syndromes and the current treatment modalities.

Circulating endothelial progenitor cells inversely associate with organ dysfunction in sepsis.

PURPOSE: Endothelial dysfunction is a primary contributor to sepsis-related organ dysfunction and death. In sepsis animal models, endothelial progenitor cells (EPC) have contributed to vascular repair. The role of endothelial progenitor cells as a biomarker for organ dysfunction is still unknown. We hypothesized that circulating numbers of endothelial progenitor cells would be associated with improved outcomes in sepsis. METHODS: Prospective, observational single-center cohort study in adult intensive care units at Grady Memorial Hospital, an affiliate of Emory University, from July 2007 through April 2009. Peripheral blood was obtained from 95 patients with sepsis, 37 intensive care unit controls, and 51 healthy controls, of whom only 86 patients with sepsis were used in the analysis because we were not able to obtain enough blood in 9 sepsis patients. Clinical data were obtained, and organ dysfunction was measured by Sepsis-Related Organ Failure Assessment (SOFA) score. Endothelial progenitor cells were assessed by a colony-forming unit (CFU) assay in which peripheral blood mononuclear cells were isolated using Ficoll density-gradient centrifugation and cultured in growth media. RESULTS: The patients with sepsis had significantly lower mean endothelial progenitor cell colony counts compared with intensive care unit controls (p = 0.035) and healthy controls (p = 0.0005). There was no difference in colony counts between ICU controls and healthy controls (p = 0.81). In the sepsis patients, EPC CFU numbers inversely associated with SOFA score, adjusting for mortality (r (2) = 0.05, p = 0.04). CONCLUSION: Increased circulating endothelial progenitor cells inversely correlate with organ dysfunction in sepsis patients.

High-performance metabolic profiling of plasma from seven mammalian species for simultaneous environmental chemical surveillance and bioeffect monitoring.

High-performance metabolic profiling (HPMP) by Fourier-transform mass spectrometry coupled to liquid chromatography gives relative quantification of thousands of chemicals in biologic samples but has had little development for use in toxicology research. In principle, the approach could be useful to detect complex metabolic response patterns to toxicologic exposures and to detect unusual abundances or patterns of potentially toxic chemicals. As an initial study to develop these possible uses, we applied HPMP and bioinformatics analysis to plasma of humans, rhesus macaques, marmosets, pigs, sheep, rats and mice to determine: (1) whether more chemicals are detected in humans living in a less controlled environment than captive species and (2) whether a subset of plasma chemicals with similar inter-species and intra-species variation could be identified for use in comparative toxicology. Results show that the number of chemicals detected was similar in humans (3221) and other species (range 2537-3373). Metabolite patterns were most similar within species and separated samples according to family and order. A total of 1485 chemicals were common to all species; 37% of these matched chemicals in human metabolomic databases and included chemicals in 137 out of 146 human metabolic pathways. Probability-based modularity clustering separated 644 chemicals, including many endogenous metabolites, with inter-species variation similar to intra-species variation. The remaining chemicals had greater inter-species variation and included environmental chemicals as well as GSH and methionine. Together, the data suggest that HPMP provides a platform that can be useful within human populations and controlled animal studies to simultaneously evaluate environmental exposures and biological responses to such exposures.

Integrating comparative effectiveness research programs into predictive health: a unique role for academic health centers.

The growing burden of chronic disease, an aging population, and rising health care costs threaten the sustainability of our current model for health care delivery. At the same time, innovations in predictive health offer a pathway to reduce disease burden by preventing and mitigating the development of disease. Academic health centers are uniquely positioned to evaluate the comparative effectiveness of predictive and personalized health interventions, given institutional core competencies in innovative knowledge development. The authors describe Emory University's commitment to integrating comparative effectiveness research (CER) into predictive health programs through the creation and concurrent evaluation of its Center for Health Discovery and Well Being (hereafter, "the Center"). Established in 2008, the Center is a clinical laboratory for testing the validity and utility of a health-focused rather than disease-focused care setting. The Center provides preventive health services based on the current evidence base, evaluates the effectiveness of its care delivery model, involves trainees in both the delivery and evaluation of its services, and collects structured physical, social, and emotional health data on all participants over time. Concurrent evaluation allows the prospective exploration of the complex interactions among health determinants as well as the comparative effectiveness of novel biomarkers in predicting health. Central to the Center is a cohort study of randomly selected university employees. The authors describe how the Center has fostered a foundation for CER through the structured recruitment of study cohorts, standardized interventions, and scheduled data collection strategies that support pilot studies by faculty and trainees.