Plasma Metabolomics in Human Pulmonary Tuberculosis Disease: A Pilot Study

We aimed to characterize metabolites during tuberculosis (TB) disease and identify new pathophysiologic pathways involved in infection as well as biomarkers of TB onset, progression and resolution. Such data may inform development of new anti-tuberculosis drugs. Plasma samples from adults with newly diagnosed pulmonary TB disease and their matched, asymptomatic, sputum culture-negative household contacts were analyzed using liquid chromatography high-resolution mass spectrometry (LC-MS) to identify metabolites. Statistical and bioinformatics methods were used to select accurate mass/charge (m/z) ions that were significantly different between the two groups at a false discovery rate (FDR) of q<0.05. Two-way hierarchical cluster analysis (HCA) was used to identify clusters of ions contributing to separation of cases and controls, and metabolomics databases were used to match these ions to known metabolites. Identity of specific D-series resolvins, glutamate and Mycobacterium tuberculosis (Mtb)-derived trehalose-6-mycolate was confirmed using LC-MS/MS analysis. Over 23,000 metabolites were detected in untargeted metabolomic analysis and 61 metabolites were significantly different between the two groups. HCA revealed 8 metabolite clusters containing metabolites largely upregulated in patients with TB disease, including anti-TB drugs, glutamate, choline derivatives, Mycobacterium tuberculosis-derived cell wall glycolipids (trehalose-6-mycolate and phosphatidylinositol) and pro-resolving lipid mediators of inflammation, known to stimulate resolution, efferocytosis and microbial killing. The resolvins were confirmed to be RvD1, aspirin-triggered RvD1, and RvD2. This study shows that high-resolution metabolomic analysis can differentiate patients with active TB disease from their asymptomatic household contacts. Specific metabolites upregulated in the plasma of patients with active TB disease, including Mtb-derived glycolipids and resolvins, have potential as biomarkers and may reveal pathways involved in TB disease pathogenesis and resolution

Hypoglycemic and Hyperglycemic Crises Among U.S. Adults With Diabetes and End-stage Kidney Disease: Population-Based Study, 2013-2017

OBJECTIVE: We characterized annual trends of severe hypoglycemic and hyperglycemic crises (diabetic ketoacidosis/hyperglycemic hyperosmolar state) in patients with diabetes and end-stage kidney disease (ESKD). RESEARCH DESIGN AND METHODS: This was a nationwide, retrospective study of adults (≥18 years old) with diabetes/ESKD, from the United States Renal Data System registry, between 2013 and 2017. Primary outcome was annual rates of emergency department visits or hospitalizations for hypoglycemic and hyperglycemic crises, reported as number of events/1,000 person-years. Event rates and risk factors were adjusted for patient age, sex, race/ethnicity, dialysis modality, comorbidities, treatment regimen, and U.S. region. RESULTS: Among 521,789 adults with diabetes/ESKD (median age 65 years [interquartile range 57-73], 56.1% male, and 46% White), overall adjusted rates of hypoglycemic and hyperglycemic crises were 53.64 and 18.24 per 1,000 person-years, respectively. For both hypoglycemia and hyperglycemia crises, respectively, the risks decreased with age and were lowest in older patients (≥75 vs. 18-44 years old: incidence rate ratio 0.35, 95% CI 0.33-0.37, and 0.03, 0.02-0.03), women (1.09, 1.06-1.12, and 1.44, 1.35-1.54), and those with smoking (1.36, 1.28-1.43, and 1.71, 1.53-1.91), substance abuse (1.27, 1.15-1.42, and 1.53, 1.23-1.9), retinopathy (1.10, 1.06-1.15, and 1.36, 1.26-1.47), and insulin therapy (vs. no therapy; 0.60, 0.59-0.63, and 0.44, 0.39-0.48). For hypoglycemia, specifically, additional risk was conferred by Black race (1.11, 1.08-1.15) and amputation history (1.20, 1.13-1.27). CONCLUSIONS: In this nationwide study of patients with diabetes/ESKD, hypoglycemic crises were threefold more common than hyperglycemic crises, greatly exceeding national reports in nondialysis patients with chronic kidney disease. Young, Black, and female patients were disproportionately affected

Linkage of trehalose-6-mycolate, phosphatidylinositol and the D-series resolvin metabolite(s) in plasma of patients without or with MDR-TB.

<p>Linkage of trehalose-6-mycolate, phosphatidylinositol and the D-series resolvin metabolite(s) in plasma of patients without or with MDR-TB.</p

Significant metabolites that distinguish TB patients from household contacts.

<p>(A) Two-way hierarchical cluster analysis (HCA) using C18 chromatography shows 8 clusters of metabolites from human plasma and illustrates the patterns distinguishing those with active TB from household contacts without evidence of TB disease. The 17 subjects with TB disease (TB; shown in green) and the 17 household contacts (HC; shown in red) are shown along the x-axis. (B) Pie chart depicts chemical classes of the 61 significant metabolites from panel 2A according to high-resolution matches to metabolite databases <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0108854#pone.0108854-Jones1" target="_blank">[6]</a>.</p

MS/MS fragmentation spectra show positive identification of resolvin D1 (RvD1), resolvin D2 (RvD2), and aspirin-triggered resolvin D1 (AT-RvD1) in plasma from subjects with TB disease.

<p>Metabololipidomics analytical methods that incorporated high-resolution liquid chromatography coupled with tandem mass spectroscopy (LC-MS/MS, ABI 5500, see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0108854#s2" target="_blank">methods</a>) were used to verify these DHA-derived specialized pro-resolving lipid mediators <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0108854#pone.0108854-Dalli1" target="_blank">[31]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0108854#pone.0108854-Yang1" target="_blank">[33]</a>.</p

Demographic characteristics of individuals with TB disease and their asymptomatic household contacts.

<p>Demographic characteristics of individuals with TB disease and their asymptomatic household contacts.</p