Faculty Bibliography

Pulmonary arterial hypertension (PAH) is a sexually dimorphic disease that for unknown reasons affects women more than men. The role of estrogens, both endogenous and exogenous, and reproductive factors in this female susceptibility is still poorly understood. It has been strongly suggested that sex hormones may influence the development and progression of the disease. We sought to determine whether sex hormone exposures and reproductive factors associate with PAH patients compared to control subjects, using a questionnaire and interview to obtain information regarding these potential risk factors. We conducted a single-center unmatched case-control study. Six hundred and thirty-four women and men with PAH, as well as 27 subjects with BMPR2 mutations but no PAH and 132 healthy population controls were enrolled from the Vanderbilt Pulmonary Hypertension Research Cohort and researchmatch.org. Questionnaires and nurse-led interviews were conducted to obtain information regarding sex hormone exposures and reproductive factors. Additional history was obtained on enrolled patients including disease severity variables and comorbidities. Responses to the questionnaires were analyzed to describe these exposures in this population as well as assess the association between disease severity variables and sex hormone exposures. Reproductive and endogenous factors that determine lifelong estrogen exposure were similar between PAH cases and controls. Patients with associated PAH were significantly more likely to be postmenopausal compared to controls. There were similar rates of "ever-use" and duration of use of oral contraceptive pills and hormone replacement therapy in patients when compared to controls. Disease severity variables were not significantly affected by any exposure after adjusting for PAH sub-group. In contrast to our hypothesis, that a greater exposure to exogenous sources of female sex hormones associates with PAH case status, we found similar rates of endogenous and exogenous sex hormone exposure between PAH patients and unmatched controls.

BACKGROUND:Deterioration of ionized calcium (Ca2+) handling in neurons could lead to neurodegenerative disease. Magnesium (Mg) antagonizes Ca during many physiologic activities, including energy metabolism and catalyzation of demethylation from 5-methylcytosine(5-mC) to 5-hydroxymethylcytosine(5-hmC). OBJECTIVE:To test the hypothesis that actively reducing the Ca:Mg intake ratio in the diet through Mg supplementation improves cognitive function, and to test whether this effect is partially mediated by modified cytosines in Apolipoprotein E (APOE). METHODS:This study is nested within the Personalized Prevention of Colorectal Cancer Trial (PPCCT), a double-blind 2×2 factorial randomized controlled trial, which enrolled 250 participants from Vanderbilt University Medical Center. Target doses for both Mg and placebo arms were personalized. RESULTS:Among those aged > 65 years old who consumed a high Ca:Mg ratio diet, we found that reducing the Ca:Mg ratio to around 2.3 by personalized Mg supplementation significantly improved cognitive function by 9.1% (p = 0.03). We also found that reducing the Ca:Mg ratio significantly reduced 5-mC at the cg13496662 and cg06750524 sites only among those aged > 65 years old (p values = 0.02 and 0.03, respectively). Furthermore, the beneficial effect of reducing the Ca:Mg ratio on cognitive function in those aged over 65 years was partially mediated by reductions in 5-mC levels (i.e., cg13496662 and cg06750524) in APOE (p for indirect effect = 0.05). CONCLUSION:Our findings suggest that, among those age 65 and over with a high dietary Ca:Mg ratio, optimal Mg status may improve cognitive function partially through modifications in APOE methylation. These findings, if confirmed, have significant implications for the prevention of cognitive aging and Alzheimer's disease.Clinical Trial Registry number and website: #100106 https://clinicaltrials.gov/ct2/show/NCT03265483.

BACKGROUND:The impact of 13-valent pneumococcal conjugate vaccine (PCV13) introduction on the occurrence of first and subsequent otitis media (OM) episodes in early childhood is unclear. We compared the risk of OM episodes among children age <2 years before and after PCV13 introduction, accounting for the dependence between OM episodes. METHODS:We identified consecutive annual (July-June) cohorts of Tennessee Medicaid-enrolled children (2006-2014) from birth through age 2 years. We identified OM episodes using coded diagnoses (we classified diagnoses <21 days apart as the same episode). We modeled adjusted hazard ratios (aHRs) for OM comparing 7-valent pneumococcal conjugate vaccine (PCV7)-era (2006-2010) and PCV13-era (2011-2014) birth cohorts, accounting for risk factors and dependence between first and subsequent episodes. Secondary analyses examined pressure equalization tube (PET) insertions and compared the risk of recurrent OM (≥3 episodes in 6 months or ≥4 episodes in 12 months) between PCV7- and PCV13-era birth cohorts. RESULTS:We observed 618 968 OM episodes and 24 875 PET insertions among 368 063 children. OM and PET insertion rates increased during the PCV7 years and declined after PCV13 introduction. OM and PET insertion risks were lower in the 2013-2014 cohort compared with the 2009-2010 cohort (aHRs [95% confidence interval], 0.92 [.91-.93] and 0.76 [.72-.80], respectively). PCV13 introduction was associated with declines in the risk of first, subsequent, and recurrent OM. CONCLUSIONS:The transition from PCV7 to PCV13 was associated with a decline of OM among children aged <2 years due to a reduction in the risk of both the first and subsequent OM episodes.

Context/UNASSIGNED:Dipeptidyl peptidase 4 (DPP4) inhibitors may increase the risk of heart failure. Decreased degradation of vasoactive peptides like substance P [also degraded by angiotensin-converting enzyme (ACE)] and Y1 agonists peptide YY (PYY 1-36) and neuropeptide Y (NPY 1-36) could contribute. Objective/UNASSIGNED:This study tested the hypothesis that there is an interactive effect of DPP4 inhibition and ACE inhibition (vs antihypertensive control subjects) on vasoactive peptides after a mixed meal. Participants and Design/UNASSIGNED:Fifty-three patients with type 2 diabetes and hypertension were randomized to double-blind treatment with ramipril, valsartan, or amlodipine for 15 weeks in parallel groups. During the 5th, 10th, and 15th weeks, participants also received placebo + placebo, sitagliptin 100 mg/d + placebo, and sitagliptin + aprepitant 80 mg/d in random order. On the last day of each crossover treatment, participants underwent a mixed-meal study. Results/UNASSIGNED:Sitagliptin increased postprandial glucagon-like peptide-1 and decreased glucose in all antihypertensive groups. Sitagliptin increased NPY 1-36 and decreased Y2 agonists NPY 3-36 and PYY 3-36 in all groups. During ramipril or valsartan, but not amlodipine, sitagliptin increased postprandial norepinephrine; substance P receptor blockade with aprepitant prevented this effect. Despite increased norepinephrine, sitagliptin decreased postprandial blood pressure during ACE inhibition. Conclusion/UNASSIGNED:DPP4 inhibition increases postprandial concentrations of the Y1 agonist NPY 1-36. During treatment with an ACE inhibitor or angiotensin receptor blocker, DPP4 inhibition increased postprandial norepinephrine through a substance P receptor-dependent mechanism. Increased NPY 1-36 and norepinephrine could increase risk of heart failure but did not result in higher postprandial blood pressure.

In a meta-analysis, we assemble a sample of independent, nonidentically distributed p-values. The Fisher's combination procedure provides a chi-squared test of whether the p-values were sampled from the null uniform distribution. After rejecting the null uniform hypothesis, we are faced with the problem of how to combine the assembled p-values. We first derive a distribution for the p-values. The distribution is parameterized by the standardized mean difference (SMD) and the sample size. It includes the uniform as a special case. The maximum likelihood estimate (MLE) of the SMD can then be obtained from the independent, nonidentically distributed p-values. The MLE can be interpreted as a weighted average of the study-specific estimate of the effect size with a shrinkage. The method is broadly applicable to p-values obtained in the maximum likelihood framework. Simulation studies show that our method can effectively estimate the effect size with as few as 6 p-values in the meta-analyses. We also present a Bayes estimator for SMD and a method to account for publication bias. We demonstrate our methods on several meta-analyses that assess the potential benefits of citicoline for patients with memory disorders or patients recovering from ischemic stroke.

Diagnostic World Health Organization (WHO) Group 1 pulmonary arterial hypertension (PAH) and Diagnostic Group 1' pulmonary veno-occlusive disease (PVOD) and/or pulmonary capillary hemangiomatosis (PCH) are progressive and fatal disorders. Past registries provided important insights into these disorders, but did not include hormonal exposures or genomic data. The United States Pulmonary Hypertension Scientific Registry (USPHSR) will provide demographic, physiologic, anorexigen and hormone exposure, genomic, and survival data in the current therapeutic era for 499 patients diagnosed with PAH, PVOD, or PCH. The USPHSR also will explore the relationship between pharmacologic, non-pharmacologic, and dietary hormonal exposures and the increased risk for women to develop idiopathic or heritable PAH.

BACKGROUND:Pulmonary arterial hypertension (PAH) is a deadly disease of the small pulmonary vasculature with an increased prevalence of insulin resistance (IR). Insulin regulates both glucose and lipid homeostasis. We sought to quantify glucose- and lipid-related IR in human PAH, testing the hypothesis that lipoprotein indices are more sensitive indices of IR in PAH. METHODS:Oral glucose tolerance testing in PAH patients and triglyceride-matched (TG-matched) controls and proteomic, metabolomics, and lipoprotein analyses were performed in PAH and controls. Results were validated in an external cohort and in explanted human PAH lungs. RESULTS:PAH patients were similarly glucose intolerant or IR by glucose homeostasis metrics compared with control patients when matched for the metabolic syndrome. Using the insulin-sensitive lipoprotein index, TG/HDL ratio, PAH patients were more commonly IR than controls. Proteomic and metabolomic analysis demonstrated separation between PAH and controls, driven by differences in lipid species. We observed a significant increase in long-chain acylcarnitines, phosphatidylcholines, insulin metabolism-related proteins, and in oxidized LDL receptor 1 (OLR1) in PAH plasma in both a discovery and validation cohort. PAH patients had higher lipoprotein axis-related IR and lipoprotein-based inflammation scores compared with controls. PAH patient lung tissue showed enhanced OLR1 immunostaining within plexiform lesions and oxidized LDL accumulation within macrophages. CONCLUSIONS:IR in PAH is characterized by alterations in lipid and lipoprotein homeostasis axes, manifest by elevated TG/HDL ratio, and elevated circulating medium- and long-chain acylcarnitines and lipoproteins. Oxidized LDL and its receptor OLR1 may play a role in a proinflammatory phenotype in PAH. FUNDING/BACKGROUND:NIH DK096994, HL060906, UL1 RR024975-01, UL1 TR000445-06, DK020593, P01 HL108800-01A1, and UL1 TR002243; American Heart Association 13FTF16070002.

Background/UNASSIGNED:While understanding of critical illness and delirium continue to evolve, the impact on clinical practice is often unknown and delayed. Our purpose was to provide insight into practice changes by characterizing analgesia and sedation usage and occurrence of delirium in different years and international regions. Methods/UNASSIGNED:We performed a retrospective analysis of two multicenter, international, prospective cohort studies. Mechanically ventilated adults were followed for up to 28 days in 2010 and 2016. Proportion of days utilizing sedation, analgesia, and performance of a spontaneous awakening trial (SAT), and occurrence of delirium were described for each year and region and compared between years. Results/UNASSIGNED: < 0.001). Conclusions/UNASSIGNED:Analgesia and sedation practices varied widely across international regions and significantly changed over time. Opportunities for improvement in care include increasing delirium monitoring, performing SATs, and decreasing use of sedation, particularly benzodiazepines.