Research Spotlight

Posted February 15th 2019

Metabolic Acidosis 1 Year Following Kidney Transplantation and Subsequent Cardiovascular Events and Mortality: An Observational Cohort Study.

Donald E. Wesson M.D.

Donald E. Wesson M.D.

Djamali, A., T. Singh, M. L. Melamed, J. H. Stein, F. Aziz, S. Parajuli, M. Mohamed, N. Garg, D. Mandelbrot, D. E. Wesson and B. C. Astor (2019). “Metabolic Acidosis 1 Year Following Kidney Transplantation and Subsequent Cardiovascular Events and Mortality: An Observational Cohort Study.” Am J Kidney Dis Jan 28. [Epub ahead of print].

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RATIONALE & OBJECTIVE: Recent studies suggest that metabolic acidosis is associated with mortality and graft failure in kidney transplant recipients. However, it is unknown whether serum bicarbonate (measured as total carbon dioxide [tCO2] in serum) levels predict cardiovascular events (CVEs) following kidney transplantation. STUDY DESIGN: Observational cohort study. SETTINGS & PARTICIPANTS: Single-center study of 2,128 kidney transplant recipients free of CVEs during the first 13.5 months following transplantation. PREDICTOR: tCO2 level at 1 year posttransplantation. OUTCOMES: Ischemic, arrhythmic, and heart failure CVEs and death from any cause. ANALYTICAL APPROACH: Independent associations were assessed using multivariable proportional hazards regression models. Restricted cubic spline Poisson models were used to explore nonlinear associations. Linear spline proportional hazards models were used to assess associations at different tCO2 levels. RESULTS: The prevalence of metabolic acidosis defined as tCO2 level < 24 mEq/L was 38.8% (n=826). There were 384 recipients with a CVE and 610 deaths during a median follow-up of 4.0 years. CVEs included 241 ischemic, 137 arrhythmic, and 150 heart failure events. tCO2 level < 20 mEq/L was associated with increased risk for CVEs (adjusted HR [aHR], 2.00; 95% CI, 1.29-3.10) compared to the reference category of tCO2 level of 24.0 to 25.9 mEq/L. This association was primarily due to ischemic CVEs (aHR, 2.28; 95% CI, 1.34-3.90). For every 1 mEq/L lower tCO2 level for those with tCO2 < 24 mEq/L, risks for all CVEs and ischemic events were 17% and 15% higher, respectively (aHR for all CVEs of 0.83 [95% CI, 0.74-0.94] and aHR for ischemic CVEs of 0.85 [95% CI, 0.74-0.99]). Notably, tCO2 level < 20 mEq/L, compared to tCO2 level of 24.0 to 25.9 mEq/L, was independently associated with all-cause mortality (aHR, 1.43; 95% CI, 1.02-2.02). For every 1-mEq/L lower tCO2 level for those with tCO2 < 24 mEq/L, there was 17% higher risk for death (aHR, 0.83; 95% CI, 0.75-0.92). LIMITATIONS: Single-center observational study. CONCLUSIONS: Metabolic acidosis is an independent risk factor for ischemic CVEs after kidney transplantation. It is unknown whether correction of acidosis improves outcomes in these patients.


Posted February 15th 2019

Spatial Network Mapping of Pulmonary Multidrug-Resistant Tuberculosis Cavities Using RNA Sequencing.

Tawanda Gumbo M.D.

Tawanda Gumbo M.D.

Dheda, K., L. Lenders, S. Srivastava, G. Magombedze, H. Wainwright, P. Raj, S. J. Bush, G. Pollara, R. Steyn, M. Davids, A. Pooran, T. Pennel, A. Linegar, R. McNerney, L. Moodley, J. G. Pasipanodya, C. T. Turner, M. Noursadeghi, R. M. Warren, E. Wakeland and T. Gumbo (2019). “Spatial Network Mapping of Pulmonary Multidrug-Resistant Tuberculosis Cavities Using RNA Sequencing.” Am J Respir Crit Care Med Jan 29. [Epub ahead of print].

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RATIONALE: There is poor understanding about protective immunity and the pathogenesis of cavitation in tuberculosis patients. OBJECTIVES: To map pathophysiological pathways at anatomically distinct positions within the human tuberculosis cavity. METHODS: Biopsies were obtained from eight pre-determined locations within lung cavities of multidrug-resistant tuberculosis patients undergoing therapeutic surgical resection (n=14) and healthy lung tissue from non-tuberculosis controls (n=10). RNA sequencing, immunohistochemistry, and bacterial load determination was performed at each cavity position. Differentially expressed genes were normalized to non-tuberculosis controls, and ontologically mapped to identify a spatially compartmentalized pathophysiological map of the cavity. In silico perturbation using a novel distance-dependent dynamical sink model was used to investigate interactions between immune networks and bacterial burden, and to integrate these identified pathways. RESULTS: The median (range) lung cavity volume on PET-CT scans was 50cm(3) (15-389cm(3)). RNA sequence reads (31% splice variants) mapped to 19,049 annotated human genes. Multiple pro-inflammatory pathways were upregulated in the cavity wall, while a downregulation ‘sink’ in the central caseum-fluid interface characterized 53% of pathways including neuroendocrine signaling, calcium signaling, TREM-1, reactive oxygen and nitrogen species production, retinoic acid-mediated apoptosis, and RIG-I-like receptor signaling. The mathematical model demonstrated that neuroendocrine, protein kinase C-theta, and TREM-1 pathways, as well as macrophage and neutrophil numbers, had the highest correlation with bacterial burden (r>0.6), while T-helper effector systems did not. CONCLUSION: These data provide novel insights into host immunity to drug-resistant Immune Mycobacterium tuberculosis-related cavitation. The pathways defined may serve as useful targets for the design of host-directed therapies, and transmission prevention interventions.


Posted February 15th 2019

Differential Impact of Heart Failure With Reduced Ejection Fraction on Men and Women.

Milton Packer M.D.

Milton Packer M.D.

Dewan, P., R. Rorth, P. S. Jhund, L. Shen, V. Raparelli, M. C. Petrie, W. T. Abraham, A. S. Desai, K. Dickstein, L. Kober, U. M. Mogensen, M. Packer, J. L. Rouleau, S. D. Solomon, K. Swedberg, M. R. Zile and J. J. V. McMurray (2019). “Differential Impact of Heart Failure With Reduced Ejection Fraction on Men and Women.” J Am Coll Cardiol 73(1): 29-40.

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BACKGROUND: Heart failure (HF) trials initiated in the last century highlighted many differences between men and women. Of particular concern was undertreatment of women compared with men, but much has changed during the past 20 years. OBJECTIVES: This study sought to identify these changes, which may give a new perspective on the management of, and outcomes in, women with HF. METHODS: The study analyzed 12,058 men and 3,357 women enrolled in 2 large HF with reduced ejection fraction (HFrEF) trials with near identical inclusion and exclusion criteria and the same principal outcomes. Outcomes were adjusted for other prognostic variables including N-terminal pro-B-type natriuretic peptide. RESULTS: Women were older and more often obese than men were, had slightly higher systolic blood pressure and heart rate, and were less likely to have most comorbidities, except hypertension. Women had more symptoms and signs (e.g., pedal edema 23.4% vs 19.9%; p < 0.0001) and worse quality of life-median Kansas City Cardiomyopathy Questionnaire Clinical Summary Score 71.3 (interquartile range: 53.4 to 86.5) versus 81.3 (interquartile range: 65.1 to 92.7; p < 0.0001)-despite similar left ventricular ejection fraction and N-terminal pro-B-type natriuretic peptide. However, women had lower mortality (adjusted hazard ratio: 0.68; 95% confidence interval: 0.62 to 0.74; p < 0.001) and risk of HF hospitalization (hazard ratio: 0.80; 95% confidence interval: 0.72 to 0.89; p < 0.001). Diuretics and anticoagulants were underutilized in women. Device therapy was underused in both men and women, but more so in women (e.g., defibrillator 8.6% vs. 16.6%; p < 0.0001). CONCLUSIONS: Although women with HFrEF live longer than men, their additional years of life are of poorer quality, with greater self-reported psychological and physical disability. The explanation for this different sex-related experience of HFrEF is unknown as is whether physicians recognize it. Women continue to receive suboptimal treatment, compared with men, with no obvious explanation for this shortfall.


Posted February 15th 2019

Challenges of Measuring and Assuring Quality for Transcatheter Aortic Valve Replacement.

Michael J. Mack M.D.

Michael J. Mack M.D.

Dehmer, G. J., R. G. Brindis, D. M. Shahian and M. J. Mack (2019). “Challenges of Measuring and Assuring Quality for Transcatheter Aortic Valve Replacement.” J Am Coll Cardiol 73(3): 336-339.

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On July 25, 2018, the U.S. Centers for Medicare and Medicaid Services (CMS) convened a meeting of the Medicare Evidence Development and Coverage Advisory Committee (MEDCAC) to examine whether there is sufficient scientific evidence to support specific procedure volume requirements for hospitals and heart team members to begin or maintain transcatheter aortic valve replacement (TAVR) programs. The meeting was organized for experts to make recommendations to CMS in anticipation of a new National Coverage Determination for TAVR to replace the original determination published in May 2012. MEDCAC panels do not make coverage determinations because that authority rests solely with CMS, but CMS considers their advice and the total body of information collected at the meeting. Three topics were common in many of the presentations, public comments, and deliberations of the committee: 1) the benefits, challenges and unintended consequences resulting from procedural volume requirements; 2) understanding the relationship between procedure volume and outcome; and 3) the challenge of measuring outcome when procedural volumes (sample sizes) are small. Assessing the overall ability of a center to treat aortic valve disease optimally involves not only TAVR but also surgical aortic valve replacement (SAVR) and, to a lesser extent, percutaneous coronary intervention (PCI). SAVR is the surgical alternative to TAVR and is occasionally required to deal with life-threatening TAVR complications. PCI is sometimes performed before TAVR or may be required on an emergency basis to correct a serious complication developing during TAVR. The relationship between TAVR and SAVR procedure volume, outcome, and quality is a specific example of the broader issue facing the U.S. health care system. As our health care system moves from one based on quantity and fee-for-service to one based more on quality and accountability for patients’ outcomes, determining what constitutes quality medical care and how to measure it will continue to increase in importance. (Excerpt from text, p. 337; abstract not available.)


Posted February 15th 2019

Can proactive rapid response team rounding improve surveillance and reduce unplanned escalations in care? A controlled before and after study.

Edgar J. Jimenez, M.D.

Edgar J. Jimenez, M.D.

Danesh, V., D. Neff, T. L. Jones, K. Aroian, L. Unruh, D. Andrews, L. Guerrier, S. J. Venus and E. Jimenez (2019). “Can proactive rapid response team rounding improve surveillance and reduce unplanned escalations in care? A controlled before and after study.” Int J Nurs Stud 91: 128-133.

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BACKGROUND: Unplanned escalations manifest as a breakdown of hospital care attributable to clinician error through missed or delayed identification of physiological instability, ineffective treatment, or iatrogenic harm. OBJECTIVES: To examine the impact of an Early Warning Score-based proactive rapid response team model on the frequency of unplanned intra-hospital escalations in care compared with a rapid response team model based on staff nurse identification of vital sign derangements. DESIGN: Pre- and post Early Warning Score-guided proactive rapid response team model intervention. SETTING: 237-bed community hospital in the southeastern United States. PARTICIPANTS: All hospitalized adults (n = 12,148) during a pre- and post-intervention period. METHODS: Logistic regressions used to examine the relationship between unplanned ICU transfers and rapid response team models (rapid response team vs. Early Warning Score-guided proactive rapid response team). RESULTS: Unplanned ICU transfers were 1.4 times more likely to occur during the rapid response team baseline period (OR = 1.392, 95% CI [1.017-1.905]) compared with the Early Warning Score-guided proactive rapid response team intervention period. CONCLUSIONS: This study reports a difference in the frequency of unplanned escalations using different rapid response models, with fewer unplanned ICU transfers occurring during the use of Early Warning Score-guided proactive rapid response team model while accounting for differences in admission volumes, age, gender and comorbidities. Implementation of this model has implications for patient outcomes, hospital operations and costs.