Research Spotlight

Scherrer, J. F., J. Salas, L. A. Copeland, E. M. Stock, F. D. Schneider, M. Sullivan, K. K. Bucholz, T. Burroughs and P. J. Lustman (2016). “Response to ruan et al. Letter to the editor: Increased risk of depression recurrence after initiation of prescription opioids in noncancer pain patients.” J Pain 17(8): 946-947.

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Whether opioids lead to depression and increase recurrence is best studied in a prospective cohort design. Our results suggest an association that now needs to be confirmed via primary data collection. Our stepwise approach to a novel research question is addressed in a cost-effective manner by starting with existing patient data to support the longer and more costly prospective study.

Schiffmann, R. and B. Banwell (2016). “Brain mri and motor function in leukodystrophies.” Neurology: 2016 Jul [Epub ahead of print].

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There is a need to develop clinical outcome measures for future treatment trials, particularly for pediatric studies and for studies of rare disorders for which such outcome metrics are neither currently well-defined nor validated.1 Patient-reported outcome measures should reflect outcomes that are meaningful to patient-perceived quality of life and sensitive to patient-identified change over time. Physician-reported outcome measures are typically quantifiable and consistently applied across multiple study sites by different investigators, which requires that the metrics be well-defined and that investigator training be rigorous. While clinically relevant outcomes are considered the “gold standard,” and are often the mandated primary outcome of federally funded research, many slowly progressive disorders do not demonstrate clinically apparent change over the time course of a clinical trial. Thus, there is a need for biomarkers, such as neuroimaging measures, that may be more sensitive to change over the typical 2- to 5-year period of a trial. Key to the applicability of such surrogate measures, however, is that they ultimately correlate with changes in neurologic function.

Schmitt, N., Y. Liu, S. E. Bentebibel and H. Ueno (2016). “Molecular mechanisms regulating t helper 1 versus t follicular helper cell differentiation in humans.” Cell Rep 16(4): 1082-1095.

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IL-12 is important for the differentiation of T follicular helper (Tfh) cells, as well as Th1 cells in humans. Still, how IL-12 signals regulate Tfh versus Th1 cell differentiation remains poorly characterized. Here we aimed to determine the molecular mechanisms that regulate the differentiation and the function of IL-12-stimulated human naive CD4(+) T cells. We found that T-bet promoted the expression of CXCR5 in human CD4(+) T cells. We provide evidence that T-bet does not strongly inhibit the Tfh cell differentiation program per se but diminishes the functions to provide help to B cells. This study also suggests that IRF4 plays an important role in driving the early differentiation of IL-12-stimulated CD4(+) T cells toward Tfh and away from Th1 by inhibiting the expression of Eomesodermin. Thus, the fate of IL-12-stimulated CD4(+) T cells is determined through interplay of multiple transcription factors at early stages.

Schlein, K. (2016). “Gastric versus small bowel feeding in critically ill adults.” Nutr Clin Pract 31(4): 514-522.

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Critically ill patients often require enteral feedings as a primary supply of nutrition. Whether enteral nutrition (EN) should be delivered as a gastric versus small bowel feeding in the critically ill patient population remains a contentious topic. The Society of Critical Care Medicine (SCCM)/American Society for Parenteral and Enteral Nutrition (ASPEN), the European Society for Parenteral and Enteral Nutrition (ESPEN), and the Canadian Clinical Practice Guidelines (CCPG) are not in consensus on this topic. No research to date demonstrates a significant difference between the two feeding routes in terms of patient mortality, ventilator days, or length of stay in the intensive care unit (ICU); however, studies provide some evidence that there may be other benefits to using a small bowel feeding route in critically ill patients. The purpose of this paper is to examine both sides of this debate and review advantages and disadvantages of both small bowel and gastric routes of EN. Practical issues and challenges to small bowel feeding tube placement are also addressed. Finally, recommendations are provided to help guide the clinician when selecting a feeding route, and suggestions are made for future research.

Edwards, F. H., V. A. Ferraris, P. A. Kurlansky, K. W. Lobdell, X. He, S. M. O’Brien, A. P. Furnary, J. S. Rankin, C. M. Vassileva, F. L. Fazzalari, M. J. Magee, V. Badhwar, Y. Xian, J. P. Jacobs, M. C. Wyler von Ballmoos and D. M. Shahian (2016). “Failure to rescue rates after coronary artery bypass grafting: An analysis from the society of thoracic surgeons adult cardiac surgery database.” Ann Thorac Surg 102(2): 458-464.

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BACKGROUND: Failure to rescue (FTR) is increasingly recognized as an important quality indicator in surgery. The Society of Thoracic Surgeons National Database was used to develop FTR metrics and a predictive FTR model for coronary artery bypass grafting (CABG). METHODS: The study included 604,154 patients undergoing isolated CABG at 1,105 centers from January 2010 to January 2014. FTR was defined as death after four complications: stroke, renal failure, reoperation, and prolonged ventilation. FTR was determined for each complication and a composite of the four complications. A statistical model to predict FTR was developed. RESULTS: FTR rates were 22.3% for renal failure, 16.4% for stroke, 12.4% for reoperation, 12.1% for prolonged ventilation, and 10.5% for the composite. Mortality increased with multiple complications and with specific combinations of complications. The multivariate risk model for prediction of FTR demonstrated a C index of 0.792 and was well calibrated, with a 1.0% average difference between observed/expected (O/E) FTR rates. With centers grouped into mortality terciles, complication rates increased modestly (11.4% to 15.7%), but FTR rates more than doubled (6.8% to 13.9%) from the lowest to highest terciles. Centers in the lowest complication rate tercile had an FTR O/E of 1.14, whereas centers in the highest complication rate tercile had an FTR O/E of 0.91. CONCLUSIONS: CABG mortality rates vary directly with FTR, but complication rates have little relation to death. FTR rates derived from The Society of Thoracic Surgeons data can serve as national benchmarks. Predicted FTR rates may facilitate patient counseling, and FTR O/E ratios have promise as valuable quality metrics.