Research Spotlight

Posted August 15th 2016

Brain MRI and motor function in leukodystrophies.

Raphael Schiffmann M.D.

Raphael Schiffmann M.D.

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.


Posted August 15th 2016

Molecular Mechanisms Regulating T Helper 1 versus T Follicular Helper Cell Differentiation in Humans.

Yong-Jun Liu M.D.

Yong-Jun Liu M.D.

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.


Posted August 15th 2016

Gastric Versus Small Bowel Feeding in Critically Ill Adults.

Kirsten Schlein M.S.

Kirsten Schlein M.S.

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.


Posted August 15th 2016

Failure to rescue rates after coronary artery bypass grafting: An analysis from the society of thoracic surgeons adult cardiac surgery database.

Mitchell J. Magee M.D.

Mitchell J. Magee M.D.

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.


Posted July 15th 2016

Ixmyelocel-T for patients with ischaemic heart failure: a prospective randomised double-blind trial.

Cara East M.D.

Cara East, M.D.

Patel, A. N., T. D. Henry, A. A. Quyyumi, G. L. Schaer, R. D. Anderson, C. Toma, C. East, A. E. Remmers, J. Goodrich, A. S. Desai, D. Recker and A. DeMaria (2016). “Ixmyelocel-t for patients with ischaemic heart failure: A prospective randomised double-blind trial.” Lancet 387(10036): 2412-2421.

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BACKGROUND: Ixmyelocel-T is an expanded, multicellular therapy produced from a patient’s own bone marrow by selectively expanding two key types of bone marrow mononuclear cells: CD90+ mesenchymal stem cells and CD45+ CD14+ auto-fluorescent+ activated macrophages. Early phase clinical trials suggest that intramyocardial delivery of ixmyelocel-T might improve clinical, functional, symptomatic, and quality-of-life outcomes in patients with heart failure due to ischaemic dilated cardiomyopathy. We aimed to assess the safety and efficacy of catheter-based transendocardial injection of ixmyelocel-T cell therapy in patients with heart failure and reduced ejection fractions. METHODS: In this randomised, double-blind, placebo-controlled phase 2B trial (ixCELL-DCM), patients from 31 sites in North America with New York Heart Association class III or IV symptomatic heart failure due to ischaemic dilated cardiomyopathy, who had left ventricular ejection fraction 35% or less, an automatic implantable cardioverter defibrillator, and who were ineligible for revascularisation procedures were randomly assigned (1:1) to receive ixmyelocel-T or placebo at the time of bone marrow aspiration and followed for 12 months. Randomisation was done through an interactive (voice/web) response system. The pharmacist, treating physician, and coordinator at each site were unblinded, but the the follow-up team was completely blinded. The primary endpoint was a composite of all-cause death, cardiovascular admission to hospital, and unplanned clinic visits to treat acute decompensated heart failure based on the blinded adjudication of an independent clinical endpoint committee. Primary efficacy endpoint analyses and safety analyses were done by modified intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01670981. FINDINGS: Between April 2, 2013, and Jan 28, 2015, 126 participants were randomly assigned to receive either ixmyelocel-T (n=66) or placebo (n=60). 114 (90%) patients comprised the modified intention-to-treat population and 109 (87%) patients were included in the per-protocol primary efficacy analysis (58 in the ixmyelocel-T group and 51 in the placebo group). The primary efficacy endpoint was observed in 47 patients: 50 events in 25 (49%) of 51 patients in the placebo group and 38 events in 22 (38%) of 58 patients in the ixmyelocel-T group, which represents a 37% reduction in cardiac events compared with placebo (risk ratio 0.63 [95% CI 0.42-0.97]; p=0.0344). 41 (75%) of 51 participants in the placebo group had serious adverse events versus 31 (53%) of 58 in the ixmyelocel-T group (p=0.0197). INTERPRETATION: To the best of our knowledge, ixCELL-DCM is the largest cell therapy study done in patients with heart failure so far. The transendocardial delivery of ixmyelocel-T in patients with heart failure and reduced ejection fraction due to ischaemic dilated cardiomyopathy resulted in a significant reduction in adjudicated clinical cardiac events compared with placebo leading to improved patient outcomes.