Research Spotlight

Schiller, L. R. (2019). “Network meta-analysis in chronic constipation: what have we learned?” Lancet Gastroenterol Hepatol Aug 29. [Epub ahead of print].

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Schiffmann, R., D. G. Bichet, E. Benjamin, X. Wu and R. Giugliani (2019). “The migalastat GLP-HEK assay is the gold standard for determining amenability in patients with Fabry disease.” Mol Genet Metab Rep Jul 19; 20:100494. eCollection 2019 Sep.

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The pharmacological chaperone migalastat is indicated for the treatment of Fabry disease in patients with an amenable GLA variant. Amenability is determined by an in vitro, good laboratory practice (GLP)-validated assay using HEK293 cells (GLP-HEK assay) performed at a single, highly experienced, GLP-certified laboratory using rigorous standards and extensive analytical validation to limit inter-assay variability. The recent report by Oommen et al. entitled “Inter-assay variability influences migalastat amenability assessments among Fabry disease variants” showed, despite technical differences between a non-GLP-validated assay and the GLP-HEK assay, 53 out of the 59 GLA variants tested in the non-GLP assay matched the GLP-HEK amenability classification. Considering the non-GLP assay was done without identical procedures and validated quality standards as in the GLP-HEK assay, differences in results are expected. We noted at least two deviations from the GLP-HEK assay that likely account for the discrepancies reported for 6 variants. First, the GLP-HEK assay uses qPCR to directly measure the amount of transfected plasmid DNA for transfection efficiency control. The method employed by Oommen et al., an indirect measurement of co-transfected, secreted embryonic alkaline phosphatase (SEAP), may be inaccurate because overexpression of mutant α-galactosidase A (α-Gal A) can affect trafficking and secretion of SEAP. Second, Oommen et al. used the relative activity (% of wild type) instead of absolute activity (nmol/mg/h) to calculate the fold-increase in α-Gal A activity in response to migalastat, causing values for 4 variants to narrowly miss the amenability criteria. In conclusion, the concern over assay variability seems unfounded, since amenability to migalastat is determined in a single GLP-certified laboratory. We believe physicians can have a high level of confidence in the approved GLP-HEK assay, which identifies GLA variants with the potential to respond to migalastat. Of course, individual response will need to be assessed clinically. (Text of letter; no abstract available.)

Roden-Foreman, J. W., N. R. Rapier, M. L. Foreman, A. L. Zagel, K. W. Sexton, W. C. Beck, C. McGraw, R. A. Coniglio, A. R. Blackmore, J. Holzmacher, B. Sarani, J. C. Hess, C. Greenwell, C. A. Adams, Jr., S. N. Lueckel, M. Weaver, V. Agrawal, J. D. Amos, C. F. Workman, D. J. Milia, A. Bertelson, W. Dorlac, M. J. Warne, J. Cull, C. A. Lyell, J. L. Regner, M. D. McGonigal, S. D. Flohr, S. Steen, M. L. Nance, M. Campbell, B. Putty, D. Sherar and T. J. Schroeppel (2019). “Rethinking the definition of major trauma: The need for trauma intervention outperforms Injury Severity Score and Revised Trauma Score in 38 adult and pediatric trauma centers.” J Trauma Acute Care Surg 87(3): 658-665.

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BACKGROUND: Patients’ trauma burdens are a combination of anatomic damage, physiologic derangement, and the resultant depletion of reserve. Typically, Injury Severity Score (ISS) >15 defines major anatomic injury and Revised Trauma Score (RTS) <7.84 defines major physiologic derangement, but there is no standard definition for reserve. The Need For Trauma Intervention (NFTI) identifies severely depleted reserves (NFTI+) with emergent interventions and/or early mortality. We hypothesized NFTI would have stronger associations with outcomes and better model fit than ISS and RTS. METHODS: Thirty-eight adult and pediatric U.S. trauma centers submitted data for 88,488 encounters. Mixed models tested ISS greater than 15, RTS less than 7.84, and NFTI's associations with complications, survivors' discharge to continuing care, and survivors' length of stay (LOS). RESULTS: The NFTI had stronger associations with complications and LOS than ISS and RTS (odds ratios [99.5% confidence interval]: NFTI = 9.44 [8.46-10.53]; ISS = 5.94 [5.36-6.60], RTS = 4.79 [4.29-5.34]; LOS incidence rate ratios (99.5% confidence interval): NFTI = 3.15 [3.08-3.22], ISS = 2.87 [2.80-2.94], RTS = 2.37 [2.30-2.45]). NFTI was more strongly associated with continuing care discharge but not significantly more than ISS (relative risk [99.5% confidence interval]: NFTI = 2.59 [2.52-2.66], ISS = 2.51 [2.44-2.59], RTS = 2.37 [2.28-2.46]). Cross-validation revealed that in all cases NFTI's model provided a much better fit than ISS greater than 15 or RTS less than 7.84. CONCLUSION: In this multicenter study, NFTI had better model fit and stronger associations with the outcomes than ISS and RTS. By determining depletion of reserve via resource consumption, NFTI+ may be a better definition of major trauma than the standard definitions of ISS greater than 15 and RTS less than 7.84. Using NFTI may improve retrospective triage monitoring and statistical risk adjustments. LEVEL OF EVIDENCE: Prognostic, level IV.

Rangaswami, J., S. Bangalore, B. Kaplan, K. A. Birdwell, A. C. Wiseman, P. A. McCullough and D. M. Dadhania (2019). “Cardiovascular disease care fragmentation in kidney transplantation: a call for action.” Kidney Int 96(3): 568-571.

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Kidney transplantation (KT) is the treatment of choice for end-stage kidney disease, offering the highest survival benefit among all the different renal replacement therapies. Long-term renal allograft and patient survival have shown substantial improvements over time: however, death with a functioning allograft remains the leading cause of late allograft loss, with cardiovascular disease (CVD)–related deaths representing a major cause of mortality. Although recipients of KT have a lower risk of CVD as compared with the 10- to 20-fold increased risk in patients on dialysis, their risk of CVD is substantially higher than that in the general population3 (Figure 1). The transplantation milieu represents the confluence of several traditional and nontraditional cardiovascular risk factors intrinsic to the backdrop of chronic kidney disease (CKD). The entry point of a patient with advanced CKD into transplantation juxtaposes several patient- and donor-related cardiovascular risk factors including preexisting diabetes and hypertension, dialysis vintage, chronic inflammation, allograft quality, donor age, and donor vascular disease. Several post-transplant risk factors are superimposed on this background, such as the chronic effects of immunosuppression with calcineurin inhibitors and steroids, episodes of allograft rejection, new-onset diabetes post-transplantation, and left ventricular hypertrophy. Reduction in CVD-related morbidity and mortality after KT poses challenges across several interfaces: the pre–kidney transplant cardiovascular evaluation, the period of active transplant listing, and post-transplant CVD care. According to the United States Renal Data System 2017 annual report, 18,021 kidney transplant procedures were performed in the United States in 2015, out of the 83,978 wait-listed candidates on maintenance dialysis alone, with a steady increase in the cumulative number of recipients living with a functioning kidney transplant.3 This mandates the need for a coordinated effort across these interfaces to optimize long-term patient and allograft outcomes. On behalf of the Cardiovascular Work Group of the Kidney Pancreas Community of Practice of the American Society of Transplantation, we summarize key factors that may contribute to CVD care fragmentation in KT and offer suggestions for optimizing CVD care delivery in this high-risk population. (Excerpt from text, p. 568-569; no abstract available.)

Packer, M. (2019). “What causes sudden death in patients with chronic heart failure and a reduced ejection fraction?” Eur Heart J Aug 7. [Epub ahead of print].

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Sudden death characterizes the mode of demise in 30-50% of patients with chronic heart failure and a reduced ejection fraction. Occasionally, these events have an identifiable pathophysiological trigger, e.g. myocardial infarction, catecholamine surges, or electrolyte imbalances, but in most circumstances, there is no acute precipitating mechanism. Instead, adverse left ventricular remodelling and fibrosis creates an exceptionally fragile and highly vulnerable substrate, which can be characterized using the model developed in theoretical physics of ‘self-organizing criticality’. This framework has been applied to describe the genesis of avalanches, nodes of traffic congestion unrelated to an accident, the abrupt system-wide failure of electrical grids, and the initiation of cancer and neurodegenerative diseases. Self-organizing criticality within the ventricular myocardium relies on complex adaptations to progressive stress and stretch, which evolve inevitably to an abrupt end (termed ‘cascading failure’), even though the rate of deterioration of the underlying disease process has not changed. The result is acute circulatory collapse (i.e. sudden death) in the absence of an identifiable triggering event. Cascading failure in a severely remodelled or fibrotic heart can become manifest electrically as a first-time ventricular tachyarrhythmia that is responsive to the shock delivered by an implantable cardioverter-defibrillator (ICD). Alternatively, it may present as an acute mechanical failure, which is manifest as (i) asystole, bradyarrhythmia, or electromechanical dissociation; or (ii) incessant ventricular fibrillation that persists despite repetitive ICD discharges; in both instances, the sudden deaths cannot be prevented by an ICD. This conceptual framework explains why anti-remodelling and antifibrotic interventions (i.e. neurohormonal antagonists and cardiac resynchronization) reduce the risk of sudden death in patients with heart failure in the absence of an ICD and provide incremental benefits in those with an ICD. The adoption of anti-remodelling and antifibrotic treatments may explain why the incidence of sudden death in clinical trials of heart failure has declined dramatically over the past 10-15 years, independent of the use of ICDs.