Baylor Research Institute

Schiffmann, R., M. E. Wallace, D. Rinaldi, I. Ledoux, M. P. Luton, S. Coleman, H. O. Akman, K. Martin, J. Y. Hogrel, D. Blankenship, J. Turner and F. Mochel (2017). “A double-blind, placebo-controlled trial of triheptanoin in adult polyglucosan body disease and open-label, long-term outcome.” J Inherit Metab Dis: 2017 Nov [Epub ahead of print].

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BACKGROUND: Adult polyglucosan body disease (APBD) is a progressive neurometabolic disorder caused by a deficiency of glycogen branching enzyme. We tested the efficacy of triheptanoin as a therapy for patients with APBD based on the hypothesis that decreased glycogen degradation leads to brain energy deficit. METHODS AND RESULTS: This was a two-site, randomized crossover trial of 23 patients (age 35-73 years; 63% men) who received triheptanoin or vegetable oil as placebo. The trial took place over 1 year and was followed by a 4-year open-label phase. Generalized linear mixed models were used to analyze this study. At baseline, using the 6-min walk test, patients could walk a mean of 389 +/- 164 m (range 95-672; n = 19), highlighting the great clinical heterogeneity of our cohort. The overall mean difference between patients on triheptanoin versus placebo was 6 m; 95% confidence interval (CI) -11 to 22; p = 0.50. Motion capture gait analysis, gait quality, and stair climbing showed no consistent direction of change. All secondary endpoints were statistically nonsignificant after false discovery rate adjustment. Triheptanoin was safe and generally well tolerated. During the open-label phase of the study, the most affected patients at baseline kept deteriorating while mildly disabled patients remained notably stable up to 4 years. CONCLUSIONS: We cannot conclude that triheptanoin was effective in the treatment of APBD over a 6-month period, but we found it had a good safety profile. This study also emphasizes the difficulty of conducting trials in very rare diseases presenting with a wide clinical heterogeneity.

Yoon, S. H., T. Schmidt, S. Bleiziffer, N. Schofer, C. Fiorina, A. J. Munoz-Garcia, E. Yzeiraj, I. J. Amat-Santos, D. Tchetche, C. Jung, B. Fujita, A. Mangieri, M. A. Deutsch, T. Ubben, F. Deuschl, S. Kuwata, C. De Biase, T. Williams, A. Dhoble, W. K. Kim, E. Ferrari, M. Barbanti, E. M. Vollema, A. Miceli, C. Giannini, G. F. Attizzani, W. K. F. Kong, E. Gutierrez-Ibanes, V. A. Jimenez Diaz, H. C. Wijeysundera, H. Kaneko, T. Chakravarty, M. Makar, H. Sievert, C. Hengstenberg, B. D. Prendergast, F. Vincent, M. Abdel-Wahab, L. Nombela-Franco, M. Silaschi, G. Tarantini, C. Butter, S. M. Ensminger, D. Hildick-Smith, A. S. Petronio, W. H. Yin, F. De Marco, L. Testa, N. M. Van Mieghem, B. K. Whisenant, K. H. Kuck, A. Colombo, S. Kar, C. Moris, V. Delgado, F. Maisano, F. Nietlispach, M. J. Mack, J. Schofer, U. Schaefer, J. J. Bax, C. Frerker, A. Latib and R. R. Makkar (2017). “Transcatheter aortic valve replacement in pure native aortic valve regurgitation.” J Am Coll Cardiol 70(22): 2752-2763.

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BACKGROUND: Limited data exist about safety and efficacy of transcatheter aortic valve replacement (TAVR) in patients with pure native aortic regurgitation (AR). OBJECTIVES: This study sought to compare the outcomes of TAVR with early- and new-generation devices in symptomatic patients with pure native AR. METHODS: From the pure native AR TAVR multicenter registry, procedural and clinical outcomes were assessed according to VARC-2 criteria and compared between early- and new-generation devices. RESULTS: A total of 331 patients with a mean STS score of 6.7 +/- 6.7 underwent TAVR. The early- and new-generation devices were used in 119 patients (36.0%) and 212 patients (64.0%), respectively. STS score tended to be lower in the new-generation device group (6.2 +/- 6.7 vs. 7.6 +/- 6.7; p = 0.08), but transfemoral access was more frequently used in the early-generation device group (87.4% vs. 60.8%; p < 0.001). Compared with the early-generation devices, the new-generation devices were associated with a significantly higher device success rate (81.1% vs. 61.3%; p < 0.001) due to lower rates of second valve implantation (12.7% vs. 24.4%; p = 0.007) and post-procedural AR >/= moderate (4.2% vs. 18.8%; p < 0.001). There were no significant differences in major 30-day endpoints between the 2 groups. The cumulative rates of all-cause and cardiovascular death at 1-year follow-up were 24.1% and 15.6%, respectively. The 1-year all-cause mortality rate was significantly higher in the patients with post-procedural AR >/= moderate compared with those with post-procedural AR /= moderate was independently associated with 1-year all-cause mortality (hazard ratio: 2.85; 95% confidence interval: 1.52 to 5.35; p = 0.001). CONCLUSIONS: Compared with the early-generation devices, TAVR using the new-generation devices was associated with improved procedural outcomes in treating patients with pure native AR. In patients with pure native AR, significant post-procedural AR was independently associated with increased mortality.

Davis, M. L., S. Papini, D. Rosenfield, K. Roelofs, S. Kolb, M. B. Powers and J. A. J. Smits (2017). “A randomized controlled study of power posing before public speaking exposure for social anxiety disorder: No evidence for augmentative effects.” J Anxiety Disord 52: 1-7.

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This manuscript details a randomized controlled study designed to test the efficacy of power posing (i.e., briefly holding postures associated with dominance and power) as an augmentative strategy for exposure therapy for social anxiety disorder (SAD). Seventy-three individuals diagnosed with SAD were assigned to one of three conditions: power posing, submissive posing, or rest (no posing) prior to participating in an exposure therapy session. Participants were assessed for between-group differences in pre- and post-manipulation salivary hormone levels, within-session subjective experiences of fear, and pre- and 1-week post-treatment SAD severity outcome measures. Though the intervention resulted in decreased SAD symptom severity one week later, analyses revealed no significant between-group differences on any tested variables. Accordingly, this study provides no evidence to suggest that power posing impacts hormone levels or exposure therapy outcomes.

Fox, R. J., R. Gold, J. T. Phillips, M. Okwuokenye, A. Zhang and J. L. Marantz (2017). “Efficacy and tolerability of delayed-release dimethyl fumarate in black, hispanic, and asian patients with relapsing-remitting multiple sclerosis: Post hoc integrated analysis of define and confirm.” Neurol Ther 6(2): 175-187.

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INTRODUCTION: Clinical course and treatment response may vary according to race/ethnicity in multiple sclerosis (MS) patients. Delayed-release dimethyl fumarate (DMF; also known as gastro-resistant DMF) demonstrated significant efficacy and a favorable benefit-risk profile in relapsing-remitting MS (RRMS) patients in the 2-year phase III DEFINE/CONFIRM studies. METHODS: In this post hoc analysis of integrated data from DEFINE/CONFIRM, we assessed clinical efficacy and safety/tolerability in black, Hispanic, and Asian patients treated with DMF 240 mg twice daily (approved dosage) or placebo. Eligible patients were 18-55 years of age with an Expanded Disability Status Scale score of 0-5.0. In the integrated intention-to-treat population, 769 and 771 patients were treated with DMF or placebo, respectively, of whom 10 and 19 were black, 31 and 23 were Hispanic, and 66 and 70 were Asian. RESULTS: In the black, Hispanic, and Asian subgroups, DMF was associated with lower annualized relapse rates at 2 years compared with placebo [rate ratio (95% confidence interval (CI)), 0.05 (0.00-1.07); 0.31 (0.10-0.95); and 0.64 (0.30-1.34), respectively]. The percentage of black, Hispanic, and Asian patients with 12-week confirmed disability progression was lower with DMF (43%, 8%, and 20%, respectively) compared with placebo [57%, 30%, and 25%, respectively; hazard ratio (95% CI), 0.53 (0.02-1.39); 0.17 (0.00-0.60); and 0.71 (0.32-1.58), respectively]. The safety/tolerability profile of DMF was generally consistent with that in the overall population of DEFINE/CONFIRM. The incidence of adverse events leading to treatment discontinuation in black, Hispanic, and Asian patients was 2/10, 2/31, and 3/66, respectively, with DMF, and 2/19, 1/23, and 8/70, respectively, with placebo. CONCLUSION: DMF may be an efficacious treatment with a favorable benefit-risk profile in black, Hispanic, and Asian patients with RRMS. Further clinical studies are needed to characterize differences in MS presentation and treatment outcomes across ethnic and racial groups.

O’Gara, P. T., T. M. Sundt, M. A. Acker, T. E. David, R. E. Michler, M. A. Borger, G. Ailawadi, V. H. Thourani, A. M. Gillinov, R. J. Damiano, M. J. Mack, R. Lee, E. A. Rose, T. J. Gardner, M. A. Miller, R. D. Weisel and A. C. Gelijns (2017). “The cardiothoracic surgical trials network: Implications for clinical practice.” J Thorac Cardiovasc Surg 154(6): 1938-1956.

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Background: Postoperative recurrence (POR) of Crohn’s disease (CD) is common. Guidelines on POR management have recently been issued, but clinical practice may vary. Aims:To examine the current clinical practice of POR management in the USA Methods: A web-based survey was sent to all members of the American Gastroenterological Association and the American College of Gastroenterology. The survey consisted of multiple-choice questions with clinical scenarios to assess how participants manage POR. Results: A total of 189 responses were received from practices in 34 states. 44% of participants were from academic settings. The median number of CD patients seen each month was 20–30 patients per participant. The majority of participants considered smoking, prior intestinal surgery, penetrating disease, perianal fistula, early disease onset, and long extent of disease as high-risk factors for POR. To diagnose and grade endoscopic recurrence, 57% of participants used an endoscopic scoring system; 86% defined clinical recurrence using a combination of symptoms and endoscopic findings; and 79% of participants routinely performed colonoscopy after surgery. In high-risk patients, 65% offered medical prophylaxis—most often biologics and/or immunomodulators—immediately after surgery, while 34% offered medical prophylaxis regardless of the patient’s risk of POR. 64% of participants never stopped medical prophylaxis once initiated. Conclusions: Most gastroenterologists routinely perform colonoscopy to guide POR management. The majority of these providers continue medical prophylaxis indefinitely regardless of subsequent endoscopic findings. Further research is needed to determine the risks and benefits of continuing versus deescalating therapy in patients with potentially surgically induced remission.