Research Spotlight

Swank, C., S. Almutairi, S. Wang-Price and F. Gao (2020). “Immediate kinematic and muscle activity changes after a single robotic exoskeleton walking session post-stroke.” Top Stroke Rehabil Feb 20:1-13. [Epub ahead of print].

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Background: Robotic Exoskeletons (EKSO) are novel technology for retraining common gait dysfunction in people post-stroke. EKSO’s capability to influence gait characteristics post-stroke is unknown.Objectives: To compare temporospatial, kinematic, and muscle activity gait characteristics before and after a single EKSO session and examine kinematic symmetry between involved and uninvolved limbs.Methods: Participants post-stroke walked under two conditions: pre-EKSO, and immediately post-EKSO. A 10-camera motion capture system synchronized with 6 force plates was used to obtain temporospatial and kinematic gait characteristics from 5 walking trials of 9 meters at a self-selected speed. Surface EMG activity was obtained from bilateral gluteus medius, rectus femoris, medial hamstrings, tibialis anterior, and soleus muscles. Wilcoxon Signed Rank tests were used to analyze differences pre- and post-EKSO. Single EKSO session consisted of 22.3+/-6.8 minutes total time (walk time=7.2+/-1.5 minutes) with 250+/-40 steps.Results: Six ambulatory (Functional Ambulation Category, range=4-5) adults (3 female; 44.7+/-14.6 years) with chronic stroke (4.5+/-1.9 years post-stroke) participated. No significant differences were observed for temporospatial gait characteristics. Muscle activity was significantly less post-EKSO in the involved leg rectus femoris during swing phase (p=0.028). Ankle dorsiflexion range of motion on the involved leg post-EKSO was significantly less during stance phase (p=0.046). Differences between involved and uninvolved joint range of motion symmetry were found pre-EKSO but not post-EKSO in swing phase hip flexion and stance phase knee flexion and knee extension.Conclusions: EKSO training appears capable of altering gait in people with chronic stroke and a viable intervention to reduce gait dysfunction post-stroke.

Sundaram, V., S. Kogachi, R. J. Wong, C. J. Karvellas, B. E. Fortune, N. Mahmud, J. Levitsky, R. S. Rahimi and R. Jalan (2020). “Effect of the clinical course of acute-on-chronic liver failure prior to liver transplantation on post-transplant survival.” J Hepatol 72(3): 481-488.

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BACKGROUND & AIMS: Patients with acute-on-chronic liver failure (ACLF) can be listed for liver transplantation (LT) because LT is the only curative treatment option. We evaluated whether the clinical course of ACLF, particularly ACLF-3, between the time of listing and LT affects 1-year post-transplant survival. METHODS: We identified patients from the United Network for Organ Sharing database who were transplanted within 28 days of listing and categorized them by ACLF grade at waitlist registration and LT, according to the EASL-CLIF definition. RESULTS: A total of 3,636 patients listed with ACLF-3 underwent LT within 28 days. Among those transplanted, 892 (24.5%) recovered to no ACLF or ACLF grade 1 or 2 (ACLF 0-2) and 2,744 (75.5%) had ACLF-3 at transplantation. One-year survival was 82.0% among those transplanted with ACLF-3 vs. 88.2% among those improving to ACLF 0-2 (p <0.001). Conversely, the survival of patients listed with ACLF 0-2 who progressed to ACLF-3 at LT (n = 2,265) was significantly lower than that of recipients who remained at ACLF 0-2 (n = 17,631) at the time of LT (83.8% vs. 90.2%, p <0.001). Cox modeling demonstrated that recovery from ACLF-3 to ACLF 0-2 at LT was associated with reduced 1-year mortality after transplantation (hazard ratio0.65; 95% CI 0.53-0.78). Improvement in circulatory failure, brain failure, and removal from mechanical ventilation were also associated with reduced post-LT mortality. Among patients >60 years of age, 1-year survival was significantly higher among those who improved from ACLF-3 to ACLF 0-2 than among those who did not. CONCLUSIONS: Improvement from ACLF-3 at listing to ACLF 0-2 at transplantation enhances post-LT survival, particularly in those who recovered from circulatory or brain failure, or were removed from the mechanical ventilator. The beneficial effect of improved ACLF on post-LT survival was also observed among patients >60 years of age. LAY SUMMARY: Liver transplantation (LT) for patients with acute-on-chronic liver failure grade 3 (ACLF-3) significantly improves survival, but 1-year survival probability after LT remains lower than the expected outcomes for transplant centers. Our study reveals that among patients transplanted within 28 days of waitlist registration, improvement of ACLF-3 at listing to a lower grade of ACLF at transplantation significantly enhances post-transplant survival, even among patients aged 60 years or older. Subgroup analysis further demonstrates that improvement in circulatory failure, brain failure, or removal from mechanical ventilation have the strongest impact on post-transplant survival.

Stack, P. S. and G. O. Ogola (2020). “Survey of Personal Use of Statins by Prescribers.” Am J Cardiol 125(4): 549-552.

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A total of 829 physicians and advanced practice providers within a large, mostly primary care network were surveyed about their personal use of statins and their attitudes toward patient use of these medications. The 239 respondents included 60 clinicians who were current users, most for extended periods, and 15 who had stopped statin use. Nearly one-third of the clinicians over age 40 who took statins used them for primary prevention, compared with just 7.6% of the general adult US population. Half of the current statin users felt that their personal use had a positive effect on their likelihood of prescribing them to patients. More than 10% of users had discontinued statin use due to muscle effects, with virtually no other adverse effects mentioned among the survey respondents. The incidence of statin-associated muscle symptoms was high enough to suggest that as yet unmeasurable statin muscle pathology may be a real phenomenon that has been overlooked.

Singhal, N. K., S. Sternbach, S. Fleming, K. Alkhayer, J. Shelestak, D. Popescu, A. Weaver, R. Clements, B. Wasek, T. Bottiglieri, E. J. Freeman and J. McDonough (2020). “Betaine restores epigenetic control and supports neuronal mitochondria in the cuprizone mouse model of multiple sclerosis.” Epigenetics Feb 25. [Epub ahead of print].

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Methionine metabolism is dysregulated in multiple sclerosis (MS). The methyl donor betaine is depleted in the MS brain where it is linked to changes in levels of histone H3 trimethylated on lysine 4 (H3K4me3) and mitochondrial impairment. We investigated the effects of replacing this depleted betaine in the cuprizone mouse model of MS. Supplementation with betaine restored epigenetic control and alleviated neurological disability in cuprizone mice. Betaine increased the methylation potential (SAM/SAH ratio), levels of H3K4me3, enhanced neuronal respiration, and prevented axonal damage. We show that the methyl donor betaine and the betaine homocysteine methyltransferase (BHMT) enzyme can act in the nucleus to repair epigenetic control and activate neuroprotective transcriptional programs. ChIP-seq data suggest that BHMT acts on chromatin to increase the SAM/SAH ratio and histone methyltransferase activity locally to increase H3K4me3 and activate transcriptional programs that support neuronal energetics. These data suggest that the methyl donor betaine may provide neuroprotection in MS where mitochondrial impairment damages axons and causes disability.

Shah, N. P., V. Garcia-Gutierrez, A. Jimenez-Velasco, S. Larson, S. Saussele, D. Rea, F. X. Mahon, M. Y. Levy, M. T. Gomez-Casares, F. Pane, F. E. Nicolini, M. J. Mauro, O. Sy, P. Martin-Regueira and J. H. Lipton (2020). “Dasatinib discontinuation in patients with chronic-phase chronic myeloid leukemia and stable deep molecular response: the DASFREE study.” Leuk Lymphoma 61(3): 650-659.

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Treatment-free remission (TFR) in patients with chronic myeloid leukemia in chronic phase (CML-CP) is considered a feasible option, especially with the ability of second-generation tyrosine kinase inhibitors to induce higher rates of sustained deep molecular response (DMR). DASFREE is an open-label, single-arm, multicenter phase II trial assessing TFR after dasatinib discontinuation in patients with CML-CP (N = 84). At 2 years, TFR was 46% in all patients. Multivariate analyses revealed statistically significant associations between 2-year TFR and duration of prior dasatinib (>/=median; p = .0051), line of therapy (first line; p = .0138), and age (>65 years; p = .0012). No disease transformation occurred, and the most common adverse events experienced off treatment were musculoskeletal (observed in 30 patients); however, dasatinib withdrawal events were reported in nine patients (11%) by the investigator. Overall, these findings support the feasibility of discontinuing dasatinib for patients with CML-CP in sustained DMR in the first line and beyond.