Baylor Research Institute

Almutairi, S. M., C. Swank, S. S. Wang-Price, F. Gao and A. Medley (2021). “Walking with and without a robotic exoskeleton in people with incomplete spinal cord injury compared to a typical gait pattern.” NeuroRehabilitation. [Epub ahead of print].

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BACKGROUND: Robotic exoskeleton (RE) enables individuals with lower extremity weakness or paralysis to stand and walk in a stereotypical pattern. OBJECTIVE: Examine whether people with chronic incomplete spinal cord injury (SCI) demonstrate a more typical gait pattern when walking overground in a RE than when walking without. METHODS: Motion analysis system synchronized with a surface electromyographic (EMG) was used to obtain temporospatial gait parameters, lower extremity kinematics, and muscle activity in ambulatory individuals with SCI and healthy adults. RESULTS: Temporospatial parameters and kinematics for participants with SCI (n = 12; age 41.4±12.5 years) with and without RE were significantly different than a typical gait (healthy adults: n = 15; age 26.2±8.3 years). EMG amplitudes during the stance phase of a typical gait were similar to those with SCI with and without RE, except the right rectus femoris (p = 0.005) and left gluteus medius (p = 0.014) when participants with SCI walked with RE. EMG amplitudes of participants with SCI during the swing phase were significantly greater compared to those of a typical gait, except for left medial hamstring with (p = 0.025) and without (p = 0.196) RE. CONCLUSIONS: First-time walking in a RE does not appear to produce a typical gait pattern in people with incomplete SCI.

Ochoa, C., Cole, M. and Froehlich-Grobe, K. (2021). “Feasibility of an Internet-Based Intervention to Promote Exercise for People With Spinal Cord Injury: Observational Pilot Study.” JMIR Rehabil Assist Technol 8(2): e24276.

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BACKGROUND: People with spinal cord injury (SCI) are less likely to be physically active and have higher chronic disease risk than those in the general population due to physical and metabolic changes that occur postinjury. Few studies have investigated approaches to promote increased physical activity (PA) for people with SCI despite evidence that they face unique barriers, including lack of accessible transportation and exercise equipment. To address these obstacles, we adapted an evidence-based phone-delivered intervention that promoted increased PA among people with SCI into a web-based platform, titled the Workout on Wheels internet intervention (WOWii). The adapted program provides participants with weekly skill-building information and activities, basic exercise equipment, and ongoing support through weekly group videoconferencing. OBJECTIVE: This pilot study was conducted to assess the feasibility of using a web-based and virtual format to deliver the WOWii program in a randomized controlled trial. METHODS: We assessed the feasibility of the web-based program by delivering an abbreviated, 4-week version to 10 participants with SCI. Rates of weekly videoconference attendance, activity completion, and exercise activity as tracked by an arm-based activity monitor were recorded for all participants. RESULTS: Participants averaged 3.3 of 4 (83%) weekly group videoconferences attended, 3.4 of 4 (85%) web-based module activities completed, and 2.3 of 4 (58%) weeks of using the arm-based activity monitor. The majority of the sample (9/10, 90%) synced their arm-based PA monitor at least once, and overall engagement as an average of each component across the 4 weeks was 75%. CONCLUSIONS: The intervention had sufficiently high levels of engagement to be used in a full randomized controlled trial to test its effectiveness in improving levels of PA among people with SCI. The knowledge we gained from this pilot study informed improvements that were made in the full randomized controlled trial.

Zerem, A., Ben-Sira, L., Vigdorovich, N., Leibovitz, Z., Fisher, Y., Schiffmann, R., Grishchuk, Y., Misko, A.L., Orenstein, N., Lev, D., Lerman-Sagie, T. and Kidron, D. (2021). “White matter abnormalities and iron deposition in prenatal mucolipidosis IV- fetal imaging and pathology.” Metab Brain Dis May 8. [Epub ahead of print].

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Mucolipidosis type IV (MLIV; OMIM 252,650) is an autosomal recessive lysosomal disorder caused by mutations in MCOLN1. MLIV causes psychomotor impairment and progressive vision loss. The major hallmarks of postnatal brain MRI are hypomyelination and thin corpus callosum. Human brain pathology data is scarce and demonstrates storage of various inclusion bodies in all neuronal cell types. The current study describes novel fetal brain MRI and neuropathology findings in a fetus with MLIV. Fetal MRI was performed at 32 and 35 weeks of gestation due to an older sibling with spastic quadriparesis, visual impairment and hypomyelination. Following abnormal fetal MRI results, the parents requested termination of pregnancy according to Israeli regulations. Fetal autopsy was performed after approval of the high committee for pregnancy termination. A genetic diagnosis of MLIV was established in the fetus and sibling. Sequential fetal brain MRI showed progressive curvilinear hypointensities on T2-weighted images in the frontal deep white matter and a thin corpus callosum. Fetal brain pathology exhibited a thin corpus callosum and hypercellular white matter composed of reactive astrocytes and microglia, multifocal white matter abnormalities with mineralized deposits, and numerous aggregates of microglia with focal intracellular iron accumulation most prominent in the frontal lobes. This is the first description in the literature of brain MRI and neuropathology in a fetus with MLIV. The findings demonstrate prenatal white matter involvement with significant activation of microglia and astrocytes and impaired iron metabolism.

Magombedze, G., Pasipanodya, J.G. and Gumbo, T. (2021). “Bacterial load slopes represent biomarkers of tuberculosis therapy success, failure, and relapse.” Commun Biol 4(1): 664.

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There is an urgent need to discover biomarkers that are predictive of long-term TB treatment outcomes, since treatment is expense and prolonged to document relapse. We used mathematical modeling and machine learning to characterize a predictive biomarker for TB treatment outcomes. We computed bacterial kill rates, γ(f) for fast- and γ(s) for slow/non-replicating bacteria, using patient sputum data to determine treatment duration by computing time-to-extinction of all bacterial subpopulations. We then derived a γ(s-)slope-based rule using first 8 weeks sputum data, that demonstrated a sensitivity of 92% and a specificity of 89% at predicting relapse-free cure for 2, 3, 4, and 6 months TB regimens. In comparison, current methods (two-month sputum culture conversion and the Extended-EBA) methods performed poorly, with sensitivities less than 34%. These biomarkers will accelerate evaluation of novel TB regimens, aid better clinical trial designs and will allow personalization of therapy duration in routine treatment programs.

Wu, Y.S., Khanna, R., Schmith, V., Lun, Y., Shen, J.S., Garcia, A., Dungan, L., Perry, A., Martin, L., Tsai, P.C., Hamler, R., Das, A.M., Schiffmann, R. and Johnson, F.K. (2021). “Migalastat Tissue Distribution: Extrapolation From Mice to Humans Using Pharmacokinetic Modeling and Comparison With Agalsidase Beta Tissue Distribution in Mice.” Clin Pharmacol Drug Dev.

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Approved therapies for Fabry disease (FD) include migalastat, an oral pharmacological chaperone, and agalsidase beta and agalsidase alfa, 2 forms of enzyme replacement therapy. Broad tissue distribution may be beneficial for clinical efficacy in FD, which has severe manifestations in multiple organs. Here, migalastat and agalsidase beta biodistribution were assessed in mice and modeled using physiologically based pharmacokinetic (PBPK) analysis, and migalastat biodistribution was subsequently extrapolated to humans. In mice, migalastat concentration was highest in kidneys and the small intestine, 2 FD-relevant organs. Agalsidase beta was predominantly sequestered in the liver and spleen (organs unaffected in FD). PBPK modeling predicted that migalastat 123 mg every other day resulted in concentrations exceeding the in vitro half-maximal effective concentration in kidneys, small intestine, skin, heart, and liver in human subjects. However, extrapolation of mouse agalsidase beta concentrations to humans was unsuccessful. In conclusion, migalastat may distribute to tissues that are inaccessible to intravenous agalsidase beta in mice, and extrapolation of mouse migalastat concentrations to humans showed adequate tissue penetration, particularly in FD-relevant organs.