Physical Activity and Fitness Levels of Individuals With Ataxia: A Cross-Sectional Study.

OBJECTIVE: To investigate physical activity levels of individuals with ataxia and correlate fitness to ataxia severity. DESIGN: An observational study SETTING: An outpatient ataxia clinic in a large, tertiary, urban hospital in the US. PARTICIPANTS: Individuals with cerebellar ataxia (N=42). INTERVENTION: Not applicable. MAIN OUTCOME MEASURE: Participants were classified as sedentary or physically active using the International Physical Activity Questionnaire-Short Form (IPAQ-SF). Maximal oxygen consumption (V̇o2max) as an indicator of fitness level was measured, and ataxia severity was determined by the Scale for the Assessment and Rating of Ataxia (SARA). Mixed effect models were used to correlate ataxia severity to fitness levels. RESULTS: Most participants (28 out of 42) lived sedentary lifestyles, and these individuals had poor fitness levels (only 67.3% of their predicted measure). The main barriers to physical activity included lack of energy, lack of time, and fear of falling. There were no differences in age, sex, disease type, disease duration, ataxia severity, fatigue level, and medication use between sedentary and active groups. Measures of V̇o2max, maximal work, maximal heart rate, and anerobic threshold demonstrated statistically significant differences between groups whereas maximal respiratory rate and expired ventilation/carbon dioxide production were similar between groups. When adjusting for age, sex, functional mobility status, and disease duration, ataxia severity was inversely correlated with fitness level in the sedentary group. There was no relationship between ataxia severity and fitness level in the 14 individuals who were physically active. CONCLUSIONS: Lower fitness levels were associated with more ataxia symptoms in the sedentary group. This relationship was not seen in individuals who were more active. Given the poor health outcomes associated with low fitness, physical activity should be encouraged in this population.

Exercise intolerance associated with impaired oxygen extraction in patients with long COVID.

OBJECTIVE: Chronic mental and physical fatigue and post-exertional malaise are the more debilitating symptoms of long COVID-19. The study objective was to explore factors contributing to exercise intolerance in long COVID-19 to guide development of new therapies. Exercise capacity data of patients referred for a cardiopulmonary exercise test (CPET) and included in a COVID-19 Survivorship Registry at one urban health center were retrospectively analyzed. RESULTS: Most subjects did not meet normative criteria for a maximal test, consistent with suboptimal effort and early exercise termination. Mean O2 pulse peak % predicted (of 79 ± 12.9) was reduced, supporting impaired energy metabolism as a mechanism of exercise intolerance in long COVID, n = 59. We further identified blunted rise in heart rate peak during maximal CPET. Our preliminary analyses support therapies that optimize bioenergetics and improve oxygen utilization for treating long COVID-19.

Home Aerobic Training for Cerebellar Degenerative Diseases: a Randomized Controlled Trial.

Balance training has shown some benefits in cerebellar ataxia whereas the effects of aerobic training are relatively unknown. To determine whether a phase III trial comparing home aerobic to balance training in ambulatory patients with cerebellar ataxia is warranted, we conducted a single-center, assessor-blinded, randomized controlled trial. Nineteen subjects were randomized to aerobic training and 17 subjects to balance training. The primary outcome was improvement in ataxia as measured by the Scale for the Assessment and Rating of Ataxia (SARA). Secondary outcomes included safety, training adherence, and balance improvements. There were no differences between groups at baseline. Thirty-one participants completed the trial, and there were no training-related serious adverse events. Compliance to training was over 70%. There was a mean improvement in ataxia symptoms of 1.9 SARA points (SD 1.62) in the aerobic group compared to an improvement of 0.6 points (SD 1.34) in the balance group. Although two measures of balance were equivocal between groups, one measure of balance showed greater improvement with balance training compared to aerobic training. In conclusion, this 6-month trial comparing home aerobic versus balance training in cerebellar ataxia had excellent retention and adherence to training. There were no serious adverse events, and training was not interrupted by minor adverse events like falls or back pain. There was a significant improvement in ataxia symptoms with home aerobic training compared to balance training, and a phase III trial is warranted. Clinical trial registration number: NCT03701776 on October 8, 2018.

Challenges and Lessons Learned for Acute Inpatient Rehabilitation of Persons With COVID-19: Clinical Presentation, Assessment, Needs, and Services Utilization.

OBJECTIVE: The aim of the study was to present: (1) physiatric care delivery amid the SARS-CoV-2 pandemic, (2) challenges, (3) data from the first cohort of post-COVID-19 inpatient rehabilitation facility patients, and (4) lessons learned by a research consortium of New York and New Jersey rehabilitation institutions. DESIGN: For this clinical descriptive retrospective study, data were extracted from post-COVID-19 patient records treated at a research consortium of New York and New Jersey rehabilitation inpatient rehabilitation facilities (May 1-June 30, 2020) to characterize admission criteria, physical space, precautions, bed numbers, staffing, employee wellness, leadership, and family communication. For comparison, data from the Uniform Data System and eRehabData databases were analyzed. The research consortium of New York and New Jersey rehabilitation members discussed experiences and lessons learned. RESULTS: The COVID-19 patients (N = 320) were treated during the study period. Most patients were male, average age of 61.9 yrs, and 40.9% were White. The average acute care length of stay before inpatient rehabilitation facility admission was 24.5 days; mean length of stay at inpatient rehabilitation facilities was 15.2 days. The rehabilitation research consortium of New York and New Jersey rehabilitation institutions reported a greater proportion of COVID-19 patients discharged to home compared with prepandemic data. Some institutions reported higher changes in functional scores during rehabilitation admission, compared with prepandemic data. CONCLUSIONS: The COVID-19 pandemic acutely affected patient care and overall institutional operations. The research consortium of New York and New Jersey rehabilitation institutions responded dynamically to bed expansions/contractions, staff deployment, and innovations that facilitated safe and effective patient care.

Phase I Single-Blinded Randomized Controlled Trial Comparing Balance and Aerobic Training in Degenerative Cerebellar Disease.

INTRODUCTION: Primary deficits in individuals with cerebellar degeneration include ataxia, unstable gait, and incoordination. Balance training is routinely recommended to improve function whereas little is known regarding aerobic training. OBJECTIVE: To determine the feasibility of conducting a randomized trial comparing balance and aerobic training in individuals with cerebellar degeneration. DESIGN: Assessor blinded randomized control phase I trial. SETTING: Assessments in medical center, home training. PARTICIPANTS: Twenty participants with cerebellar degeneration were randomized to home balance or aerobic training. INTERVENTION: Aerobic training consisted of 4 weeks of stationary bicycle training, five times per week for 30-minute sessions. Home balance training consisted of performing the same duration of easy, moderate, and/or hard exercises. OUTCOME MEASURES: Scale for the Assessment and Rating of Ataxia (SARA), maximal oxygen consumption (VO2 max), Dynamic Gait Index, Timed Up and Go, gait speed. RESULTS: All 20 participants completed assigned training with no major adverse events. Seven of each group attained target training duration, frequency, and intensity. Although both groups had significant improvements in ataxia severity, balance, and gait measures, there were greater improvements in individuals who performed aerobic training in ataxia severity and maximal oxygen consumption when compared to balance training. The effect size for these outcome measures was determined to be large, indicating a phase II trial comparing the benefits of aerobic and balance training was feasible and required 26 participants per group. Improvements in SARA score and VO2 max remained in the aerobic training group at 3 months posttraining, but these improvements were trending back to baseline. In contrast, all balance group measures for pretraining and 3 months posttraining were statistically similar. CONCLUSIONS: A phase II trial comparing balance and aerobic training in individuals with cerebellar degeneration is feasible. Benefits trended back toward baseline after training stopped, although benefits of longer duration exercise programs still need to be determined.

Rehabilitation Medicine Response to the COVID-19 Pandemic.

The COVID-19 pandemic has spread across the globe at a rapid rate, affecting large numbers of individuals in different countries with varying healthcare systems and infrastructure. In the United States, New York City has been the epicenter of the COVID-19 outbreak, and the peak impact in this region has come earlier in this location than most other parts of the country. We report our experience preparing for this pandemic in a New York City academic medical center and its regional healthcare system, the issues confronted during the rise and peak of the number of cases, and the plans for the postpeak recovery and adjustment to the new reality of providing rehabilitation in an environment where COVID-19 remains prevalent.

Investigating the Clinical Significance and Research Discrepancies of Balance Training in Degenerative Cerebellar Disease: A Systematic Review.

OBJECTIVE: The aims of this study were to understand the clinical significance of balance training in degenerative cerebellar disease and to analyze inconsistencies among published data. DESIGN: Five databases were searched from inception to October 8, 2019. Cochrane guidelines informed review methods, and Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed. The Australian National Health and Medical Research Council Evidence Hierarchy, PEDro scale, and Joanna Briggs Institute Critical Appraisal Tools were used to evaluate methodological quality. Outcome measures examined included ataxia severity, gait speed, and balance. RESULTS: Fourteen articles were identified that met inclusion criteria. The quality of evidence was moderate to high, with recent articles being of higher quality. Nine of 12 articles showed statistical improvements in ataxia severity (reduction ranging from 1.4 to 2.8 in the Scale for the Assessment and Rating of Ataxia points), three of eight showed statistical improvements in gait speed (average increase of 0.1 m/sec), and six of nine showed improvements in balance measures (average increase of 1.75 in Berg Balance Scale and 1.5 in Dynamic Gait Index). CONCLUSION: Most studies showed statistical and clinically significant ataxia severity improvements in subjects who performed balance training. The amount of balance challenge and frequency of training were important factors in determining the extent of training benefit. Gait speed may also improve if walking exercises are included in the balance training, but more studies need to be conducted. Balance measures statistically improved with training, but these improvements did not meet criteria for clinical significance. TO CLAIM CME CREDITS: Complete the self-assessment activity and evaluation online at http://www.physiatry.org/JournalCME CME OBJECTIVES: Upon completion of this article, the reader should be able to: (1) Describe the cause(s) of discrepancies in the literature regarding the benefits of balance training in degenerative cerebellar disease; (2) Determine if benefits from balance training are clinically meaningful for individuals with cerebellar degeneration; and (3) Understand the best practices gleaned from the current literature regarding balance training for these diseases. LEVEL: Advanced ACCREDITATION: The Association of Academic Physiatrists is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.The Association of Academic Physiatrists designates this Journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should only claim credit commensurate with the extent of their participation in the activity.

Measurements of Hand Function in Degenerative Cerebellar Disease: A Case-Control Pilot Study.

OBJECTIVE: The aim of the study was to determine the association of Nine Hole Peg Test, Box and Block Test, Jebsen-Taylor Hand Function Test, and kinematic measures of a simple reaching task with ataxia severity in adults with degenerative cerebellar disease. DESIGN: Fourteen adults with cerebellar degeneration were recruited, and ataxia severity was determined using the Scale for the Assessment and Rating of Ataxia. The median Scale for the Assessment and Rating of Ataxia score was used to divide participants into less and more severe ataxia groups. The two groups' average scores on the hand function tests were compared, and correlation of each test with ataxia severity was determined. RESULTS: The Nine Hole Peg Test, Box and Block Test, and Jebsen-Taylor Hand Function Test all differentiated between less and more severe ataxia groups, and the Nine Hole Peg Test performed with the participant's dominant hand had the highest correlation with ataxia severity (rs = 0.92, P < 0.01). Although accuracy, precision, and number of submovements were statistically different between healthy individuals and the more ataxic participant group, most kinematic measures were not significantly different between the less and more severe ataxic groups. CONCLUSION: Overall, our results indicate that all three clinical tests correlate with ataxia severity. Larger future studies should examine the reliability and validity of these hand function measures in adults with degenerative cerebellar disease.

Phase I randomized single-blinded controlled study investigating the potential benefit of aerobic exercise in degenerative cerebellar disease.

OBJECTIVES: To investigate whether people with cerebellar degeneration can perform rigorous aerobic exercise and to assess the clinical impact of training. DESIGN: Randomized single-blinded controlled, feasibility study comparing aerobic training to no training. SETTING: Home intervention, assessments conducted at an academic medical center. SUBJECTS: Twenty individuals with cerebellar degeneration caused by a range of genetic disorders. INTERVENTION: Aerobic training consisted of four weeks of stationary bicycle training, five times per week for 30-minute sessions. Intensity ranged from 65% to 80% of the participant's maximal heart rate determined during cardiopulmonary exercise testing. MAIN MEASURES: Primary outcome measure was change in the Scale for the Assessment and Rating of Ataxia scores. Recruitment rate, adherence, drop-out, and adverse events were also determined. The treatment was considered technically feasible if participants achieved target training frequency, duration, and intensity. RESULTS: The 20 participants mean age was 50 years (standard deviation 15.65 years) and average Scale for the Assessment and Rating of Ataxia score was 9.6 (standard deviation 3.13). Ten participants were randomized to aerobic training and 10 to no training. Seven participants in the aerobic group attained target training duration, frequency, and intensity. There was a mean reduction in ataxia severity of 2.1 points (standard deviation 1.26) with four weeks of aerobic training, whereas ataxia severity increased by 0.3 (standard deviation 0.62) in the control group over the same period. Walking speed, balance measures, and fitness also improved in individuals who performed aerobic exercise. CONCLUSIONS: Rigorous aerobic training is feasible in people with cerebellar degeneration. Improvements in ataxia, balance, and gait are promising.

Induction of innate and adaptive immunity by delivery of poly dA:dT to dendritic cells.

Targeted delivery of antigens to dendritic cells (DCs) is a promising vaccination strategy. However, to ensure immunity, the approach depends on coadministration of an adjuvant. Here we ask whether targeting of both adjuvant and antigen to DCs is sufficient to induce immunity. Using a protein ligation method, we develop a general approach for linking the immune stimulant, poly dA:dT (pdA:dT), to a monoclonal antibody (mAb) specific for DEC205 (DEC). We show that DEC-specific mAbs deliver pdA:dT to DCs for the efficient production of type I interferon in human monocyte-derived DCs and in mice. Notably, adaptive T-cell immunity is elicited when mAbs specific for DEC-pdA:dT are used as the activation stimuli and are administered together with a DC-targeted antigen. Collectively, our studies indicate that DCs can integrate innate and adaptive immunity in vivo and suggest that dual delivery of antigen and adjuvant to DCs might be an efficient approach to vaccine development.

Dendritic cells mediate the induction of polyfunctional human IL17-producing cells (Th17-1 cells) enriched in the bone marrow of patients with myeloma.

IL17-producing (Th17) cells are a distinct lineage of T helper cells that regulate immunity and inflammation. The role of antigen-presenting cells in the induction of Th17 cells in humans remains to be fully defined. Here, we show that human dendritic cells (DCs) are efficient inducers of Th17 cells in culture, including antigen-specific Th17 cells. Although most freshly isolated circulating human Th17 cells secrete IL17 alone or with IL2, those induced by DCs are polyfunctional and coexpress IL17 and IFNgamma (Th17-1 cells). The capacity of DCs to expand Th17-1 cells is enhanced upon DC maturation, and mature DCs are superior to monocytes for the expansion of autologous Th17 cells. In myeloma, where tumors are infiltrated by DCs, Th17 cells are enriched in the bone marrow relative to circulation. Bone marrow from patients with myeloma contains a higher proportion of Th17-1 cells compared with the marrow in preneoplastic gammopathy (monoclonal gammopathy of undetermined significance [MGUS]). Uptake of apoptotic but not necrotic myeloma tumor cells by DCs leads to enhanced induction of Th17-1 cells. These data demonstrate the capacity of DCs to induce expansion of polyfunctional IL17-producing T cells in humans, and suggest a role for DCs in the enrichment of Th17-1 cells in the tumor bed.

A stapled BID BH3 helix directly binds and activates BAX.

BAX is a multidomain proapoptotic BCL-2 family protein that resides in the cytosol until activated by an incompletely understood trigger mechanism, which facilitates BAX translocation to mitochondria and downstream death events. Whether BAX is activated by direct contact with select BH3-only members of the BCL-2 family is highly debated. Here we detect and quantify a direct binding interaction between BAX and a hydrocarbon-stapled BID BH3 domain, which triggers the functional activation of BAX at nanomolar doses in vitro. Chemical reinforcement of BID BH3 alpha helicity was required to reveal the direct BID BH3-BAX association. We confirm the specificity of this BH3 interaction by characterizing a stapled BAD BH3 peptide that interacts with antiapoptotic BCL-X(L) but does not bind or activate BAX. We further demonstrate that membrane targeting of stapled BID BH3 optimizes its ability to activate BAX, supporting a model in which BID directly engages BAX to trigger mitochondrial apoptosis.

A membrane-targeted BID BCL-2 homology 3 peptide is sufficient for high potency activation of BAX in vitro.

The multidomain pro-apoptotic proteins BAX and BAK constitute an essential gateway to mitochondrial dysfunction and programmed cell death. Among the "BCL-2 homology (BH) 3-only" members of pro-apoptotic proteins, truncated BID (tBID) has been implicated in direct BAX activation, although an explicit molecular mechanism remains elusive. We find that BID BH3 peptide alone at submicromolar concentrations cannot activate BAX or complement BID BH3 mutant-tBID in mitochondrial and liposomal release assays. Because tBID contains structurally defined membrane association domains, we investigated whether membrane targeting of BID BH3 peptide would be sufficient to restore its pro-apoptotic activity. We developed a Ni(2+)-nitrilotriacetic acid liposomal assay system that efficiently conjugates histidine-tagged peptides to a simulated outer mitochondrial membrane surface. Strikingly, nanomolar concentrations of a synthetic BID BH3 peptide that is chemically tethered to the liposomal membrane activated BAX almost as efficiently as tBID itself. These results highlight the importance of membrane targeting of the BID BH3 domain in tBID-mediated BAX activation and support a model in which tBID engages BAX to trigger its pro-apoptotic activity.

Conformational changes in BID, a pro-apoptotic BCL-2 family member, upon membrane binding. A site-directed spin labeling study.

The BCL-2 family proteins constitute a critical control point in apoptosis. BCL-2 family proteins display structural homology to channel-forming bacterial toxins, such as colicins, transmembrane domain of diphtheria toxin, and the N-terminal domain of delta-endotoxin. By analogy, it has been hypothesized the BCL-2 family proteins would unfold and insert into the lipid bilayer upon membrane association. We applied the site-directed spin labeling method of electron paramagnetic resonance spectroscopy to the pro-apoptotic member BID. Here we show that helices 6-8 maintain an alpha-helical conformation in membranes with a lipid composition resembling mitochondrial outer membrane contact sites. However, unlike colicins and the transmembrane domain of diphtheria toxin, these helices of BID are bound to the lipid bilayer without adopting a transmembrane orientation. Our study presents a more detailed model for the reorganization of the structure of tBID on membranes.

Activation of apoptosis in vivo by a hydrocarbon-stapled BH3 helix.

BCL-2 family proteins constitute a critical control point for the regulation of apoptosis. Protein interaction between BCL-2 members is a prominent mechanism of control and is mediated through the amphipathic alpha-helical BH3 segment, an essential death domain. We used a chemical strategy, termed hydrocarbon stapling, to generate BH3 peptides with improved pharmacologic properties. The stapled peptides, called "stabilized alpha-helix of BCL-2 domains" (SAHBs), proved to be helical, protease-resistant, and cell-permeable molecules that bound with increased affinity to multidomain BCL-2 member pockets. A SAHB of the BH3 domain from the BID protein specifically activated the apoptotic pathway to kill leukemia cells. In addition, SAHB effectively inhibited the growth of human leukemia xenografts in vivo. Hydrocarbon stapling of native peptides may provide a useful strategy for experimental and therapeutic modulation of protein-protein interactions in many signaling pathways.