Predicting clinical outcomes of SARS-CoV-2 infection during the Omicron wave using machine learning.

The Omicron SARS-CoV-2 variant continues to strain healthcare systems. Developing tools that facilitate the identification of patients at highest risk of adverse outcomes is a priority. The study objectives are to develop population-scale predictive models that: 1) identify predictors of adverse outcomes with Omicron surge SARS-CoV-2 infections, and 2) predict the impact of prioritized vaccination of high-risk groups for said outcome. We prepared a retrospective longitudinal observational study of a national cohort of 172,814 patients in the U.S. Veteran Health Administration who tested positive for SARS-CoV-2 from January 15 to August 15, 2022. We utilized sociodemographic characteristics, comorbidities, and vaccination status, at time of testing positive for SARS-CoV-2 to predict hospitalization, escalation of care (high-flow oxygen, mechanical ventilation, vasopressor use, dialysis, or extracorporeal membrane oxygenation), and death within 30 days. Machine learning models demonstrated that advanced age, high comorbidity burden, lower body mass index, unvaccinated status, and oral anticoagulant use were the important predictors of hospitalization and escalation of care. Similar factors predicted death. However, anticoagulant use did not predict mortality risk. The all-cause death model showed the highest discrimination (Area Under the Curve (AUC) = 0.903, 95% Confidence Interval (CI): 0.895, 0.911) followed by hospitalization (AUC = 0.822, CI: 0.818, 0.826), then escalation of care (AUC = 0.793, CI: 0.784, 0.805). Assuming a vaccine efficacy range of 70.8 to 78.7%, our simulations projected that targeted prevention in the highest risk group may have reduced 30-day hospitalization and death in more than 2 of 5 unvaccinated patients.

Metformin prescription for U.S. veterans with prediabetes, 2010-2019.

Affecting an estimated 88 million Americans, prediabetes increases the risk for developing type 2 diabetes mellitus (T2DM), and independently, cardiovascular disease, retinopathy, nephropathy, and neuropathy. Nevertheless, little is known about the use of metformin for diabetes prevention among patients in the Veterans Health Administration, the largest integrated healthcare system in the U.S. This is a retrospective observational cohort study of the proportion of Veterans with incident prediabetes who were prescribed metformin at the Veterans Health Administration from October 2010 to September 2019. Among 1,059,605 Veterans with incident prediabetes, 12,009 (1.1%) were prescribed metformin during an average 3.4 years of observation after diagnosis. Metformin prescribing was marginally higher (1.6%) among those with body mass index (BMI) ≥35 kg/m2, age <60 years, HbA1c≥6.0%, or those with a history of gestational diabetes, all subgroups at a higher risk for progression to T2DM. In a multivariable model, metformin was more likely to be prescribed for those with BMI ≥35 kg/m2 incidence rate ratio [IRR] 2.6 [95% confidence intervals (CI): 2.1-3.3], female sex IRR, 2.4 [95% CI: 1.8-3.3], HbA1c≥6% IRR, 1.93 [95% CI: 1.5-2.4], age <60 years IRR, 1.7 [95% CI: 1.3-2.3], hypertriglyceridemia IRR, 1.5 [95% CI: 1.2-1.9], hypertension IRR, 1.5 [95% CI: 1.1-2.1], Major Depressive Disorder IRR, 1.5 [95% CI: 1.1-2.0], or schizophrenia IRR, 2.1 [95% CI: 1.2-3.8]. Over 20% of Veterans with prediabetes attended a comprehensive structured lifestyle modification clinic or program. Among Veterans with prediabetes, metformin was prescribed to 1.1% overall, a proportion that marginally increased to 1.6% in the subset of individuals at highest risk for progression to T2DM.

A genetically supported drug repurposing pipeline for diabetes treatment using electronic health records.

BACKGROUND: The identification of new uses for existing drug therapies has the potential to identify treatments for comorbid conditions that have the added benefit of glycemic control while also providing a rapid, low-cost approach to drug (re)discovery. METHODS: We developed and tested a genetically-informed drug-repurposing pipeline for diabetes management. This approach mapped genetically-predicted gene expression signals from the largest genome-wide association study for type 2 diabetes mellitus to drug targets using publicly available databases to identify drug-gene pairs. These drug-gene pairs were then validated using a two-step approach: 1) a self-controlled case-series (SCCS) using electronic health records from a discovery and replication population, and 2) Mendelian randomization (MR). FINDINGS: After filtering on sample size, 20 candidate drug-gene pairs were validated and various medications demonstrated evidence of glycemic regulation including two anti-hypertensive classes: angiotensin-converting enzyme inhibitors as well as calcium channel blockers (CCBs). The CCBs demonstrated the strongest evidence of glycemic reduction in both validation approaches (SCCS HbA1c and glucose reduction: -0.11%, p = 0.01 and -0.85 mg/dL, p = 0.02, respectively; MR: OR = 0.84, 95% CI = 0.81, 0.87, p = 5.0 x 10-25). INTERPRETATION: Our results support CCBs as a strong candidate medication for blood glucose reduction in addition to cardiovascular disease reduction. Further, these results support the adaptation of this approach for use in future drug-repurposing efforts for other conditions. FUNDING: National Institutes of Health, Medical Research Council Integrative Epidemiology Unit at the University of Bristol, UK Medical Research Council, American Heart Association, and Department of Veterans Affairs (VA) Informatics and Computing Infrastructure and VA Cooperative Studies Program.

Kinematic changes in gait in boys with Duchenne Muscular Dystrophy: Utility of the Gait Deviation Index, the Gait Profile Score and the Gait Variable Scores.

BACKGROUND: Duchenne Muscular Dystrophy (DMD) is an X-linked muscle disorder caused by a mutation or deletion in the dystrophin gene. In boys with DMD, muscle weakness progresses in a proximal to distal pattern, leading to gait abnormalities at all joints, in all planes of motion. Longitudinal studies are imperative to quantify changes in gait function due to DMD and are of particular importance when examining the efficacy of treatment interventions. RESEARCH QUESTION: The purpose of this study was to examine the sensitivity of the Gait Deviation Index (GDI) and Movement Analysis Profile (Gait Profile Score (GPS) and Gait Variable Score (GVS)) to quantify the longitudinal ambulatory decline in boys with DMD. A secondary aim was to quantify the effect of corticosteroid (CS) treatment. METHODS: The gait patterns of 75 boys were assessed longitudinally, 11 were steroid naïve (SN), and 64 received CS treatment. Joint kinematics were collected using either a VICON 612 or a Motion Analysis Corporation 3-D system. Representative trials were used to compute the GDI, GPS and the nine GVS for each boy for each visit. RESULTS: At baseline, GVS for the boys with DMD revealed abnormalities in all lower extremity joints and in all planes of movement compared to TD peers. GDI and GPS indices verified that the overall quality of gait in boys with DMD decreases at a significant rate with age. Boys who were steroid naïve changed at a rate 3 times greater than boys on CS in coronal plane hip motion. SIGNIFICANCE: The gait indices of GDI and GPS are able to identify changes in the quality of gait patterns in boys with DMD. Although boys on steroids had greater gait deviations than boys who were SN at baseline, the rate of decline in gait quality was slower in boys on CS.

A Population-Level Analysis of the Protective Effects of Androgen Deprivation Therapy Against COVID-19 Disease Incidence and Severity.

Background: The incidence and severity of coronavirus disease 19 (COVID-19) is substantially higher in men. Sex hormones may be a potential mechanism for differences in COVID-19 outcome in men and women. We hypothesized that men treated with androgen deprivation therapy (ADT) have lower incidence and severity of COVID-19. Methods: We conducted an observational study of male Veterans treated in the Veterans Health Administration from February 15th to July 15th, 2020. We developed a propensity score model to predict the likelihood to undergo Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) testing. We performed multivariable logistic regression modeling adjusted with inverse probability weighting to examine the relationship between ADT and COVID-19 incidence. We conducted logistic regression analysis among COVID-19 patients to test the association between ADT and COVID-19 severity. Results: We identified a large cohort of 246,087 VA male patients who had been tested for SARS-CoV-2, of whom 3,057 men were exposed to ADT, and 36,096 men with cancer without ADT. Of these, 295 ADT patients and 2,427 cancer patients not on ADT had severe COVID-19 illness. In the primary, propensity-weighted comparison of ADT patients to cancer patients not on ADT, ADT was associated with decreased likelihood of testing positive for SARS-CoV-2 (adjusted OR, 0.88 [95% CI, 0.81-0.95]; p = 0.001). Furthermore, ADT was associated with fewer severe COVID-19 outcomes (OR 0.72 [95% CI 0.53-0.96]; p = 0.03). Conclusion: ADT is associated with reduced incidence and severity of COVID-19 amongst male Veterans. Testosterone and androgen receptor signaling may confer increased risk for SARS-CoV-2 infection and contribute to severe COVID-19 pathophysiology in men.

Using Mendelian randomisation to identify opportunities for type 2 diabetes prevention by repurposing medications used for lipid management.

BACKGROUND: Maintaining a healthy lifestyle to reduce type 2 diabetes (T2D) risk is challenging and additional strategies for T2D prevention are needed. We evaluated several lipid control medications as potential therapeutic options for T2D prevention using tissue-specific predicted gene expression summary statistics in a two-sample Mendelian randomisation (MR) design. METHODS: Large-scale European genome-wide summary statistics for lipids and T2D were leveraged in our multi-stage analysis to estimate changes in either lipid levels or T2D risk driven by tissue-specific predicted gene expression. We incorporated tissue-specific predicted gene expression summary statistics to proxy therapeutic effects of three lipid control medications [i.e., statins, icosapent ethyl (IPE), and proprotein convertase subtilisin/kexin type-9 inhibitors (PCSK-9i)] on T2D susceptibility using two-sample Mendelian randomisation (MR). FINDINGS: IPE, as proxied via increased FADS1 expression, was predicted to lower triglycerides and was associated with a 53% reduced risk of T2D. Statins and PCSK-9i, as proxied by reduced HMGCR and PCSK9 expression, respectively, were predicted to lower LDL-C levels but were not associated with T2D susceptibility. INTERPRETATION: Triglyceride lowering via IPE may reduce the risk of developing T2D in populations of European ancestry. However, experimental validation using animal models is needed to substantiate our results and to motivate randomized control trials (RCTs) for IPE as putative treatment for T2D prevention. FUNDING: Only summary statistics were used in this analysis. Funding information is detailed under Acknowledgments.

A Longitudinal Study of Quantitative Muscle Strength and Functional Motor Ability in Ambulatory Boys with Duchenne Muscular Dystrophy.

BACKGROUND: Duchenne muscular dystrophy (DMD) is an X-linked recessive genetic disorder, that is characterized by progressive muscle degeneration and loss of ambulation between 7-13 years of age. Novel pharmacological agents targeting the genetic defects and disease mechanisms are becoming available; however, corticosteroid (CS) therapy remains the standard of care. OBJECTIVE: The purpose of this longitudinal study was to elucidate the effect of CS therapy on the rate of muscle strength and gross motor skill decline in boys with DMD and assess the sensitivity of selected outcome measures. METHODS: Eighty-four ambulatory boys with DMD (49-180 months), 70 on CS, 14 corticosteroid naïve (NCS), participated in this 8-year multi-site study. Outcomes included; isokinetic dynamometry, the Standing (STD) and Walking/Running/jumping (WRJ) dimensions of the Gross Motor Function Measure (GMFM), and Timed Function Tests (TFTs). Nonlinear mixed modeling procedures determined the rate of change with age and the influence of steroids. RESULTS: Despite CS therapy the rate of decline in strength with age was significant in all muscle groups assessed. CS therapy significantly slowed decline in knee extensor strength, as the NCS group declined at 3x the rate of the CS group. Concurrently, WRJ skills declined in the NCS group at twice the rate of the CS group. 4-stair climb and 10 meter walk/run performance was superior in the boys on CS therapy. CONCLUSION: CS therapy slowed the rate of muscle strength decline and afforded longer retention of select gross motor skills in boys on CS compared to boys who were NCS. Isokinetic dynamometry, Walk/Run/Jump skills, and select TFTs may prove informative in assessing the efficacy of new therapeutics in ambulatory boys with DMD.

Longitudinal changes in energy cost during walking in boys with Duchenne Muscular Dystrophy (DMD).

BACKGROUND: In boys with DMD, muscle weakness progresses in a proximal to distal pattern, leading to compensatory gait strategies, including hyperlordosis and equinus, that increase energy cost and accelerate the loss of walking capacity. RESEARCH QUESTION: The purpose of this study was to determine the changes in the energy cost of walking that occur with disease progression and to determine the optimal normalization scheme for the longitudinal assessment of the energy cost of walking in boys with DMD. METHODS: Energy cost was assessed with the COSMED K4b2. Three normalization schemes were examined: gross energy cost (EC), net non-dimensional oxygen cost (NNcost) and speed-matched control energy cost (SMC-EC). Nonlinear mixed modeling procedures determined the rate of change with age. Linear regression was used to asses the relationship between each normalization scheme and age and body height. RESULTS: 74 boys with DMD were assessed for the energy cost of walking. Velocity decreased at a significant rate (-.00245/month, p = .03) across time; (Fig. 2), while gross EC (.003248/month, p = 0.0026), NNcost (.006155/month, p < 0.0001) and SMC-EC (.001690/month, p = 0.03) all increased significantly. Age and height were significantly associated with NNcost and SMC-EC. The sensitivity of NNcost and SMC-EC to age over time were similar, while SMC-EC was less sensitive to changes in height over time than NNcost. SIGNIFICANCE: In contrast to able-bodied peers, boys with DMD decrease their velocity while all walking energy cost measures increased over time. Both SMC-EC and NNcost proved appropriate normalization schemes for boys with DMD. Compared to gross EC, both NNcost and SMC-EC were less sensitive to changes in age over time, while SMC-EC was less sensitive to changes in height than NNcost. Therefore, both NNCost and SMC-EC are suggested normalization schemes for the longitudinal assessment of energy cost in boys with DMD.

Longitudinal community walking activity in Duchenne muscular dystrophy.

INTRODUCTION: Natural history studies for Duchenne muscular dystrophy (DMD) have not included measures of community ambulation. METHODS: Step activity (SA) monitors quantified community ambulation in 42 boys (ages 4-16 years) with DMD with serial enrollment up to 5 years by using a repeated-measures mixed model. Additionally, data were compared with 10-meter walk/run (10mWR) speed to determine validity and sensitivity. RESULTS: There were significant declines in average strides/day and percent strides at moderate, high and pediatric high rates as a function of age (P < 0.05). Significant correlations for 10mWR versus high and low stride rates were found at baseline (P < 0.05). SA outcomes were sensitive to change over 1 year, but the direction and parameter differed by age group (younger vs. older). Changes in strides/day and percentages of high frequency and low frequency strides correlated significantly with changes in 10mWR speed (P < 0.05). DISCUSSION: Community ambulation data provide valid and sensitive real-world measures that may inform clinical trials. Muscle Nerve 57: 401-406, 2018.

Can Quantitative Muscle Strength and Functional Motor Ability Differentiate the Influence of Age and Corticosteroids in Ambulatory Boys with Duchenne Muscular Dystrophy?

BACKGROUND: In the absence of a curative treatment for Duchenne Muscular Dystrophy (DMD), corticosteroid therapy (prednisone, deflazacort) has been adopted as the standard of care, as it slows the progression of muscle weakness and enables longer retention of functional mobility. The ongoing development of novel pharmacological agents that target the genetic defect underlying DMD offer hope for a significant alteration in disease progression; however, substantiation of therapeutic efficacy has proved challenging. Identifying functional outcomes sensitive to the early, subtle changes in muscle function has confounded clinical trials. Additionally, the alterations in disease progression secondary to corticosteroid therapy are not well described making it difficult to ascertain the benefits of novel agents, often taken concurrently with corticosteroids. OBJECTIVE: The purpose of this study was to examine outcome responsiveness to corticosteroid therapy and age at the onset of a natural history study of ambulatory boys with DMD. METHODS: Eighty-five ambulatory boys with DMD (mean age 93 mo, range 49 to 180 mo) were recruited into this study. Fifty participants were on corticosteroid therapy, while 33 were corticosteroid naïve at the baseline assessment. Within each treatment group boys were divided in two age groups, 4 to 7 years and 8 and greater years of age. The Biodex System 3 Pro isokinetic dynamometer was used to assess muscle strength. Motor skills were assessed using the upper two dimensions (standing/walking, running & jumping) of the Gross Motor Function Measure (GMFM 88) and Timed Motor Tests (TMTs) (10-meter run, sit to stand, supine to stand, climb 4-stairs). Two way analysis of variance and Pearson correlations were used for analysis. RESULTS: A main effect for age was seen in select lower extremity muscle groups (hip flexors, knee extensors and ankle dorsiflexors), standing dimension skills, and all TMTs with significantly greater weakness and loss of motor skill ability seen in the older age group regardless of treatment group. Interaction effects were seen for the walking, running, and jumping dimension of the GMFM with the naïve boys scoring higher in the younger group and boys on corticosteroid therapy scoring higher in the older group. The TMT of climb 4-stairs demonstrated a significant treatment effect with the boys on corticosteroid therapy climbing stairs faster than those who were naïve, regardless of age. Examination of individual items within the upper level GMFM dimensions revealed select motor skills are more informative of disease progression than others; indicating their potential to be sensitive indicators of alterations in disease progression and intervention efficacy. Analysis of the relationship between muscle group strength and motor skill performance revealed differences in use patterns in the corticosteroid versus naïve boys. CONCLUSION: Significant muscle weakness is apparent in young boys with DMD regardless of corticosteroid treatment; however, older boys on corticosteroid therapy tend to have greater retention of muscle strength and motor skill ability than those who are naive. Quantification of muscle strength via isokinetic dynamometry is feasible and sensitive to the variable rates of disease progression in lower extremity muscle groups, but possibly most informative are the subtle changes in the performance characteristics of select motor skills. Further analysis of longitudinal data from this study will explore the influence of corticosteroid therapy on muscle strength and further clarify its impact on motor performance.

Hip kinetics during gait are clinically meaningful outcomes in young boys with Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is an X-linked genetic neuromuscular disorder characterized by progressive proximal to distal muscle weakness. The success of randomized clinical trials for novel therapeutics depends on outcome measurements that are sensitive to change. As the development of motor skills may lead to functional improvements in young boys with DMD, their inclusion may potentially confound clinical trials. Three-dimensional gait analysis is an under-utilized approach that can quantify joint moments and powers, which reflect functional muscle strength. In this study, gait kinetics, kinematics, spatial-temporal parameters, and timed functional tests were quantified over a one-year period for 21 boys between 4 and 8 years old who were enrolled in a multisite natural history study. At baseline, hip moments and powers were inadequate. Between the two visits, 12 boys began a corticosteroid regimen (mean duration 10.8±2.4 months) while 9 boys remained steroid-naïve. Significant between-group differences favoring steroid use were found for primary kinetic outcomes (peak hip extensor moments (p=.007), duration of hip extensor moments (p=.007), peak hip power generation (p=.028)), and spatial-temporal parameters (walking speed (p=.016) and cadence (p=.021)). Significant between-group differences were not found for kinematics or timed functional tests with the exception of the 10m walk test (p=.03), which improves in typically developing children within this age range. These results indicate that hip joint kinetics can be used to identify weakness in young boys with DMD and are sensitive to corticosteroid intervention. Inclusion of gait analysis may enhance detection of a treatment effect in clinical trials particularly for young boys with more preserved muscle function.

Bone density in premenopausal women and men under 50 years of age with cerebral palsy.

OBJECTIVE: To determine bone mineral density (BMD) z scores in adults with cerebral palsy (CP), an understudied population. DESIGN: Cross-sectional. SETTING: Medical facility. PARTICIPANTS: Adults (N=48; mean age, 34.3±5.8y; range, 25-46y) with CP. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: BMD z scores at the lumbar spine and hip using dual-energy x-ray absorptiometry, Gross Motor Function Classification System (GMFCS), body mass index (BMI), and ambulatory status. RESULTS: Mean BMD z scores were -1.40 for the lumbar spine, -1.36 for the total hip, and -1.02 for the femoral neck. The z scores were significantly lower for the nonambulatory group at all 3 sites (P<.05). Significant differences were found among GMFCS levels for the lumbar spine and total hip z scores (P<.05). For the lumbar spine, the mean z scores for level V (the lowest mobility level) were significantly lower than the mean for levels I/II (P=.001), III (P=.002), and IV (P=.013). For the total hip, the mean z scores for level V were significantly lower than the mean for levels I/II (P=.045). A significant positive relationship between the z scores and age was found for the lumbar spine (Spearman ρ=.40, P=.005). Significant positive relationships between BMI and z scores were found for all sites (P<.05). CONCLUSIONS: This study contributes to the sparse literature about bone health in adults with CP. In contrast with pediatric data, z scores did not decrease as a function of age in this adult cohort. This information is important for clinicians considering treatment options for this population.

What are the functional outcomes of endoprosthestic reconstructions after tumor resection?

BACKGROUND: The majority of published functional outcome data for tumor megaprostheses comes in the form of subjective functional outcome scores. Sparse objective data exist demonstrating functional results, activity levels, and efficiency of gait after endoprosthetic reconstruction in patients treated for orthopaedic tumors. Patients embarking on massive surgical operations, often in the setting of debilitating medical therapies, face mortality and a myriad of unknowns. Objective functional outcomes provide patients with reasonable expectations and a means to envision life after treatment. Objective outcomes also provide a means for surgeons to compare techniques, rehabilitation protocols, and implants. QUESTIONS/PURPOSES: We asked the following questions: (1) What is the efficiency of gait (ie, oxygen consumption) at final recovery from endoprosthetic reconstruction for oncologic resections? (2) What is the knee strength after lower extremity endoprosthetic reconstruction as compared with the contralateral limb? (3) How active are patients with tumor megaprostheses at home and in the community? METHODS: Sixty-nine patients with endoprosthetic reconstructions for primary lower extremity bone sarcoma met inclusion criteria and were invited by mailing to undergo oxygen cost study and strength testing. Twenty-four patients (seven proximal femoral replacements, nine distal femoral replacements, and eight proximal tibia replacements) underwent evaluation in the gait laboratory at a mean of 13.2 years after their reconstruction. All patients were then asked to wear step activity monitors at home and in the community for 7 consecutive days. RESULTS: Median O2 consumption (in mL/kg/m) among the endoprothesis groups was not different from the control patients with the numbers available (proximal femoral replacement 0.17, distal femoral replacement 0.16, proximal tibia replacement 0.18, control 0.15, p = 0.21). With the numbers available, there was no difference in walking speed as compared with the control group (proximal femoral replacement 1.20 m/s, distal femoral replacement 1.27 m/s, proximal tibia replacement 1.12 m/s, control 1.27 m/s, p = 0.08). Patients with proximal tibia replacements had reduced knee extension and flexion strength compared with patients in other reconstruction groups (84% reduction in extension versus those with proximal femoral replacements, 35%, and distal femoral replacement, 53%, p = 0.001, and 43% reduction in flexion versus proximal femoral replacement, 11%, distal femoral replacement, 2%, p = 0.006). With the numbers available, mean strides per day were not different among the reconstruction groups (proximal femoral replacement = 4709 strides/day [3094-6696], distal femoral replacement = 2854 [2461-6015], and proximal tibia replacement = 4411 [3093-6215], p = 0.53). CONCLUSIONS: Although knee strength was reduced in patients with proximal tibia replacements compared with femoral reconstructions, all groups had an efficient gait and were active at home and in the community at a mean of 13.2 years after surgery. Despite the magnitude of these surgeries, these patients are similarly active as patients after standard total hip arthroplasty. These findings provide objective data from which patients undergoing tumor megaprosthesis reconstructions of the lower extremity can reasonably base expectations of efficient gait and active lifestyles outside of the hospital setting. These data may provide hope and long-term goals for patients facing the uncertainty of chemotherapy and surgical treatment. LEVEL OF EVIDENCE: Level III, therapeutic study. See Instructions for Authors for a complete description of levels of evidence.

Initial biomechanical evaluation of wearable tactile feedback system for gait rehabilitation in peripheral neuropathy.

Peripheral neuropathy (PN) is a significant public health concern, resulting in abnormal gait biomechanics, diminished postural stability, and increased risk of falls. A wearable tactile feedback system previously developed for sensory augmentation of prosthetic limbs has been adapted for individuals with PN and evaluated in a pilot group of 4 participants with idiopathic bilateral PN, as well as one with Charcot-Marie-Tooth Disease. Participants were assessed both for their abilities to perceive tactile stimuli, and for the effect of tactile biofeedback on their gait. Preliminary data indicate that most participants could localize tactile stimuli and make meaningful modifications to their gait in real time, but that the effect of feedback on gait was highly variable from subject to subject, demanding further investigation.