Ataluren treatment of patients with nonsense mutation dystrophinopathy.

INTRODUCTION: Dystrophinopathy is a rare, severe muscle disorder, and nonsense mutations are found in 13% of cases. Ataluren was developed to enable ribosomal readthrough of premature stop codons in nonsense mutation (nm) genetic disorders. METHODS: Randomized, double-blind, placebo-controlled study; males ≥ 5 years with nm-dystrophinopathy received study drug orally 3 times daily, ataluren 10, 10, 20 mg/kg (N=57); ataluren 20, 20, 40 mg/kg (N=60); or placebo (N=57) for 48 weeks. The primary endpoint was change in 6-Minute Walk Distance (6MWD) at Week 48. RESULTS: Ataluren was generally well tolerated. The primary endpoint favored ataluren 10, 10, 20 mg/kg versus placebo; the week 48 6MWD Δ=31.3 meters, post hoc P=0.056. Secondary endpoints (timed function tests) showed meaningful differences between ataluren 10, 10, 20 mg/kg, and placebo. CONCLUSIONS: As the first investigational new drug targeting the underlying cause of nm-dystrophinopathy, ataluren offers promise as a treatment for this orphan genetic disorder with high unmet medical need.

Using step activity monitoring to characterize ambulatory activity in community-dwelling older adults.

OBJECTIVES: To explore the potential of using step activity monitoring to detect differences in ambulatory activity associated with advancing age and declining function in community-dwelling seniors. DESIGN: Cross-sectional pilot study. SETTING: General communities of Seattle, Washington; Catonsville, Maryland; and Durham, North Carolina. PARTICIPANTS: Thirty healthy younger adults, 28 healthy older adults, and 12 older adults reporting functional limitations. MEASUREMENTS: Ambulatory activity data were collected over 6 days with the StepWatch 3. Average daily values were calculated for number of steps, number of minutes of activity, number of activity bouts, variability of minute-to-minute activity, and randomness of minute-to-minute activity fluctuations. RESULTS: Healthy older adults engaged in fewer bouts of activity (P=.03) and displayed less-variable activity (P=.02) than younger adults. Older adults reporting functional limitations not only engaged in fewer bouts of activity (P=.009) and less variable activity (P<.001) than younger adults, but also accumulated fewer total steps (P=.003) and minutes of activity (P=.008) and had less-random minute-to-minute activity fluctuations (P=.02). CONCLUSION: Step activity monitoring data were useful for detecting differences in ambulatory activity according to age and functional limitation. Monitor-based measures reflecting patterns of ambulatory activity show promise for use in studies of physical functioning.

Comparison of a computerized algorithm and prosthetists' judgment in rating functional levels based on daily step activity in transtibial amputees.

The Medicare Functional Classification Levels: "K-Level" system is a standard scale for functional levels of amputees. But it is problematic to document objectively and reliably. The K-Levels are based on three characteristics: potential to ambulate, cadence variability and energy level of the amputees. Actual mobility patterns of transtibial amputees recorded by a step activity monitor (StepWatch™) were translated using a computerized algorithm to match the three K-Level characteristics: the most active one minute, the ratio of low:medium:high step rates, and the total daily steps, respectively. This study compared prosthetists' ratings of functional levels based on a visual inspection of step activity patterns with the ratings calculated by the computerized algorithm based on the same step activity data in 81 transtibial amputees. The computerized algorithm produced functional level values that closely matched the average of the ratings by 14 experienced prosthetists. The slope of the linear regression line was 1.04 with an R 2 value of 0.829, indicating good linearity and concordance across the range of the two scales. The results of this study demonstrated concurrent validity of the computerized algorithm and suggested that it could potentially serve as a useful tool in rating functional levels of transtibial amputees based on real-world step activities and complement a clinic-based test.

Microprocessor-based ambulatory activity monitoring in stroke patients.

PURPOSE: Recovery of ambulatory function after stroke is routinely assessed using standardized subject- or observer-rated instruments that do not directly measure ambulatory activities in the home-community setting. Accuracy of conventional pedometers in stroke patients is not established, limiting their application in mobility outcomes monitoring. This study investigates the accuracy and reliability of a mechanical pedometer versus microprocessor-based step activity monitoring (SAM) in gait-impaired hemiparetic stroke patients. METHODS: Accuracy and test-retest reliability of ankle-worn SAM and belt-worn pedometer were tested directly against hand tallied stride counts and cadence during a battery of timed walks in 16 chronic hemiparetic stroke patients. Patients performed replicate 1-min floor walks at self-selected and fastest comfortable paces, and two 6-min walks on separate days. RESULTS: SAM cadence and total stride counts are more accurate than pedometers during 1-min walks at self-selected (99 +/- 1 vs 87 +/- 11.3%, mean +/- SD, P < 0.01); fast pace (98 +/- 2.3% vs 85 +/- 15%, P < 0.01); and repeated 6-min walks performed on separate days (99 +/- 1% vs 89 +/- 12%, P < 0.01). Although SAM is highly reliable (r = 0.97, P < 0.0001) and accurate in all patients under every walking condition tested, the mechanical pedometer demonstrates this high level of accuracy in only half of stroke patients and has poor test-retest reliability (r = 0.64, P < 0.05). CONCLUSION: SAM, but not the conventional pedometer, provides accurate and reliable measures of cadence and total stride counts in hemiparetic stroke patients. Portable microprocessor-based gait monitoring offers potential to quantitatively measure home-community-based ambulatory activity levels in this population.

Influence of malalignment on socket reaction moments during gait in amputees with transtibial prostheses.

Alignment - the process and measured orientation of the prosthetic socket relative to the foot - is important for proper function of a transtibial prosthesis. Prosthetic alignment is performed by prosthetists using visual gait observation and amputees' feedback. The aim of this study was to investigate the effect of transtibial prosthesis malalignment on the moments measured at the base of the socket: the socket reaction moments. Eleven subjects with transtibial amputation were recruited from the community. An instrumented prosthesis alignment component was used to measure socket reaction moments during ambulation under 17 alignment conditions, including nominally aligned using conventional clinical methods, and angle perturbations of 3° and 6° (flexion, extension, abduction, and adduction) and translation perturbations of 5mm and 10mm (anterior, posterior, lateral, and medial) referenced from the nominal alignment. Coronal alignment perturbations caused systematic changes in the coronal socket reaction moments. All angle and translation perturbations revealed statistically significant differences on coronal socket reaction moments compared to the nominal alignment at 30% and 75% of stance phase (P<0.05). The effect of sagittal alignment perturbations on sagittal socket reaction moments was not as responsive as that of the coronal perturbations. The sagittal angle and translation perturbations of the socket led to statistically significant changes in minimum moment, maximum moment, and moments at 45% of stance phase in the sagittal plane. Therefore, malalignment affected the socket reaction moments in amputees with transtibial prostheses.

Perception of socket alignment perturbations in amputees with transtibial prostheses.

A person with amputation's subjective perception is the only tool available to describe fit and comfort to a prosthetist. However, few studies have investigated the effect of alignment on this perception. The aim of this article is to determine whether people with amputation could perceive the alignment perturbations of their prostheses and effectively communicate them. A randomized controlled perturbation of angular (3 and 6 degrees) and translational (5 and 10 mm) alignments in the sagittal (flexion, extension, and anterior and posterior translations) and coronal (abduction, adduction, and medial and lateral translations) planes were induced from an aligned condition in 11 subjects with transtibial prostheses. The perception was evaluated when standing (static) and immediately after walking (dynamic) using software that used a visual analog scale under each alignment condition. In the coronal plane, Friedman test demonstrated general statistical differences in static (p < 0.001) and dynamic (p < 0.001) measures of perceptions with angular perturbations. In the sagittal plane, it also demonstrated general statistical differences in late-stance dynamic measures of perceptions (p < 0.001) with angular perturbations, as well as in early-stance dynamic measures of perceptions (p < 0.05) with translational perturbations. Fisher exact test suggested that people with amputation's perceptions were good indicators for coronal angle malalignments but less reliable when defining other alignment conditions.

Accelerometer monitoring of home- and community-based ambulatory activity after stroke.

OBJECTIVES: To investigate the utility of a novel microprocessor-linked Step Watch Activity Monitor (SAM) to quantify ambulatory activity after stroke and to evaluate the validity and reliability of conventional accelerometers to measure free-living physical activity in this population. DESIGN: Cross-sectional with repeated measures of 2 separate 48-hour recordings in 17 persons wearing an ankle-mounted SAM and Caltrac, a hip-mounted mechanical accelerometer. SETTING: Home and community. PARTICIPANTS: Seventeen subjects with chronic hemiparetic gait after stroke. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: The SAM derived stride counts per day and Caltrac estimated the daily caloric expenditure of physical activity. RESULTS: SAM data revealed that stroke patients had a mean strides per day +/- standard deviation of 3035+/-1944 and demonstrated a broad range of daily activity profiles (400-6472 strides). SAM test-retest reliability was high across separate monitoring periods (r=.96, P<.001). Although Caltrac also revealed a broad range of daily activity calories (346+/-217 kcal/d; range, 83-1222 kcal/d), reliability was poor (r=.044, P=not significant) and Caltrac accounted for only 64% of the ambulatory activity quantified by the SAM. CONCLUSIONS: Microprocessor-linked accelerometer monitoring, but not conventional accelerometers, are accurate and highly reliable for quantifying ambulatory activity levels in stroke patients. These findings support the utility of personal status monitoring of ambulatory activity as an outcomes instrument and metric in programs to increase physical activity and cardiovascular health after stroke.

Ambulatory activity in men with diabetes: relationship between self-reported and real-world performance-based measures.

The measurement of physical activity, especially walking activity, is important for many outcome studies. In many investigations, the Physical Activity scale of the short-form-36 (SF-36) health assessment questionnaire is used in lieu of an actual physical measurement of walking. This study determined the relationship between the SF-36 questionnaire and the Step Activity Monitor (SAM), a real-world performance-based tool that counts the actual number of steps taken during daily activities. We studied the physical activity of 57 men with diabetes using step count monitoring and the SF-36 questionnaire. The subjects averaged 3,293 steps/day, but had a very wide range (111-11,654) and a large standard deviation (SD = 2,037). The correlations between total daily steps and the SF-36 Physical Component Summary score, and the Physical Function, Bodily Pain, and Vitality scales of the SF-36 were only fair (Pearson's r = 0.376, 0.488, 0.332, 0.380, respectively). The corresponding coefficients of determination range from only 7.7% to 23.8%. Physical activity is a complex concept not completely represented by either the SF-36 or the step counts. The correlation between actual walking activity and the SF-36 is not as strong as many researchers believe. Caution should be exercised with the use of the SF-36 to specifically measure walking activity.

Quantification of prosthetic outcomes: elastomeric gel liner with locking pin suspension versus polyethylene foam liner with neoprene sleeve suspension.

For this randomized crossover trial, we compared two common transtibial socket suspension systems: the Alpha liner with distal locking pin and the Pe-Lite liner with neoprene suspension sleeve. Our original hypotheses asserted that increased ambulatory activity, wear time, comfort, and satisfaction would be found with the elastomeric suspension system. Thirteen subjects completed the study. Following 2.5-month accommodation to each condition, ambulatory activity was recorded (steps/minute for 2 weeks), and subjects completed three questionnaires specific to prosthesis use and pain: the Prosthesis Evaluation Questionnaire (PEQ), a Brief Pain Inventory (BPI) excerpt, and the Socket Comfort Score (SCS). Upon completion, subjects selected their favored system for continued use. Ten subjects preferred the Pe-Lite and three the Alpha. Subjects spent 82% more time wearing the Pe-Lite and took 83% more steps per day. Ambulatory intensity distribution did not differ between systems. No statistically significant differences were found in questionnaire results. Subject feedback for each system was both positive and negative.