Clinical Relevance of Physical Function Outcomes in Cancer Cachexia.

Managing clinical manifestations of cancer/treatment burden on functional status and quality of life remains paramount across the cancer trajectory, particularly for patients with cachexia who display reduced functional capacity. However, clinically relevant criteria for classifying functional impairment at a single point in time or for classifying meaningful functional changes subsequent to disease and/or treatment progression are lacking. This unmet clinical need remains a major obstacle to the development of therapies for cancer cachexia. This review aims to describe current literature-based evidence for clinically meaningful criteria for (1) functional impairment at a single timepoint between cancer patients with or without cachexia and (2) changes in physical function over time across interventional studies conducted in patients with cancer cachexia. The most common functional assessment in cross-sectional and interventional studies was hand grip strength (HGS). We observed suggestive evidence that an HGS deficit between 3 and 6 kg in cancer cachexia may display clinical relevance. In interventional studies, we observed that long-duration multimodal therapies with a focus on skeletal muscle may benefit HGS in patients with considerable weight loss. Future studies should derive cohort-specific clinically relevant criteria to confirm these observations in addition to other functional outcomes and investigate appropriate patient-reported anchors.

Defining Clinically Meaningful Cut Points for Leg Power Impairment Using Physical Performance in Older Adults: A Secondary Analysis From Boston RISE.

OBJECTIVE: To identify clinically meaningful thresholds of leg power impairment identified by the stair climb power test (SCPT). DESIGN: Cross-sectional analysis using the baseline data from an observational cohort study. SETTING: The Boston Rehabilitative Impairment Study of the Elderly. PARTICIPANTS: Community-dwelling older adults (N=413). MAIN OUTCOME MEASURES: SCPT and the Short Physical Performance Battery (SPPB). RESULTS: Using the receiver operating characteristic curves and Youden's J statistics, the optimal threshold for the SCPT associated with mobility limitation as defined by an SPPB score ≤9 was 3.07 Watts/kg for men with a sensitivity of 74%, a specificity of 73% and, an area under the curve (AUC) value of 0.78. For women, the optimal threshold was 2.59 Watts/kg with a sensitivity of 83%, a specificity of 69%, and an AUC value of 0.81. The classification and regression tree sensitivity analysis demonstrated similar thresholds, 2.88 Watts/kg and 2.53 Watts/kg for men and women, respectively. CONCLUSIONS: The study identified clinically meaningful thresholds of impairment for the SCPT for mobility limited older primary care patients. These thresholds may be used to inform rehabilitation care to improve functional mobility of older adults and should be validated in larger more representative clinical trials.

Oxygen uptake efficiency slope in community-dwelling ambulant stroke survivors during walking and stair climbing: a cross-sectional study.

BACKGROUND: Oxygen uptake efficiency slope during submaximal tests has been proposed as a more appropriate measure of aerobic capacity after suffering a stroke, since some individuals cannot tolerate maximal exercise testing. However, it has not yet been investigated whether the oxygen uptake efficiency slope is able to differentiate between healthy individuals and those who have suffered a stroke. OBJECTIVES: To compare the oxygen uptake efficiency slope during walking and stair climbing between stroke survivors and age- and sex-matched healthy controls. METHODS: This is a cross-sectional study in which 18 individuals who had suffered a stroke (stroke survivors) and 18 healthy controls matched for sex and age were included. Oxygen consumption and minute ventilation were collected breath-by-breath during walking (6-min Walk Test) and stair climbing. The oxygen uptake efficiency slope was estimated by the slope of the line obtained through linear regression. RESULTS: The stroke survivors had a lower oxygen uptake efficiency slope during the 6-min Walk Test than the healthy controls (MD 498, 95% CI 122 to 873, p = .01). The between-group difference for the Stair Test was smaller and not statistically significant (MD 349, 95%CI -73 to 772, p = .10). CONCLUSIONS: Stroke survivors had lower oxygen uptake efficiency slope during the performance of the 6-min Walk Test when compared to sex- and age-matched healthy controls. This suggests that stroke survivors have worse cardiopulmonary capacity.

Gait parameters, functional performance and physical activity in active and inactive Juvenile Idiopathic Arthritis.

BACKGROUND: Children with Juvenile Idiopathic Arthritis (JIA) may adopt different movement patterns and participate in physical activity during different states of disease. RESEARCH QUESTION: Which specific features of gait and physical function performance differ among children with active or inactive JIA compared to healthy children? METHODS: Forty-three children participated (14.5 ± 4.2 yrs; 60 % female). 3D-motion analysis methods were coupled with force measures from an instrumented treadmill captured gait mechanical measures. The 30-second Chair Rise Test (repetitions) and stair ascent-descent tests were performed, and the 11-point Wong-Baker face scale assessed pain after each test. RESULTS: Compared to healthy controls children with active and inactive JIA had worse outcomes (12-21 % slower self-selected and fast walking speeds, 28-34 % slower stair navigation times, 28 % fewer chair rise repetitions in 30 s; all p < .05). Children with active JIA had 8-13 % slower gait speeds, 4 % fewer chair rise repetitions and 14-16 % slower stair navigation times. At faster walking speed, children with active JIA had less hip joint flexion/extension excursion in the sagittal plane during the gait cycle, produced higher leg stiffness, and demonstrated greater interlimb asymmetry in GRF vertical impulse during loading than healthy children (all p < .05). The Pedi-FABS subscore of "Duration: performing athletic activity for as long as you would like without stopping" was rated lower in children with active JIA compared to controls (p < .05). CONCLUSION: Gait speed, specific load-bearing functional tasks and leg stiffness features of gait may be informative 'functional biomarkers' for assessing JIA burden and tracking treatment efficacy. Additional prospective studies are needed to determine how these features change over time with pain change, and understand impact on quality of life and physical activity participation.

Wearable-Based Stair Climb Power Estimation and Activity Classification.

Stair climb power (SCP) is a clinical measure of leg muscular function assessed in-clinic via the Stair Climb Power Test (SCPT). This method is subject to human error and cannot provide continuous remote monitoring. Continuous monitoring using wearable sensors may provide a more comprehensive assessment of lower-limb muscular function. In this work, we propose an algorithm to classify stair climbing periods and estimate SCP from a lower-back worn accelerometer, which strongly agrees with the clinical standard (r = 0.92, p < 0.001; ICC = 0.90, [0.82, 0.94]). Data were collected in-lab from healthy adults (n = 65) performing the four-step SCPT and a walking assessment while instrumented (accelerometer + gyroscope), which allowed us to investigate tradeoffs between sensor modalities. Using two classifiers, we were able to identify periods of stair ascent with >89% accuracy [sensitivity = >0.89, specificity = >0.90] using two ensemble machine learning algorithms, trained on accelerometer signal features. Minimal changes in model performances were observed using the gyroscope alone (±0−6% accuracy) versus the accelerometer model. While we observed a slight increase in accuracy when combining gyroscope and accelerometer (about +3−6% accuracy), this is tolerable to preserve battery life in the at-home environment. This work is impactful as it shows potential for an accelerometer-based at-home assessment of SCP.

Deriving stair-climbing performance outcome measures using the smartphone barometer: Results of an algorithm development study.

As we seek to gain richer insights to understand intervention effects, and increasingly decentralise aspects of clinical trials to simplify participation, there is a growing interest in leveraging wearables and sensors to generate novel and informative clinical outcome measures for at-home assessment. The sensors embedded within smartphone technology provide one approach to capture of this data, and may be particularly useful when patients are already using mobile devices for at-home capture of other clinical trials data, such as patient-reported outcomes. We describe the results of an initial algorithm development study to determine whether the atmospheric pressure data provided by an onboard smartphone sensor is sufficiently informative to enable detection of a small height gain, such as that achieved during a short stair climb performance test. We were able to sufficiently distinguish height changes of 0.6 m in indoor conditions, representing around 4 stairs on an average staircase. This suggests that the smartphone barometer may indeed be suitable for inclusion within future work developing a stair-climbing performance outcome test instrumented using a mobile application.

Neuromuscular determinants of simulated occupational performance in career firefighters.

PURPOSE: Although firefighters are required to perform various high-intensity critically essential tasks, the influence of neuromuscular function on firefighter occupational performance is unclear. The primary aim of the current study was to identify the key neuromuscular determinants of stair climb (SC) performance in firefighters. METHODS: Leg extension isometric peak torque (PT), peak power (PP), torque steadiness at 10% (Steadiness10%) and 50% (Steadiness50%) of PT, fatigability following 30 repeated isotonic concentric contractions at 40% of PT, percent body fat (%BF), and a weighted and timed SC task were examined in 41 (age: 32.3 ± 8.2 yrs; %BF: 24.1 ± 7.9%) male career firefighters. RESULTS: Faster SC times (74.7 ± 13.4 s) were associated with greater PT and PP, less fatigability, younger age, and lower %BF (r = -0.530-0.629; P ≤ 0.014), but not Steadiness10% or Steadiness50% (P ≥ 0.193). Stepwise regression analyses indicated that PP and Steadiness50% were the strongest predictors of SC time (R2 = 0.442, P < 0.001). However, when age and %BF were included in the model, these variables became the only significant predictors of SC time (R2 = 0.521, P < 0.001) due to age and %BF being collectively associated with all the neuromuscular variables (excluding Steadiness10%). CONCLUSIONS: Lower extremity neuromuscular function, specifically PP and steadiness, and %BF are important modifiable predictors of firefighter SC performance, which becomes increasingly important in aging firefighters.

Quantitative muscle MRI biomarkers in Duchenne muscular dystrophy: cross-sectional correlations with age and functional tests.

Aim: Using baseline data from a clinical trial of domagrozumab in Duchenne muscular dystrophy, we evaluated the correlation between functional measures and quantitative MRI assessments of thigh muscle. Patients & methods: Analysis included timed functional tests, knee extension/strength and North Star Ambulatory Assessment. Patients (n = 120) underwent examinations of one thigh, with MRI sequences to enable measurements of muscle volume (MV), MV index, mean T2 relaxation time via T2-mapping and fat fraction. Results: MV was moderately correlated with strength assessments. MV index, fat fraction and T2-mapping measures had moderate correlations (r ∼ 0.5) to all functional tests, North Star Ambulatory Assessment and age. Conclusion: The moderate correlation between functional tests, age and baseline MRI measures supports MRI as a biomarker in Duchenne muscular dystrophy clinical trials. Trial registration: ClinicalTrials.gov, NCT02310763; registered 4 November 2014.

Lay abstract Clinical trials in Duchenne muscular dystrophy have proven to be challenging, due in part to the lack of robust biomarkers that are sensitive to detecting disease progression. While physical function, such as walking or climbing stairs, will be critical to demonstrating the long-term efficacy of a therapeutic, MRI may be a more objective approach that could detect subtle changes in disease status and offer earlier signals of clinical efficacy. In this study, researchers used baseline data from a Phase II clinical study (NCT02310763) to evaluate the relationship between measures of physical function and quantitative MRI assessments. They found that many MRI measures were moderately correlated with physical function, and muscle volume measurements were correlated with measures of strength. This study supports the use of MRI as a biomarker in Duchenne muscular dystrophy clinical trials.

Evaluation of physical function and its association with body composition, quality of life and biomarkers in cancer cachexia patients.

BACKGROUND & AIMS: There are currently no approved treatments for cancer cachexia. One of the main barriers to developing a treatment for this indication is the lack of consensus on clinically important tools for assessing functional impairment in this setting. This issue is of critical importance because functional improvement is likely to be required for approval by regulatory agencies. This cross-sectional study aimed to evaluate various functional performance measures and establish their association with body composition, energy expenditure, biomarkers, and patient-reported quality of life (QOL). METHODS: Physical function, body composition, energy expenditure, cytokines, testosterone, and patient-reported QOL were compared between men with solid tumors with cachexia (CAC; N = 48), without cachexia (CNC; N = 48), and weight-stable patients without cancer (CON; N = 37). Receiver Operator Characteristic curves and multivariate regression were performed to identify functional impairment cut-points and predictors of physical function, respectively. RESULTS: Patients with CAC displayed lower total lean and appendicular lean mass, stair climb power (SCP), upper body strength, and bioavailable testosterone, and displayed higher energy expenditure than CNC or CON (p ≤ 0.03); CAC showed lower handgrip, respiratory quotient, and appetite, and higher cytokines and fatigue than CON (p ≤ 0.032). A cut-point of 336 Watts for SCP provided 78% sensitivity and 77% specificity for classification of CAC (p = 0.001); SCP also performed better than other measures tested when compared to CON-derived normatives. Upper body strength exhibited moderate sensitivity and specificity for classification of CAC (p ≤ 0.02). Elevated relative energy expenditure and cytokines negatively predicted, and muscle mass positively predicted, various muscle strength outcomes. CONCLUSION: Stair climb power and upper body strength may have potential as discriminatory tests for functional impairment in patients with cancer cachexia.

Randomized phase 2 trial and open-label extension of domagrozumab in Duchenne muscular dystrophy.

We report results from a phase 2, randomized, double-blind, 2-period trial (48 weeks each) of domagrozumab and its open-label extension in patients with Duchenne muscular dystrophy (DMD). Of 120 ambulatory boys (aged 6 to <16 years) with DMD, 80 were treated with multiple ascending doses (5, 20, and 40 mg/kg) of domagrozumab and 40 treated with placebo. The primary endpoints were safety and mean change in 4-stair climb (4SC) time at week 49. Secondary endpoints included other functional tests, pharmacokinetics, and pharmacodynamics. Mean (SD) age was 8.4 (1.7) and 9.3 (2.3) years in domagrozumab- and placebo-treated patients, respectively. Difference in mean (95% CI) change from baseline in 4SC at week 49 for domagrozumab vs placebo was 0.27 (-7.4 to 7.9) seconds (p = 0.94). There were no significant between-group differences in any secondary clinical endpoints. Most patients had ≥1 adverse event in the first 48 weeks; most were mild and not treatment-related. Median serum concentrations of domagrozumab increased with administered dose within each dose level. Non-significant increases in muscle volume were observed in domagrozumab- vs placebo-treated patients. Domagrozumab was generally safe and well tolerated in patients with DMD. Efficacy measures did not support a significant treatment effect. Clinicaltrials.gov identifiers: NCT02310763 and NCT02907619.

Stair climbing ability in patients with early knee osteoarthritis: Defining the clinical hallmarks of early disease.

BACKGROUND: A growing clinical interest has been shown towards identifying knee osteoarthritis (OA) patients at earlier stages. The early detection of knee OA may allow for more effective interventions. RESEARCH QUESTION: The aim of this study was to determine the discriminative ability of a stair-climb test (SCT) in identifying patients with early knee OA, and to determine if descending stair time during the SCT is better than ascending stair time for the identification of these patients. METHODS: This study was a secondary, cross-sectional analysis of baseline data from a randomized controlled trial. Adults with moderate to severe knee pain were enrolled (n = 57; mean age 58.9 years; 71.9% women). Each participant performed an 11-step SCT (11-SCT) while wearing shoes with a pressure sensor insole. A receiver operating characteristic analysis was used to examine the discriminative power of 11-SCT for identifying early knee OA (Kellgren and Lawrence grade 1). The discriminative power was also compared between the ascending and descending 11-SCT time as evaluated by the pressure sensor. RESULTS: The 11-SCT time in patients with early knee OA was 0.55 s longer than that in those with symptomatic non-radiographic OA. A one-second increase in the 11-SCT time was significantly associated with 1.9-fold increased odds of early knee OA being present. The 11-SCT value with the best balance of sensitivity and specificity for identifying early knee OA was 8.33 s (area under the curve: 0.711). The descending time was not significantly better than the ascending time for identifying early knee OA. SIGNIFICANCE: This study determined the time values of an 11-SCT that may be useful for identifying early knee OA patients. These preliminary findings may serve as the foundation for future studies investigating the clinical hallmarks associated with early knee OA.

Concurrent validity and measurement error of stair climb test in people with pre-radiographic to mild knee osteoarthritis.

BACKGROUND: Stair climbing is the task first affected in patients with knee osteoarthritis (OA); therefore, the precise measurement of time required to climb stairs is important to identify mobility limitations, particularly in the early phase of knee OA. RESEARCH QUESTION: This study aimed to examine the test-retest reliability, measurement error, and concurrent validity of the stopwatch-based stair-climb test (SCT) in adults with pre-radiographic to mild knee OA. METHODS: Fifty-nine participants (mean age, 59.1 [range, 50-69] years; 72.9% female) with Kellgren and Lawrence grade ≤2 disease underwent an 11-step SCT (11-SCT) in accordance with the Osteoarthritis Research Society International recommended method while wearing pressure sensor-mounted standard shoes that is used as a gold standard procedure. Test-retest reliability, measurement errors, and the concurrent validity of the stopwatch-based 11-SCT were evaluated. RESULTS: The test-retest reliability of the stopwatch-based 11-SCT was excellent (intra-class correlation coefficient1,1 [ICC1,1], 0.952; 95% confidence interval [CI], 0.560 to 0.985; p < 0.001) and the minimal detectable change95 was 0.102 s. Concurrent validity was excellent (ICC2,1: 0.957; 95% CI: 0.661 to 0.986; p < 0.001). SIGNIFICANCE: The stopwatch-based 11-SCT had high test-retest reliability and high concurrent validity, which justify its clinical use for identifying mobility limitations in individuals with pre-radiographic to mild knee OA. A difference of 0.2 s in the stopwatch-based 11-SCT time would be considered a true difference beyond a 95% measurement error.

Predictors of Physical and Functional Loss in Advanced-Stage Lung Cancer Patients Receiving Platinum Chemotherapy.

INTRODUCTION: Muscle wasting has detrimental effects, including increased mortality. Identifying patients at risk can guide treatment efforts. METHODS: POWER 1 and 2 were randomized, double-blind, placebo-controlled, multinational phase III trials that studied 600 patients with lung cancer at the start of chemotherapy; the studies' aim was to assess the efficacy of enobosarm on prevention and treatment of muscle loss. We performed a secondary analysis restricted to the control group, using a cumulative logit model for ordinal outcome to determine which baseline characteristics predicted physical and functional loss during chemotherapy. RESULTS: In all, 53% of patients had loss of lean body mass and 49% had loss of stair climb power (SCP) at day 84 of treatment. Of the 322 patients who received placebo, 232 with observable outcome and baseline covariates were included for lean body mass analysis and 236 for SCP analysis. More advanced disease predicted a higher probability of greater physical loss (OR = 1.96; 95% confidence interval [CI]: 1.14-3.36). Three factors predicted higher probability of SCP loss: taxane chemotherapy (OR = 1.73; 95% CI: 1.06-2.83), tobacco use before chemotherapy (OR = 2.15, 95% CI: 1.10-4.18), and SCP at baseline (OR = 1.01, 95% CI: 1.004-1.015). Higher body mass index was a protective factor for functional loss (OR = 0.85; 95% CI: 0.73-0.98). A higher Eastern Cooperative Oncology Group Performance Status trended toward being predictive of greater probability of both physical loss (0.767) and functional loss (0.070), but the results were not statistically significant. CONCLUSIONS: Approximately 50% of patients with advanced lung cancer who were undergoing chemotherapy had ongoing loss of muscle mass and muscle function. Advanced stage predicted physical loss. Tobacco use and taxane chemotherapy predicted functional loss. Body mass index was a protective factor for functional loss. We identified predictors of physical and functional loss that could be used as therapeutic targets or to guide treatment efforts.

Quadriceps Rate of Torque Development and Disability in Persons With Tibiofemoral Osteoarthritis.

Background Declines in the ability to rapidly generate quadriceps muscle torque may underlie disability in individuals with tibiofemoral osteoarthritis. Objective To determine whether quadriceps rate of torque development (RTD) predicts self-reported disability and physical performance outcomes in individuals with tibiofemoral osteoarthritis. Methods This controlled laboratory, cross-sectional study assessed quadriceps strength and RTD in 76 individuals (55% female; mean ± SD age, 61.83 ± 7.11 years) with symptomatic and radiographic tibiofemoral osteoarthritis. Early (0-50 milliseconds), late (100-200 milliseconds), and overall peak RTDs were quantified in the symptomatic (involved) and contralateral limbs and used to calculate bilateral average values. Disability was assessed using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) function subscale and 3 physical performance tests, including the (1) 20-m fast-paced walk, (2) 30-second chair stand, and (3) timed stair climb. Separate univariate regression models were used to determine the unique associations among measures of quadriceps RTD, WOMAC function score, and physical performance outcomes after accounting for quadriceps strength (change in R2). Results Greater involved-side late RTD and greater bilateral average early RTD were associated with faster walking (change in R2 = 0.05, P = .013 and change in R2 = 0.05, P = .043, respectively). Greater bilateral average late RTD was associated with faster walking (change in R2 = 0.20, P<.001) and faster stair climb (change in R2 = 0.11, P = .001). No quadriceps RTD variable was significantly associated with WOMAC function score (change in R2 range, <0.01-0.017). Conclusion Involved-limb quadriceps RTD was weakly associated with physical performance outcomes, but not self-reported disability, in individuals with tibiofemoral osteoarthritis. Bilateral average quadriceps RTD was moderately associated with walking speed. Level of Evidence Prognosis, level 2b. J Orthop Sports Phys Ther 2018;48(9):694-703. Epub 22 May 2018. doi:10.2519/jospt.2018.7898.

Gait Speed and Mobility Disability: Revisiting Meaningful Levels in Diverse Clinical Populations.

OBJECTIVES: To investigate the heterogeneity of clinically meaningful levels of gait speed relative to self-reported mobility disability (SR-MD). DESIGN: Five longitudinal studies with older adults in different health states (onset of acute event, presence of chronic condition, sedentary, community living) were used to explore the relationship between gait speed and SR-MD. SETTING: Lifestyle Interventions and Independence for Elders Pilot (LIFE-P), LIFE, Trial of Angiotensin-Converting Enzyme Inhibition and Novel Cardiovascular Risk Factors (TRAIN), Baltimore Hip Fracture Study (BHS2), Invecchiare in Chianti (InCHIANTI). PARTICIPANTS: Individuals aged 65 and older (N=3,540): sedentary, community dwelling (LIFE-P/LIFE), with hip fracture (BHS2), random population-based sample (InCHIANTI), high cardiovascular risk (TRAIN). MEASUREMENTS: Usual-pace gait speed across 3 to 4 m and SR-MD, defined as inability to walk approximately 1 block or climb 1 flight of stairs. RESULTS: The mean gait speed of participants without SR-MD was greater than 1.0 m/s in InCHIANTI and TRAIN, 0.79 m/s in LIFE-P/LIFE, and 0.46 m/sec in BHS2. Of individuals with SR-MD, mean gait speed was 0.08 m/s slower in LIFE-P/LIFE, 0.19 m/s slower in TRAIN, 0.22 m/s slower in BHS2, and 0.36 m/s slower in InCHIANTI. The optimal gait speed cutpoint for minimizing SR-MD misclassification rates ranged from 0.3 m/s in BHS2 to 1.0 m/s in TRAIN. In longitudinal analyses, development of SR-MD was dependent on initial gait speed and change in gait speed (p<.001). CONCLUSION: The relationship between absolute levels of gait speed and SR-MD may be context specific, and there may be variations between populations. Across diverse clinical populations, clinical interpretations of how change in usual pace gait speed relates to development of SR-MD depend on where on the gait speed continuum change occurs.

Elosulfase alfa enzyme replacement therapy attenuates disease progression in a non-ambulatory Japanese patient with Morquio A syndrome (case report).

Enzyme replacement therapy (ERT) with elosulfase alfa is the only approved therapy in Japan for patients with Morquio A syndrome, a lysosomal storage disorder inherited in an autosomal recessive fashion. The experience with ERT in severely affected, non-ambulatory patients has not been reported in previous studies. This case report describes clinical evidence for the 1-year efficacy and safety of ERT with elosulfase alfa in a severely affected, non-ambulatory, 47-year-old patient with Morquio A syndrome who needs intensive respiratory management. ERT with elosulfase alfa was well tolerated in this patient. Because of the possibility of potential hypersensitivity adverse events, special attention is needed when using ERT in patients with respiratory disorders. However, under the appropriate management of specialists, the patient in this case report showed significant respiratory improvement after starting ERT, and abdominal bloating was improved by gas evacuation. In addition, the patient was able to lift up her arms, reach behind her back, and move her legs slightly, and she recovered her grip strength. Her hearing loss improved and she could hear without a hearing aid. This report shows that ERT with elosulfase alfa can be used with appropriate respiratory care in patients with severe respiratory dysfunction.

Moderate-Load Muscular Endurance Strength Training Did Not Improve Peak Power or Functional Capacity in Older Men and Women.

The present study determined the effects of muscular endurance strength training on maximum strength and power, functional capacity, muscle activation and hypertrophy in older men and women. Eighty-one men and women acted as an intervention group while 22 acted as non-training controls (age range 64-75 y). Intervention training included super-sets (i.e., paired exercises, immediately performing the second exercises following completion of the first) with short rest intervals (30-60 s between sets) at an intensity of 50-60% one-repetition maximum (1-RM) for 15-20 repetitions. Concentric leg press actions measured maximum strength (1-RM) and concentric peak power. Functional capacity was assessed by maximum speed walking tests (i.e., forward walk, backward walk, timed-up-and-go, and stair climb tests). Quadriceps muscle activation was assessed by surface electromyogram and twitch interpolation technique. Vastus lateralis cross-sectional area was measured by panoramic ultrasound. Compared to control, the intervention groups increased maximum strength (1-RM; men: 10 ± 7% vs. 2 ± 3%, women: 14 ± 9% vs. 1 ± 6% both P < 0.01) and vastus lateralis cross-sectional area (men: 6 ± 7% vs. -3 ± 6%, women: 10 ± 10% vs. 0 ± 4% both P < 0.05). But there were no between-group differences in peak power, muscle activation or functional capacity (e.g., stair climb; men: -5 ± 7% vs. -4 ± 3%, women: -5 ± 6% vs. -2 ± 5% both P > 0.05). While benefits occurred during muscular endurance strength training, specific stimuli are probably needed to target all aspects of age-related health.

Effects of different strength training frequencies on maximum strength, body composition and functional capacity in healthy older individuals.

There is controversy in the literature regarding the dose-response relationship of strength training in healthy older participants. The present study determined training frequency effects on maximum strength, muscle mass and functional capacity over 6months following an initial 3-month preparatory strength training period. One-hundred and six 64-75year old volunteers were randomly assigned to one of four groups; performing strength training one (EX1), two (EX2), or three (EX3) times per week and a non-training control (CON) group. Whole-body strength training was performed using 2-5 sets and 4-12 repetitions per exercise and 7-9 exercises per session. Before and after the intervention, maximum dynamic leg press (1-RM) and isometric knee extensor and plantarflexor strength, body composition and quadriceps cross-sectional area, as well as functional capacity (maximum 7.5m forward and backward walking speed, timed-up-and-go test, loaded 10-stair climb test) were measured. All experimental groups increased leg press 1-RM more than CON (EX1: 3±8%, EX2: 6±6%, EX3: 10±8%, CON: -3±6%, P<0.05) and EX3 improved more than EX1 (P=0.007) at month 9. Compared to CON, EX3 improved in backward walk (P=0.047) and EX1 in timed-up-and-go (P=0.029) tests. No significant changes occurred in body composition. The present study found no evidence that higher training frequency would induce greater benefit to maximum walking speed (i.e. functional capacity) despite a clear dose-response in dynamic 1-RM strength, at least when predominantly using machine weight-training. It appears that beneficial functional capacity improvements can be achieved through low frequency training (i.e. 1-2 times per week) in previously untrained healthy older participants.

Albuterol as an adjunctive treatment to enzyme replacement therapy in infantile-onset Pompe disease.

BACKGROUND: Early initiation of enzyme replacement therapy (ERT) with recombinant human acid alpha-glucosidase is an effective treatment for patients with infantile-onset Pompe disease (IOPD) but cannot prevent a slow progression of myopathy. Albuterol has been shown to be helpful in adult patients with Pompe disease, and therefore, we administered an open-label adjunctive therapy with albuterol in IOPD patients undergoing ERT. METHODS: Fourteen patients, aged 2 to 12 years, were enrolled in this study; all of them had a disease onset before 12 months of life, and 13 of them were ambulatory because of early initiation of ERT. All patients received albuterol (also referred to as salbutamol) 12 mg daily for 26 weeks. The outcome measurements included a 6-minute walk test, four-stair climb test (SCT), the standing/walking/running/jumping domains of Gross Motor Function Measure-88, speech quality, serum creatine kinase, and urinary glucose tetrasaccharide. Outcome and safety measurements were evaluated at baseline, and at 1, 3, and 6 months (26 weeks) after entering the trial. RESULTS: After a period of 26 weeks, among the 12 patients who were able to complete the SCT, the median time needed decreased by 22% (p = 0.034). Other parameters inconsistently improved in a variety of individuals. Eleven adverse events, including nausea, urinary frequency, and tachycardia, were potentially related to the study drug, but all were mild and disappeared after a brief drug withdrawal. One patient was actively withdrawn from the trial because of poor compliance. CONCLUSIONS: The results of our study suggest that albuterol showed a good safety profile as an adjunctive treatment in our IOPD cohort, although the benefits are limited.

Long-term galsulfase enzyme replacement therapy in Taiwanese mucopolysaccharidosis VI patients: A case series.

BACKGROUND: Information regarding the long-term outcome of enzyme replacement therapy (ERT) with recombinant human N-acetylgalactosamine 4-sulfatase (rhASB, galsulfase, Naglazyme®, BioMarin Pharmaceutical Inc.) for Taiwanese patients with mucopolysaccharidosis (MPS) VI is limited. METHODS: Nine Taiwanese patients with MPS VI (4 males and 5 females; age range, 1.4 to 21.1 years) treated with weekly intravenous infusions of galsulfase (1.0 mg/kg) in 5 medical centers in Taiwan were reviewed. A set of biochemical and clinical assessments were evaluated annually. RESULTS: After 6.2 to 11.2 years of galsulfase treatment, 6 patients experienced improvement over baseline in the 6-minute walk test by a mean of 150 m (59% change over time), and 3 patients also increased the 3-minute stair climb test by a mean of 60 steps (46%). In a manual dexterity test, 3 patients decreased the time required to pick up 10 coins and put the coins into a cup by 15 s (33%). Shoulder range of motion in all 9 patients improved, and Joint Pain and Stiffness Questionnaire scores improved by 0.42 points (21%). Four patients showed improved pulmonary function. Five patients had positive effects on cardiac-wall diameters. Four patients had improved cardiac diastolic function. Liver and spleen sizes as measured by abdominal ultrasonography remained the same or decreased in all 9 patients. However, the severity degree of valvular stenosis or regurgitation did not show improvement despite ERT. A mean overall 69% decrease in urinary glycosaminoglycan (GAG) excretion indicated a satisfactory biomarker response. CONCLUSIONS: Long-term ERT was beneficial and safe for Taiwanese patients with MPS VI. This treatment reduced urinary GAG and had positive effects on a wide range of clinical functional assessments including endurance, mobility, joint function, pulmonary function, liver and spleen size, cardiac hypertrophy and diastolic dysfunction.