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Objective: To systematically evaluate post-exercise outcomes related to function and quality of life in people with ALS. Methods: PRISMA guidelines were used for identifying and extracting articles. Levels of evidence and quality of articles were judged based on The Oxford Centre for Evidence-based Medicine Levels of Evidence and the QualSyst. Outcomes were analyzed with Comprehensive Meta-Analysis V2 software, random effects models, and Hedge's G. Effects were examined at 0-4 months, up to 6 months, and > 6 months. Pre-specified sensitivity analyses were performed for 1) controlled trials vs. all studies and 2) ALSFRS-R bulbar, respiratory, and motor subscales. Heterogeneity of pooled outcomes was computed with the I2 statistic. Results: 16 studies and seven functional outcomes met inclusion for the meta-analysis. Of the outcomes explored, the ALSFRS-R demonstrated a favorable summary effect size and had acceptable heterogeneity and dispersion. While FIM scores demonstrated a favorable summary effect size, heterogeneity limited interpretations. Other outcomes did not demonstrate a favorable summary effect size and/or could not be reported due to few studies reporting outcomes. Conclusions: This study provides inconclusive guidance regarding exercise regimens to maintain function and quality of life in people with ALS due to study limitations (e.g., small sample size, high attrition rate, heterogeneity in methods and participants, etc.). Future research is warranted to determine optimal treatment regimens and dosage parameters in this patient population.

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Background: Despite well-established efficacy for patients with a cardiovascular diagnosis or event, exercise-based cardiac rehabilitation program participation and completion has remained alarmingly low due to both system-level barriers and patient-level factors. Patient mental health, particularly depression, is now recognized as significantly associated with reduced enrollment, participation, attendance, and completion of a cardiac rehabilitation program. More recently, anxiety sensitivity has emerged as an independent construct, related to but distinct from both depression and anxiety. Anxiety sensitivity has been reported to be adversely associated with participation in exercise and, thus, may be important for patients in cardiac rehabilitation. Accordingly, the objective of this study was to conduct a scoping review to summarize the evidence for associations between anxiety sensitivity and cardiovascular disease risk factors, exercise, and clinical outcomes in cardiac rehabilitation. Methods: A formal scoping review, following PRISMA-ScR guidelines, was undertaken. Searches of MEDLINE, Web of Science, CINAHL, PSYCINFO, and Scopus databases were conducted, supplemented by hand searches; studies published through December of 2020 were included. The initial screening was based on titles and abstracts and the second stage of screening was based on full text examination. Results: The final search results included 28 studies. Studies reported statistically significant associations between anxiety sensitivity and exercise, cardiovascular disease, and participation in cardiac rehabilitation. Many studies, however, were conducted in non-clinical, community-based populations; there were few studies conducted in cardiovascular disease and cardiac rehabilitation clinical patient populations. Additionally, significant gaps remain in our understanding of the sex-based differences in the complex relationships between anxiety sensitivity, exercise and cardiac rehabilitation. Conclusion: More research is needed to understand specific associations between anxiety sensitivity and clinical outcomes among clinical cardiovascular disease patients and participants in cardiac rehabilitation programs. Treatment of anxiety sensitivity to optimize clinical outcomes in cardiac rehabilitation programs should be investigated in future studies.

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Objective: To conduct a systematic review examining the effect of exercise and rehabilitation in people with Ehlers-Danlos syndrome (EDS). Data Sources: The following databases were systematically searched: MEDLINE, MEDLINE In-Process/ePubs, Embase, Cochrane Central Register of Controlled Trials, PsycINFO, and Cumulative Index to Nursing and Allied Health. The final time point captured by the search is November 27, 2020. Study Selection: Eligible study designs included case-control, case-series, prospective cohort, retrospective cohort, and intervention studies of structured exercise or rehabilitation interventions. Eligible populations included adults (18 years or older) with EDS (all subtypes) and hypermobility spectrum disorders. The search was restricted to articles published in English. Data Extraction: Data were extracted by 2 independent reviewers. Risk of bias was assessed using the Physiotherapy Evidence Database (PEDro) scale for randomized controlled trials (RCTs) and Risk Of Bias In Nonrandomized Studies of Interventions (ROBINS-I) for non-RCTs. Reporting quality of RCTs was assessed using the Consolidated Standards for Reporting of Trials statement with the harms extension. Reporting was guided by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist. Data Synthesis: The search yielded 10 eligible studies including 330 participants. The study designs included 5 RCTs, 1 cohort, 2 single-arm interventions, 1 retrospective, and 1 feasibility study. All studies showed some improvement in a physical and/or psychological outcome after the intervention period. One adverse event (nonserious) potentially related to the intervention was reported. Of the 5 RCTs, 2 were rated as high quality with low risk of bias using PEDro, and the majority of non-RCTs were rated as critical risk of bias by ROBINS-I. Conclusions: The results suggest that exercise and rehabilitation may be beneficial for various physical and psychological outcomes. Adequately powered and rigorous RCTs of exercise and rehabilitation interventions for people with EDS are needed.

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Background: Endothelial dysfunction is associated with increased risk of cardiovascular disease (CVD). Currently available noninvasive methods of measuring endothelial function have limitations. We tested a novel device that provides an automated measurement of the difference between baseline and post-ischemic, hyperemia-induced, brachial arterial compliance, a phenomenon known to be endothelium-dependent. The association between the calculated index, Flow-mediated Compliance Response (FCR), and established CVD risk indices was determined. Methods: Adults with CVD risk factors or known coronary artery disease (CAD) were enrolled. Framingham Risk Score (FRS) was calculated and presence of metabolic syndrome (MetSyn) was assessed. Carotid artery plaques were identified by ultrasound. Cardiorespiratory fitness was assessed by 6-minute walk test (6MWT). FCR was measured using the device. Results: Among 135 participants, mean age 49.3 +/- 17.9 years, characteristics included: 48% female, 7% smokers, 7% CAD, 10% type 2 diabetes, 34% MetSyn, and 38% with carotid plaque. Those with MetSyn had 24% lower FCR than those without (p < 0.001). Lower FCR was associated with higher FRS percentile (r = -0.29, p < 0.001), more MetSyn factors (r = -0.30, p < 0.001), more carotid plaques (r = -0.22, p = 0.01), and lower 6MWT (r = 0.34, p < 0.0001). Conclusion: FCR, an index of arterial reactivity obtained automatically using a novel, operator-independent device, was inversely associated with established CVD risk indices, increased number of carotid plaques, and lower cardiorespiratory fitness. Whether measuring FCR could play a role in screening for CVD risk and assessing whether endothelial function changes in response to treatments aimed at CVD risk reduction, warrants further study.

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INTRODUCTION: Impairment in pulmonary function tests and radiological abnormalities are a major concern in COVID-19 survivors. Our aim is to evaluate functional respiratory parameters, changes in chest CT, and correlation with peripheral blood biomarkers involved in lung fibrosis at two and six months after SARS-CoV-2 pneumonia. METHODS: COVID-FIBROTIC (clinicaltrials.gov NCT04409275) is a multicenter prospective observational cohort study aimed to evaluate discharged patients. Pulmonary function tests, circulating serum biomarkers, chest radiography and chest CT were performed at outpatient visits. RESULTS: In total, 313, aged 61.12 ± 12.26 years, out of 481 included patients were available. The proportion of patients with DLCO < 80% was 54.6% and 47% at 60 and 180 days. Associated factors with diffusion impairment at 6 months were female sex (OR: 2.97, 95%CI 1.74-5.06, p = 0.001), age (OR: 1.03, 95% CI: 1.01-1.05, p = 0.005), and peak RALE score (OR: 1.22, 95% CI 1.06-1.40, p = 0.005). Patients with altered lung diffusion showed higher levels of MMP-7 (11.54 ± 8.96 vs 6.71 ± 4.25, p = 0.001), and periostin (1.11 ± 0.07 vs 0.84 ± 0.40, p = 0.001). 226 patients underwent CT scan, of whom 149 (66%) had radiological sequelae of COVID-19. In severe patients, 68.35% had ground glass opacities and 38.46% had parenchymal bands. Early fibrotic changes were associated with higher levels of MMP7 (13.20 ± 9.20 vs 7.92 ± 6.32, p = 0.001), MMP1 (10.40 ± 8.21 vs 6.97 ± 8.89, p = 0.023), and periostin (1.36 ± 0.93 vs 0.87 ± 0.39, p = 0.001). CONCLUSION: Almost half of patients with moderate or severe COVID-19 pneumonia had impaired pulmonary diffusion six months after discharge. Severe patients showed fibrotic lesions in CT scan and elevated serum biomarkers involved in pulmonary fibrosis.

INTRODUCCIÓN: El deterioro de la función pulmonar en las pruebas correspondientes y las alteraciones radiológicas son las preocupaciones principales en los supervivientes de la COVID-19. Nuestro objetivo fue evaluar los parámetros de la función respiratoria, los cambios en la TC de tórax y la correlación con los biomarcadores en sangre periférica involucrados en la fibrosis pulmonar a los 2 y a los 6 meses tras la neumonía por SARS-CoV-2. MÉTODOS: El ensayo COVID-FIBROTIC (clinicaltrials.gov NCT04409275) es un estudio de cohortes multicéntrico, prospectivo y observacional cuyo objetivo fue evaluar los pacientes dados de alta. Se realizaron pruebas de función pulmonar, detección de biomarcadores en plasma circulante y radiografía y TC de tórax durante las visitas ambulatorias. RESULTADOS: En total 313 pacientes, de 61,12 ± 12,26 años, de los 481 incluidos estuvieron disponibles.La proporción de pacientes con DLCO < 80% fue del 54,6 y del 47% a los 60 y 180 días.Los factores que se asociaron a la alteración de la difusión a los 6 meses fueron el sexo femenino (OR: 2,97; IC del 95%: 1,74-5,06; p = 0,001), la edad (OR: 1,03; IC del 95%: 1,01-1,05; p = 0,005) y la puntuación RALE más alta (OR: 1,22; IC del 95%: 1,06-1,40; p = 0,005). Los pacientes con alteración de la difusión pulmonar mostraron niveles más altos de MMP-7 (11,54 ± 8,96 frente a 6,71 ± 4,25; p = 0,001) y periostina (1,11 ± 0.07 frente a 0,84 ± 0,40; p = 0,001). Se le realizó una TC a 226 pacientes de los cuales 149 (66%) presentaban secuelas radiológicas de la COVID-19. En los pacientes graves, el 68,35% mostraban opacidades en vidrio esmerilado y el 38,46%, bandas parenquimatosas. Los cambios fibróticos tempranos se asociaron a niveles más altos de MMP7 (13,20 ± 9,20 frente a 7,92 ± 6,32; p = 0,001), MMP1 (10,40 ± 8,21 frente a 6,97 ± 8,89; p = 0,023), y periostina (1,36 ± 0,93 frente a 0,87 ± 0,39; p = 0,001). CONCLUSIÓN: Casi la mitad de los pacientes con neumonía moderada o grave por COVID-19 presentaba alteración de la difusión pulmonar 6 meses después del alta. Los pacientes graves mostraban lesiones fibróticas en laTC y un aumento de los biomarcadores séricos relacionados con la fibrosis pulmonar.

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Transthyretin cardiac amyloidosis (ATTR-CA) is increasingly diagnosed owing to the emergence of noninvasive imaging and improved awareness. Clinical penetrance of pathogenic alleles is not complete and therefore there is a large cohort of asymptomatic transthyretin variant carriers. Screening strategies, monitoring, and treatment of subclinical ATTR-CA requires further study. Perhaps the most important translational triumph has been the development of effective therapies that have emerged from a biological understanding of ATTR-CA pathophysiology. These include recently proven strategies of transthyretin protein stabilization and silencing of transthyretin production. Data on neurohormonal blockade in ATTR-CA are limited, with the primary focus of medical therapy on judicious fluid management. Atrial fibrillation is common and requires anticoagulation owing to the propensity for thrombus formation. Although conduction disease and ventricular arrhythmias frequently occur, little is known regarding optimal management. Finally, aortic stenosis and ATTR-CA frequently coexist, and transcatheter valve replacement is the preferred treatment approach.

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Little is known about the effect of wearing a facemask on the physiological and perceptual responses to exercise in patients with pulmonary arterial hypertension (PAH). We performed a single-center retrospective study to evaluate whether facemask wearing impacted distanced covered, rating of perceived exertion (RPE), and arterial oxygen saturation (SpO2) during a 6-minute walk test (6MWT) in PAH patients. Forty-five patients being treated for group 1 PAH and who performed a 6MWT before and after implementation of a facemask mandate were included in the analysis. Each included patient performed a 6MWT without (test 1) and with (test 2) a facemask between October 1, 2019, and October 31, 2020. At both time points, all patients also underwent a submaximal cardiopulmonary exercise test, echocardiogram, and blood laboratory tests, with a Registry to Evaluate Early and Long-Term PAH Disease Management Lite 2.0 score calculated. The two 6MWTs were performed 81±51 days apart, and all patients were clinically stable at both testing timepoints. Six-minute walk test distance was not different between test 1 and test 2 (405±108 m vs 400±103 m, P=.81). Similarly, both end-test RPE and lowest SpO2 during the 6MWT were not different in test 1 and test 2 (RPE: 2.5±1.7 vs 2.5±2.1, P=.91; SpO2 nadir: 92.8±3.4% vs 93.3±3.3%, P=.55). Our findings show that wearing a facemask has no discernable impact on the arterial oxygen saturation and perceptual responses to exercise or exercise capacity in patients with moderate-to-severe PAH. This study reinforces the evidence that wearing a facemask is safe in PAH patients, even during exercise.

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OBJECTIVE: To compare agreement and reliability between clinician-measured and patient self-measured clinical and functional assessments for use in remote monitoring, in a home-based setting, using telehealth. DESIGN: Reliability study: repeated-measure, within-subject design. SETTING: Trained clinicians measured standard clinical and functional parameters at a face-to-face clinic appointment. Participants were instructed on how to perform the measures at home and to repeat self-assessments within 1 week. PARTICIPANTS: Liver transplant recipients (LTRs) (N=18) (52±14y, 56% men, 5.4±4.3y posttransplant] completed the home self-assessments. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: The outcomes assessed were body weight, systolic and diastolic blood pressure (SBP and DBP), waist circumference, repeated chair sit-to-stand (STST), maximal push-ups, and the 6-minute walk test (6MWT). Intertester reliability and agreement between face-to-face clinician and self-reported home-based participant measures were determined by intraclass-correlation coefficients (ICCs) and Bland-Altman plots, which were compared with minimal clinically important differences (MCID) (determined a priori). RESULTS: The mean difference (95% confidence interval) and [limits of agreement] for measures (where positive values indicate lower participant value) were weight, 0.7 (0.01-1.4) kg [-2.2 to 3.6kg]; waist 0.4 (-1.2 to 2.0) cm [-5.9 to 6.8cm]; SBP 7.7 (0.6-14.7 ) mmHg [-19.4 to 34.9mmHg]; DBP 2.4 (-1.4 to 6.2 ) mmHg [-12.2 to 17.0mmHg]; 6MWT, 7.5 (-29.1 to 44.1) m [-127.3 to 142.4m]; STST 0.5 (-0.8 to 1.7) seconds [-4.3 to 5.3s]; maximal push-ups -2.2 (-4.4 to -0.1) [-10.5 to 6.0]. ICCs were all >0.75 except for STST (ICC=0.73). Mean differences indicated good agreement than MCIDs; however, wide limits of agreement indicated large individual variability in agreement. CONCLUSIONS: Overall, LTRs can reliably self-assess clinical and functional measures at home. However, there was wide individual variability in accuracy and agreement, with no functional assessment being performed within acceptable limits relative to MCIDs >80% of the time.

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OBJECTIVE: To investigate the effect of age and Gross Motor Function Classification System (GMFCS) level on walking endurance after 20 weeks of vibration therapy in children and young people with cerebral palsy (CP). DESIGN: The study was a clinical trial without control group comparing baseline and postintervention outcomes within participants. SETTING: Vibration therapy was performed at school or at home. Assessments took place in a clinical research unit. PARTICIPANTS: Children and young people (N=59) with CP, aged 5-20 years, GMFCS level II, III, or IV, recruited through schools, physiotherapy services, and District Health Board clinics, Auckland, New Zealand. INTERVENTIONS: Participants performed side-alternating whole-body vibration therapy (WBVT) at 20 Hz and 3-mm amplitude, 9 minutes per day, 4 times per week for 20 weeks. MAIN OUTCOME MEASURES: Distance walked in the 6-minute walk test (6MWT) was recorded before and after the intervention. RESULTS: Participants baseline results for the 6MWT were lower, independent of age or GMFCS, when compared to non-CP literature. On average, participants walked 12% further in the 6MWT after the intervention (P<.001). There was significant improvement in 6MWT distance in all age groups (5-10y: 16%, P<.001; 11-15y: 10%, P=.001; 16-20y: 13%, P<.001) and all GMFCS levels (level II: 10%, P<.001, level III: 40%, P=.013, level IV: 57%, P=.007). There was a greater percentage improvement in the distance walked in those with GMFCS level III and level IV than level II (P=.049 and P<.001, respectively). CONCLUSIONS: WBVT had a beneficial effect on walking endurance in children and young people with CP, independent of age and GMFCS.

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OBJECTIVE: To determine classes of motor performance based on community deployable motor impairment and functional tests in a heterogeneous adult population. DESIGN: Sixteen tests of limb-specific and whole-body measures of motor impairment and function were obtained. Linear regression analysis was used to dichotomize performance on each test as falling within or outside the age- and sex-predicted values. Latent class analysis was used to determine 3 classes of motor performance. The chi-square test of association and the Fisher exact test were used for categorical variables, and analysis of variance and the Kruskal-Wallis test were used for continuous variables to evaluate the relationship between demographic characteristics and latent classes. SETTING: General community. PARTICIPANTS: Individuals (N=118; 50 men) participated in the study. Quota sampling was used to recruit individuals who self-identified as healthy (n=44) or currently living with a preexisting chronic health condition, including arthritis (n=19), multiple sclerosis (n=18), Parkinson disease (n=17), stroke (n=18), or low functioning (n=2). INTERVENTION: Not applicable. MAIN OUTCOME MEASURE: Latent classes of motor performance. RESULTS: Across the entire sample, 3 latent classes of motor performance were determined that clustered individuals with motor performance falling: (1) within predicted values on most of the tests (expected class), (2) outside predicted values on some of the tests (moderate class), and (3) outside predicted values on most of the tests (severe class).The ability to distinguish between the respective classes based on the percent chance of falling outside predicted values was achieved using the following community deployable motor performance tests: 10-meter walk test (22%, 80%, and 100%), 6-minute walk test (14.5%, 37.5%, and 100%), grooved pegboard test (23%, 38%, and 100%), and modified physical performance test (3%, 54%, and 96%). CONCLUSIONS: In this heterogeneous group of adults, we found 3 distinct classes of motor performance, with the sample clustering into an expected test score group, a moderate test score deficiency group, and a severed test score deficiency group. Based on the motor performance tests, we established that community deployable, easily administered testing could accurately predict the established clusters of motor performance.

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OBJECTIVE: To investigate the effects of in-bed cycle exercise in addition to usual care in patients with acute stroke, National Institutes of Health Stroke Scale (NIHSS) 7-42, regarding walking ability, functional outcomes, and inpatient care days. DESIGN: Randomized controlled trial. SETTING: Hospital care. PARTICIPANTS: Patients (N=56) with stroke NIHSS 7-42 were recruited 24-48 hours after stroke onset from 2 stroke units in Sweden. INTERVENTIONS: Both groups received usual care. The intervention group also received 20 minutes bed cycling 5 days per week with a maximum of 15 sessions. MAIN OUTCOME MEASURES: The primary outcome was median change in walking ability measured with the 6-minute walk test (6MWT). Secondary outcome measures included the median change in modified Rankin Scale (mRS), Barthel Index (BI) for activities of daily living, and inpatient care days. Measurements were performed at baseline, post intervention (3 weeks), and at 3-month follow-up. RESULTS: There was no significant difference in change of walking ability (6MWT) from baseline to follow-up between the intervention and control groups (median, 105m [interquartile range [IQR, 220m] vs 30m [IQR, 118m], respectively, P=.147, d=0.401). There were no significant differences between groups regarding mRS, BI, or inpatient care days. Patients with less serious stroke (NIHSS 7-12) seemed to benefit from the intervention. CONCLUSION: Although this study may have been underpowered, patients with stroke NIHSS 7-42 did not benefit from in-bed cycle exercise in addition to usual care after acute stroke. A larger study is needed to confirm our results.

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The primary objective of this study was to investigate the association of loneliness and the incidence of ED visits in a large and well-characterized cohort of patients with severe chronic obstructive pulmonary disease (COPD); the association of loneliness with performance measures and health perception was the secondary objective. Baseline data were used from the National Emphysema Treatment Trial (NETT), which investigated the effectiveness of lung volume reduction surgery in patients with moderate-to-severe COPD. Patients received Quality of Wellbeing questionnaires, which asked about loneliness and social isolation. For comparing baseline variables between lonely and non-lonely subjects, we used χ2 tests for categorical variables and Wilcoxon tests for continuous variables. The association of loneliness with ED visits and health perception was assessed with a logistic model that adjusted for multiple critical confounders. The study took place from December 2002, to December 2004, with a follow-up period of 5 years to assess loneliness and 24 months to assess use of the emergency department. There were 1218 patients analyzed, mean age 65 (standard deviation [SD] 12), 47% were women, FEV 1% 41 (SD 12); 7.9% of participants reported feeling lonely. These individuals had worse health ratings, 6-minute walk tests (6MWTs), and breathlessness. Loneliness was independently associated with ED visits after adjusting for age, lung function, dyspnea, 6MWT, treatment, and gender, odds ratio (OR) 1.57 (95% confidence interval [CI], 1.005-2.466), P=.04. This study suggests that loneliness in patients with COPD is significantly and independently associated to ED visits and reduced health perception. Addressing loneliness of patients with COPD in the outpatient setting may contribute to improved health perception and less health care utilization.

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INTRODUCTION: Mucopolysaccharidosis (MPS) type IVA is a rare, autosomal recessive lysosomal storage disease causing substrate accumulation in various organs and tissues. MPS IVA is associated with both obstructive and restrictive airway disease, with the former often resulting in sleep disordered breathing (SDB). Respiratory failure is a primary cause of death in this condition. The aim of this study was to characterise and catalogue the long-term respiratory changes in patients with MPS IVA treated with, or without, enzyme replacement therapy (ERT). METHODS: In this retrospective, longitudinal, repeated-measures cohort study, descriptive statistics and non-parametric correlation were performed for demographic, respiratory function and oximetry variables over a study period from January 2009 to December 2018. Composite clinical endpoints used in this study for evaluating pulmonary function included spirometry variables (FEV1, FEV1 [%Pred] FVC, FVC [%Pred] and FEV1/FVC), oximetry variables (median %Spo2, ODI 3%, mean nadir 3%, ODI 4%, mean nadir 4% and min dip SpO2 [%]) and 6MWT to assess functional exercise capacity and thus integrated cardiopulmonary function. RESULTS: Sequential spirometry and oximetry values were collected from 16 patients, of which 13/16 were ERT treated. In general, during the study period there was a global reduction in static spirometry values in all subjects, as well as cardiorespiratory function as assessed by the 6MWT, with the decline being delayed in the ERT group. Oximetry changed to a minor degree over time in the ERT group, whereas it declined in the non-ERT group. FEV1, FVC [%predicted] and ODI 3% exhibited a strong, combined positive correlation (r 0.74-95% CI 0.61 to 0.83; p < .0001). Non-invasive ventilation (NIV) and adenotonsillectomy appeared more effective in the ERT group, either improving pulmonary function or attenuating deterioration. CONCLUSIONS: Whilst spirometry values showed a gradual decline across all groups, oximetry showed modest improvement in respiratory function. The amalgamation of FEV1, FVC [%predicted] and ODI 3% appeared predictive of changes in respiratory function in this study, suggestive as being composite endpoints for monitoring disease progression as well as guiding response to ERT in MPS IVA patients.

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OBJECTIVE: To describe the clinical and personal factors associated with work status, distress regarding work status, and the desire to resume employment and receive help to address work challenges reported by women living with advanced breast cancer. DESIGN: Descriptive statistics and univariate and multivariate logistic regression were used to explore factors related to employment challenges in this secondary analysis of an existing dataset. SETTING: Participants were recruited from an outpatient oncology clinic specializing in breast cancer at a free-standing comprehensive cancer center. PARTICIPANTS: English-speaking women older than 18 years living with metastatic breast cancer with intact mental status and Karnofsky Performance Scale scores between 40 and 90 (N=163). INTERVENTION: Not applicable. MAIN OUTCOME MEASURES: Dependent variables included (1) continued employment if working at the time of cancer diagnosis; (2) interest in resuming employment if working at the time of cancer diagnosis and now no longer working; (3) distress regarding vocational limitations; and (4) interest in receiving help to resume work. RESULTS: Seventy percent of the sample was working before their cancer diagnosis (n=114), yet only 21% (n=35) was working when surveyed. Lower functional status and higher symptom burden were strongly and consistently associated with lack of work retention, distress related to vocational role limitations, and desire for help in addressing limitations (all P values<.01). CONCLUSIONS: With more people living longer with metastatic cancer, there is a need to assess and support survivors' desire and capacity to maintain employment. Participants' reduced employment was strongly associated with potentially actionable clinical targets (ie, higher symptom burden and lower functional status) that fall within cancer rehabilitation's mission.

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OBJECTIVE: To compare the efficacy of high- and low-frequency noninvasive translingual neurostimulation (TLNS) plus targeted physical therapy (PT) for treating chronic balance and gait deficits due to mild-to-moderate traumatic brain injury (mmTBI). DESIGN: Participants were randomized 1:1 in a 26-week double-blind phase 1/2 study (NCT02158494) with 3 consecutive treatment stages: in-clinic, at-home, and no treatment. Arms were high-frequency pulse (HFP) and low-frequency pulse (LFP) TLNS. SETTING: TLNS plus PT training was initiated in-clinic and then continued at home. PARTICIPANTS: Participants (N=44; 18-65y) from across the United States were randomized into the HFP and LFP (each plus PT) arms. Forty-three participants (28 women, 15 men) completed at least 1 stage of the study. Enrollment requirements included an mmTBI ≥1 year prior to screening, balance disorder due to mmTBI, a plateau in recovery with current PT, and a Sensory Organization Test (SOT) score ≥16 points below normal. INTERVENTIONS: Participants received TLNS (HFP or LFP) plus PT for a total of 14 weeks (2 in-clinic and 12 at home), twice daily, followed by 12 weeks without treatment. MAIN OUTCOME MEASURES: The primary endpoint was change in SOT composite score from baseline to week 14. Secondary variables (eg, Dynamic Gait Index [DGI], 6-minute walk test [6MWT]) were also collected. RESULTS: Both arms had a significant (P<.0001) improvement in SOT scores from baseline at weeks 2, 5, 14 (primary endpoint), and 26. DGI scores had significant improvement (P<.001-.01) from baseline at the same test points; 6MWT evaluations after 2 weeks were significant. The SOT, DGI, and 6MWT scores did not significantly differ between arms at any test point. There were no treatment-related serious adverse events. CONCLUSIONS: Both the HFP+PT and LFP+PT groups had significantly improved balance scores, and outcomes were sustained for 12 weeks after discontinuing TLNS treatment. Results between arms did not significantly differ from each other. Whether the 2 dosages are equally effective or whether improvements are because of provision of PT cannot be conclusively established at this time.

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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.

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Early initiation of enzyme replacement therapy (ERT) has demonstrated clinical benefit in patients with mucopolysaccharidosis type VI (MPS VI), a progressive, multisystem autosomal recessive lysosomal disorder caused by N-acetylgalactosamine-4-sulphatase (ASB) deficiency and the consequent accumulation of glycosaminoglycan. A previous case report highlighted that 3 years of ERT with recombinant human ASB (galsulfase) was well tolerated and effective in two Japanese siblings with MPS VI who initiated ERT at 5.6 years and 6 weeks of age, respectively. This report describes 10-year follow-up data from these two siblings who continued ERT with weekly infusions of galsulfase 1 mg/kg. Ten years of ERT was well tolerated, and the older sibling reached puberty. He had typical MPS VI phenotypic features, but exhibited significant improvement in shoulder range of motion and had largely unchanged hearing and cardiac function. His skeletal deformity remained unchanged. In contrast, in the younger sibling, typical symptoms of MPS VI, including progressive dysmorphic facial features, hepatosplenomegaly, and hearing impairment were largely absent. Her joint mobility was preserved, although skeletal deformity, including claw-hand deformity, was observed. Both siblings had progressive corneal clouding. The observations in these two patients suggest that early ERT initiated in newborns can be well tolerated and effective in preventing or slowing MPS VI disease progression, but is limited in terms of its effects on bone symptoms. For this, new approaches or bone-targeting treatments would be necessary.

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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.