Molecular therapy : the journal of the American Society of Gene Therapy, Apr 6, 2017
Sporadic inclusion body myositis, a variant of inflammatory myopathy, has features distinct from ... more Sporadic inclusion body myositis, a variant of inflammatory myopathy, has features distinct from polymyositis/dermatomyositis. The disease affects men more than women, most commonly after age 50. Clinical features include weakness of the quadriceps, finger flexors, ankle dorsiflexors, and dysphagia. The distribution of weakness is similar to Becker muscular dystrophy, where we previously reported improvement following intramuscular injection of an isoform of follistatin (FS344) by AAV1. For this clinical trial, rAAV1.CMV.huFS344, 6 × 10(11) vg/kg, was delivered to the quadriceps muscles of both legs of six sporadic inclusion body myositis subjects. The primary outcome for this trial was distance traveled for the 6-min walk test. The protocol included an exercise regimen for each participant. Performance, annualized to a median 1-year change, improved +56.0 m/year for treated subjects compared to a decline of -25.8 m/year (p = 0.01) in untreated subjects (n = 8), matched for age, gen...
S190 different doses, regimens (2, 3, 4, and 5 injections), and different spacing intervals betwe... more S190 different doses, regimens (2, 3, 4, and 5 injections), and different spacing intervals between subsequent doses. Both antibody and T cell responses were observed in 83% of animals 2 weeks following the fi rst injection and 100% of animals after the 2 nd injection. The macaques were challenged with a lethal dose of the EBOV Guinea-Makona outbreak strain (1000pfu, 7-U virus) and monitored for 28 days following infection. 100% of animals receiving at least 3 injections at 4 week intervals survived lethal challenge. Animals were fully protected against signs of disease and did not exhibit elevated blood chemistry. Interestingly, 50% of animals receiving 2 injections survived lethal challenge. The surviving animals exhibited minimal signs of disease, suggesting that with further optimization complete protection with 2 injections is potentially achievable. In additional optimization studies in mice, single injections were found to be 100% protective and we observed that long-term immune responses 8 months post vaccination were induced. Further studies in NHP are now in progress. 480.
or to dilution by other tumor cell types. Electrotransfer is an effi cient means of enhancing pla... more or to dilution by other tumor cell types. Electrotransfer is an effi cient means of enhancing plasmid DNA introduction into tissues such as skin, muscle, and tumors for therapeutic application. Localized infl ammation and induced cell death may contribute to cancer gene therapies but may impede gene therapies for which these effects are not desirable.
Spinal Muscular Atrophy is the most common genetic cause of infant death. Due to its severity, th... more Spinal Muscular Atrophy is the most common genetic cause of infant death. Due to its severity, there is a need for methods for automated estimation of disease progression. In this paper we propose a Convolutional-Neural-Network (CNN) model to estimate disease progression during infants’ natural behavior. With the proposed methodology, we were able to predict each child’s score on current behavior-based clinical exams with an average per-subject error of 6.96 out of 72 points (<10 % difference), using 30-second videos in leave-one-subject-out-cross-validation setting. When simple statistics were used over 30-second video-segments to estimate a score for longer videos, we obtained an average error of 5.95 (\(\sim \)8 % error rate). By showing promising results on a small dataset (N \(=\) 70, 2-minute samples, which were handled as 1487, 30-second video segments), our methodology demonstrates that it is possible to benefit from CNNs on small datasets by proper design and data handling choices.
Journal of Pediatric Rehabilitation Medicine, 2016
Managing the stresses of parenting a child with cerebral palsy (CP) can be challenging. This stud... more Managing the stresses of parenting a child with cerebral palsy (CP) can be challenging. This study sought to identify factors that are associated with higher levels of caregiver stress. A retrospective review of data from the Learn From Every Patient™ project conducted in an interdisciplinary CP clinic were used to compare caregiver responses on 2 subsets (financial and time/emotional) of the Assessment of Caregiver Experience in Neuromuscular Disorders (ACEND) and physical and medical characteristics of the child. The range of scores in both the financial and emotional subset was large. The presence of behavior problems, seizures, and severity of CP showed the strongest associations with emotional stress and accounted for 14% of the variance in scaled scores (r= 0.392, adj R2= 14.3, p&amp;amp;amp;amp;amp;amp;lt; 0.01). The child&amp;amp;amp;amp;amp;amp;#39;s age was not significantly related to parental stress. The most highly reported areas of stress were worry about the child&amp;amp;amp;amp;amp;amp;#39;s pain, and the financial impact of lost wages. Caregiver experience varied widely and is associated with a range of factors among families caring for a child with CP. Further research is needed to test whether interventions to minimize the areas of greatest stress could make a meaningful difference in family functioning.
The ability to individualize recommendations or expectations of disease progression based on a pa... more The ability to individualize recommendations or expectations of disease progression based on a patient's unique characteristics has merit for use in sporadic inclusion body myositis (sIBM). Fifty-five subjects with sIBM completed a battery of strength and functional outcomes at 2 study visits. These were used to develop mathematical models of disease progression in patients with sIBM for use in clinical and research settings. The six minute walk test (6MWT) distance declined an average of 27.5 meters (12%) per year. Significant factors that predict 6MWT were knee extension and plantarflexion strength and body weight, whereas the ability to stand from a chair was impacted by elbow extension strength. Stepping up on a curb was influenced by the patient's age at diagnosis and by knee extension. Statistical models to predict functional decline in sIBM were developed. Statistical models help explain the complex factors that influence decreased walking ability and other functional...
ABBREVIATIONS EHR Electronic health record LFEP 'Learn From Every Patient' LHS Learning health sy... more ABBREVIATIONS EHR Electronic health record LFEP 'Learn From Every Patient' LHS Learning health system AIM The convergence of three major trends in medicine, namely conversion to electronic health records (EHRs), prioritization of translational research, and the need to control healthcare expenditures, has created unprecedented interest and opportunities to develop systems that improve care while reducing costs. However, operationalizing a 'learning health system' requires systematic changes that have not yet been widely demonstrated in clinical practice. METHOD We developed, implemented, and evaluated a model of EHR-supported care in a cohort of 131 children with cerebral palsy that integrated clinical care, quality improvement, and research, entitled 'Learn From Every Patient' (LFEP). RESULTS Children treated in the LFEP Program for a 12-month period experienced a 43% reduction in total inpatient days (p=0.030 vs prior 12mo period), a 27% reduction in inpatient admissions, a 30% reduction in emergency department visits (p=0.001), and a 29% reduction in urgent care visits (p=0.046). LFEP Program implementation also resulted in reductions in healthcare costs of 210% (US$7014/child) versus a Time control group, and reductions of 176% ($6596/child) versus a Program Activities control group. Importantly, clinical implementation of the LFEP Program has also driven the continuous accumulation of robust research-quality data for both publication and implementation of evidence-based improvements in clinical care.
Reference values for head shape do not currently exist making it difficult to consistently and ac... more Reference values for head shape do not currently exist making it difficult to consistently and accurately identify infants with deformational plagiocephaly (DP). To identify reference values for head shape for typically developing infants using a modified version of plagiocephalometry (PCM). Prospective cohort study METHODS: 134 typically developing infants four to nine months of age were recruited randomly from center-based daycares or via a convenience sample from in-home settings. A modified version of PCM was completed to assess head shape. The median values were as follows: ear difference (ED) =3 mm, anterior-sinistra minus anterior-dextra (ASAD) =3 mm, posterior-dextra minus posterior-sinistra (PDPS) =2 mm, oblique diameter difference (ODD) =3 mm, oblique diameter difference index (ODDI) =102.1%, and cranio proportional index (CPI) =84.8%. The 75(th) percentile (Q3) values were ED=6mm, ASAD=5 mm, PDPS=3 mm, ODD=5 mm, ODDI=103.5%, and CPI=88.3%. Values were not significantly di...
Pediatric Physical Therapy the Official Publication of the Section on Pediatrics of the American Physical Therapy Association, Jun 1, 2014
To describe and report the effect of an 8-week individualized, progressive, treadmill training pr... more To describe and report the effect of an 8-week individualized, progressive, treadmill training program on the ambulatory ability of a 4-year-old child with myelomeningocele without functional ambulation. Heart rate and speed on the 2-minute walk test (2MWT) were used to individualize training. Ambulatory outcome measures taken at baseline, postintervention, and 6 weeks postintervention included the 2MWT and the Timed &amp;amp;amp;amp;amp;amp;quot;Up and Go&amp;amp;amp;amp;amp;amp;quot; (TUG). The Pediatric Evaluation of Disability Index was used to measure functional mobility. Improvements were noted in ambulatory ability after training (2MWT, 64.10%; TUG, 34.66%) and at the 6-week follow-up (2MWT, 58.97%; TUG, 34.24%). The Pediatric Evaluation of Disability Index showed no significant difference. Use of an individualized treadmill training program may have improved the ambulatory skills of a preschooler with myelomeningocele. More rigorous studies are needed to determine the effects of treadmill training with the spina bifida population and identify optimal training parameters.
Outcomes sensitive to change over time in non-ambulatory boys/men with Duchenne muscular dystroph... more Outcomes sensitive to change over time in non-ambulatory boys/men with Duchenne muscular dystrophy (DMD) are not well-established. Subjects (n=91; 16.8 ± 4.5 years) were assessed at baseline and 6-month intervals for 2 years. We analyzed all subjects using an intent-to-treat model and a subset of stronger subjects with Brooke Scale score ≤ 4 using repeated measures. Eight (12-33 years) died during the study. Sixty-six completed12-month follow-up; 51 completed 24-month follow-up. Those taking corticosteroids performed better at baseline, but rates of decline were similar. FVC% predicted declined significantly only after 2 years. However, Brooke scale, Egen Klassifikation (EK) scale, elbow flexion and grip strength declined significantly over both 1 and 2 years. Brooke scale, EK scale, and elbow flexion and grip strength were outcomes most responsive to change. FVC% predicted was responsive to change over 2 years. Corticosteroids benefited non-ambulatory DMD subjects but did not affec...
Sporadic inclusion body myositis (sIBM) is a progressive idiopathic inflammatory myopathy charact... more Sporadic inclusion body myositis (sIBM) is a progressive idiopathic inflammatory myopathy characterized by atrophy and weakness of proximal and distal muscle groups resulting in a loss of independence and the need for assistive devices and supportive care. To assess treatment benefit of new therapies, a patient-reported outcome measure of physical function was developed. The tool was rigorously developed in accordance with the U.S. Food and Drug Administration (FDA) Patient Report Outcomes (PRO) Guidance. A single-visit, observational study was conducted. Standard qualitative analytical methods were employed to analyze interview data and generate questionnaire items. Twenty concept elicitation and 19 cognitive debriefing interviews were conducted, and 6 expert physicians were consulted. The tool consists of 11 items scored on a 0-10 numerical rating scale. Subjects completed the questionnaire utilizing either paper or electronic administration. We have developed a PRO tool in alignment with FDA PRO Guidance for use in the functional assessment of treatment benefit in sIBM. This article is protected by copyright. All rights reserved.
To assess self-reported physical functioning in patients with sporadic inclusion body myositis (s... more To assess self-reported physical functioning in patients with sporadic inclusion body myositis (sIBM), the sIBM Physical Functioning Assessment (sIFA) was developed. This research establishes the validity, reliability, and responsiveness of the sIFA in patients with sIBM. Data from 3 small, noninterventional, observational studies were analyzed. Several measures of physical function were included to assess validity. Reliability (Cronbach alpha, test-retest intraclass correlations), construct validity (correlations, analyses of variance), and responsiveness (effect size estimates) were evaluated. Cronbach alphas (range=0.86-0.91) and test-retest reliability (0.91) were highly satisfactory. Correlations with other measures provided evidence of convergent validity. sIBM patients able to walk without assistive devices scored significantly better on the sIFA (means=36.0-47.05) than those who require power mobility or wheelchairs (means=54.9-71.5), demonstrating the discriminating ability...
Sporadic inclusion body myositis is the most common inflammatory muscle disorder preferentially a... more Sporadic inclusion body myositis is the most common inflammatory muscle disorder preferentially affecting males over the age of 40 years. Progressive muscle weakness of the finger flexors and quadriceps muscles results in loss of independence with activities of daily living and eventual wheelchair dependence. Initial signs of disease are often overlooked and can lead to mis-or delayed diagnosis. The underlying cause of disease is unknown, and disease progression appears refractory to available treatment options. This review discusses the clinical presentation of inclusion body myositis and the current efforts in diagnosis, and focuses on the current state of research for both nonpharmacological and pharmacological treatment options for this patient group.
Objective: To continue evaluation of the long-term efficacy and safety of eteplirsen, a phosphoro... more Objective: To continue evaluation of the long-term efficacy and safety of eteplirsen, a phosphorodiamidate morpholino oligomer designed to skip DMD exon 51 in patients with Duchenne muscular dystrophy (DMD). Three-year progression of eteplirsen-treated patients was compared to matched historical controls (HC). Methods: Ambulatory DMD patients who were 7 years old and amenable to exon 51 skipping were randomized to eteplirsen (30/50mg/kg) or placebo for 24 weeks. Thereafter, all received eteplirsen on an open-label basis. The primary functional assessment in this study was the 6-Minute Walk Test (6MWT). Respiratory muscle function was assessed by pulmonary function testing (PFT). Longitudinal natural history data were used for comparative analysis of 6MWT performance at baseline and months 12, 24, and 36. Patients were matched to the eteplirsen group based on age, corticosteroid use, and genotype. Results: At 36 months, eteplirsen-treated patients (n 5 12) demonstrated a statistically significant advantage of 151m (p < 0.01) on 6MWT and experienced a lower incidence of loss of ambulation in comparison to matched HC (n 5 13) amenable to exon 51 skipping. PFT results remained relatively stable in eteplirsen-treated patients. Eteplirsen was well tolerated. Analysis of HC confirmed the previously observed change in disease trajectory at age 7 years, and more severe progression was observed in patients with mutations amenable to exon skipping than in those not amenable. The subset of patients amenable to exon 51 skipping showed a more severe disease course than those amenable to any exon skipping. Interpretation: Over 3 years of follow-up, eteplirsen-treated patients showed a slower rate of decline in ambulation assessed by 6MWT compared to untreated matched HC.
Children with many types of motor dysfunction have problems maintaining postural stability. Becau... more Children with many types of motor dysfunction have problems maintaining postural stability. Because maintenance of postural stability is an integral part of all movements, therapists evaluate and treat to improve postural stability in these children. This article reviews current pediatric assessment tools for postural stability and issues affecting testing this construct in children. The tests and measurements are classified according to their testing purpose and the National Center for Medical Rehabilitation Research disablement framework, focusing on the impairment and functional limitation dimensions. Postural stability is defined from a systems perspective with tests related to the sensory, motor, and biomechanical systems described. Reliability and validity information on the measurements is discussed. Relatively few measurements of postural stability in children are available that have acceptable reliability and validity documentation. Suggestions for research on test development in this area are discussed. [Westcott SL, Lowes LP, Richardson PK. Evaluation of postural stability in children: current theories and assessment tools.
DMD is a rare, degenerative, genetic disease that results in progressive muscle loss and prematur... more DMD is a rare, degenerative, genetic disease that results in progressive muscle loss and premature death and affects 1:5000 male births. Clinically manifest pulmonary dysfunction often occurs when DMD patients become non-ambulant and is preceded by subclinical deterioration of pulmonary function tests (PFTs). Specifically, MIP and MEP % predicted deteriorate by approximately 4 % per year between the ages of 8–19. Eteplirsen is an investigational drug designed to enable functional dystrophin production in boys who are amenable to skipping exon 51. When dosed for up to 120 weeks, stabilization of 6 min walk distance was demonstrated in a Phase 2b study. 12 boys were randomized 1:1:1 to 30/50 mg/kg or placebo. Upon completion of a 24-week double-blind, placebo-controlled phase, all patients were enrolled in an open-label extension and the placebo-treated patients initiated eteplirsen treatment. FVC, FVC % predicted, MIP, MEP and MIP and MEP % predicted were assessed every 12 to 24 weeks. For all 12 patients changes in function at Week 120 were examined from Week 1, and from last assessment pre-eteplirsen administration (Week 1 for 8 patients and Week 24 for 4 patients). One-sample t-test was used for statistical analysis. Reported here are the results for all 12 patients, including two patients who became non ambulant by Week 24. Median age at Week 120 was 12 years. The 120 week data for 5 of the 6 PFT parameters were not statistically different from baseline, with the exception of a statistically significant increase in MEP. Furthermore, individual patient values for all 12 patients continue to be in the age-adjusted normal ranges indicative of continued normal pulmonary function without the need for any ventilation assistance or respiratory failure. A PFT update after 3 years of treatment (Week 144) will be provided. Eteplirsen dosed for up to 120 weeks demonstrated stability on PFT measures contrary to a steady decline expected in DMD patients of this age.
Molecular therapy : the journal of the American Society of Gene Therapy, Apr 6, 2017
Sporadic inclusion body myositis, a variant of inflammatory myopathy, has features distinct from ... more Sporadic inclusion body myositis, a variant of inflammatory myopathy, has features distinct from polymyositis/dermatomyositis. The disease affects men more than women, most commonly after age 50. Clinical features include weakness of the quadriceps, finger flexors, ankle dorsiflexors, and dysphagia. The distribution of weakness is similar to Becker muscular dystrophy, where we previously reported improvement following intramuscular injection of an isoform of follistatin (FS344) by AAV1. For this clinical trial, rAAV1.CMV.huFS344, 6 × 10(11) vg/kg, was delivered to the quadriceps muscles of both legs of six sporadic inclusion body myositis subjects. The primary outcome for this trial was distance traveled for the 6-min walk test. The protocol included an exercise regimen for each participant. Performance, annualized to a median 1-year change, improved +56.0 m/year for treated subjects compared to a decline of -25.8 m/year (p = 0.01) in untreated subjects (n = 8), matched for age, gen...
S190 different doses, regimens (2, 3, 4, and 5 injections), and different spacing intervals betwe... more S190 different doses, regimens (2, 3, 4, and 5 injections), and different spacing intervals between subsequent doses. Both antibody and T cell responses were observed in 83% of animals 2 weeks following the fi rst injection and 100% of animals after the 2 nd injection. The macaques were challenged with a lethal dose of the EBOV Guinea-Makona outbreak strain (1000pfu, 7-U virus) and monitored for 28 days following infection. 100% of animals receiving at least 3 injections at 4 week intervals survived lethal challenge. Animals were fully protected against signs of disease and did not exhibit elevated blood chemistry. Interestingly, 50% of animals receiving 2 injections survived lethal challenge. The surviving animals exhibited minimal signs of disease, suggesting that with further optimization complete protection with 2 injections is potentially achievable. In additional optimization studies in mice, single injections were found to be 100% protective and we observed that long-term immune responses 8 months post vaccination were induced. Further studies in NHP are now in progress. 480.
or to dilution by other tumor cell types. Electrotransfer is an effi cient means of enhancing pla... more or to dilution by other tumor cell types. Electrotransfer is an effi cient means of enhancing plasmid DNA introduction into tissues such as skin, muscle, and tumors for therapeutic application. Localized infl ammation and induced cell death may contribute to cancer gene therapies but may impede gene therapies for which these effects are not desirable.
Spinal Muscular Atrophy is the most common genetic cause of infant death. Due to its severity, th... more Spinal Muscular Atrophy is the most common genetic cause of infant death. Due to its severity, there is a need for methods for automated estimation of disease progression. In this paper we propose a Convolutional-Neural-Network (CNN) model to estimate disease progression during infants’ natural behavior. With the proposed methodology, we were able to predict each child’s score on current behavior-based clinical exams with an average per-subject error of 6.96 out of 72 points (<10 % difference), using 30-second videos in leave-one-subject-out-cross-validation setting. When simple statistics were used over 30-second video-segments to estimate a score for longer videos, we obtained an average error of 5.95 (\(\sim \)8 % error rate). By showing promising results on a small dataset (N \(=\) 70, 2-minute samples, which were handled as 1487, 30-second video segments), our methodology demonstrates that it is possible to benefit from CNNs on small datasets by proper design and data handling choices.
Journal of Pediatric Rehabilitation Medicine, 2016
Managing the stresses of parenting a child with cerebral palsy (CP) can be challenging. This stud... more Managing the stresses of parenting a child with cerebral palsy (CP) can be challenging. This study sought to identify factors that are associated with higher levels of caregiver stress. A retrospective review of data from the Learn From Every Patient™ project conducted in an interdisciplinary CP clinic were used to compare caregiver responses on 2 subsets (financial and time/emotional) of the Assessment of Caregiver Experience in Neuromuscular Disorders (ACEND) and physical and medical characteristics of the child. The range of scores in both the financial and emotional subset was large. The presence of behavior problems, seizures, and severity of CP showed the strongest associations with emotional stress and accounted for 14% of the variance in scaled scores (r= 0.392, adj R2= 14.3, p&amp;amp;amp;amp;amp;amp;lt; 0.01). The child&amp;amp;amp;amp;amp;amp;#39;s age was not significantly related to parental stress. The most highly reported areas of stress were worry about the child&amp;amp;amp;amp;amp;amp;#39;s pain, and the financial impact of lost wages. Caregiver experience varied widely and is associated with a range of factors among families caring for a child with CP. Further research is needed to test whether interventions to minimize the areas of greatest stress could make a meaningful difference in family functioning.
The ability to individualize recommendations or expectations of disease progression based on a pa... more The ability to individualize recommendations or expectations of disease progression based on a patient's unique characteristics has merit for use in sporadic inclusion body myositis (sIBM). Fifty-five subjects with sIBM completed a battery of strength and functional outcomes at 2 study visits. These were used to develop mathematical models of disease progression in patients with sIBM for use in clinical and research settings. The six minute walk test (6MWT) distance declined an average of 27.5 meters (12%) per year. Significant factors that predict 6MWT were knee extension and plantarflexion strength and body weight, whereas the ability to stand from a chair was impacted by elbow extension strength. Stepping up on a curb was influenced by the patient's age at diagnosis and by knee extension. Statistical models to predict functional decline in sIBM were developed. Statistical models help explain the complex factors that influence decreased walking ability and other functional...
ABBREVIATIONS EHR Electronic health record LFEP 'Learn From Every Patient' LHS Learning health sy... more ABBREVIATIONS EHR Electronic health record LFEP 'Learn From Every Patient' LHS Learning health system AIM The convergence of three major trends in medicine, namely conversion to electronic health records (EHRs), prioritization of translational research, and the need to control healthcare expenditures, has created unprecedented interest and opportunities to develop systems that improve care while reducing costs. However, operationalizing a 'learning health system' requires systematic changes that have not yet been widely demonstrated in clinical practice. METHOD We developed, implemented, and evaluated a model of EHR-supported care in a cohort of 131 children with cerebral palsy that integrated clinical care, quality improvement, and research, entitled 'Learn From Every Patient' (LFEP). RESULTS Children treated in the LFEP Program for a 12-month period experienced a 43% reduction in total inpatient days (p=0.030 vs prior 12mo period), a 27% reduction in inpatient admissions, a 30% reduction in emergency department visits (p=0.001), and a 29% reduction in urgent care visits (p=0.046). LFEP Program implementation also resulted in reductions in healthcare costs of 210% (US$7014/child) versus a Time control group, and reductions of 176% ($6596/child) versus a Program Activities control group. Importantly, clinical implementation of the LFEP Program has also driven the continuous accumulation of robust research-quality data for both publication and implementation of evidence-based improvements in clinical care.
Reference values for head shape do not currently exist making it difficult to consistently and ac... more Reference values for head shape do not currently exist making it difficult to consistently and accurately identify infants with deformational plagiocephaly (DP). To identify reference values for head shape for typically developing infants using a modified version of plagiocephalometry (PCM). Prospective cohort study METHODS: 134 typically developing infants four to nine months of age were recruited randomly from center-based daycares or via a convenience sample from in-home settings. A modified version of PCM was completed to assess head shape. The median values were as follows: ear difference (ED) =3 mm, anterior-sinistra minus anterior-dextra (ASAD) =3 mm, posterior-dextra minus posterior-sinistra (PDPS) =2 mm, oblique diameter difference (ODD) =3 mm, oblique diameter difference index (ODDI) =102.1%, and cranio proportional index (CPI) =84.8%. The 75(th) percentile (Q3) values were ED=6mm, ASAD=5 mm, PDPS=3 mm, ODD=5 mm, ODDI=103.5%, and CPI=88.3%. Values were not significantly di...
Pediatric Physical Therapy the Official Publication of the Section on Pediatrics of the American Physical Therapy Association, Jun 1, 2014
To describe and report the effect of an 8-week individualized, progressive, treadmill training pr... more To describe and report the effect of an 8-week individualized, progressive, treadmill training program on the ambulatory ability of a 4-year-old child with myelomeningocele without functional ambulation. Heart rate and speed on the 2-minute walk test (2MWT) were used to individualize training. Ambulatory outcome measures taken at baseline, postintervention, and 6 weeks postintervention included the 2MWT and the Timed &amp;amp;amp;amp;amp;amp;quot;Up and Go&amp;amp;amp;amp;amp;amp;quot; (TUG). The Pediatric Evaluation of Disability Index was used to measure functional mobility. Improvements were noted in ambulatory ability after training (2MWT, 64.10%; TUG, 34.66%) and at the 6-week follow-up (2MWT, 58.97%; TUG, 34.24%). The Pediatric Evaluation of Disability Index showed no significant difference. Use of an individualized treadmill training program may have improved the ambulatory skills of a preschooler with myelomeningocele. More rigorous studies are needed to determine the effects of treadmill training with the spina bifida population and identify optimal training parameters.
Outcomes sensitive to change over time in non-ambulatory boys/men with Duchenne muscular dystroph... more Outcomes sensitive to change over time in non-ambulatory boys/men with Duchenne muscular dystrophy (DMD) are not well-established. Subjects (n=91; 16.8 ± 4.5 years) were assessed at baseline and 6-month intervals for 2 years. We analyzed all subjects using an intent-to-treat model and a subset of stronger subjects with Brooke Scale score ≤ 4 using repeated measures. Eight (12-33 years) died during the study. Sixty-six completed12-month follow-up; 51 completed 24-month follow-up. Those taking corticosteroids performed better at baseline, but rates of decline were similar. FVC% predicted declined significantly only after 2 years. However, Brooke scale, Egen Klassifikation (EK) scale, elbow flexion and grip strength declined significantly over both 1 and 2 years. Brooke scale, EK scale, and elbow flexion and grip strength were outcomes most responsive to change. FVC% predicted was responsive to change over 2 years. Corticosteroids benefited non-ambulatory DMD subjects but did not affec...
Sporadic inclusion body myositis (sIBM) is a progressive idiopathic inflammatory myopathy charact... more Sporadic inclusion body myositis (sIBM) is a progressive idiopathic inflammatory myopathy characterized by atrophy and weakness of proximal and distal muscle groups resulting in a loss of independence and the need for assistive devices and supportive care. To assess treatment benefit of new therapies, a patient-reported outcome measure of physical function was developed. The tool was rigorously developed in accordance with the U.S. Food and Drug Administration (FDA) Patient Report Outcomes (PRO) Guidance. A single-visit, observational study was conducted. Standard qualitative analytical methods were employed to analyze interview data and generate questionnaire items. Twenty concept elicitation and 19 cognitive debriefing interviews were conducted, and 6 expert physicians were consulted. The tool consists of 11 items scored on a 0-10 numerical rating scale. Subjects completed the questionnaire utilizing either paper or electronic administration. We have developed a PRO tool in alignment with FDA PRO Guidance for use in the functional assessment of treatment benefit in sIBM. This article is protected by copyright. All rights reserved.
To assess self-reported physical functioning in patients with sporadic inclusion body myositis (s... more To assess self-reported physical functioning in patients with sporadic inclusion body myositis (sIBM), the sIBM Physical Functioning Assessment (sIFA) was developed. This research establishes the validity, reliability, and responsiveness of the sIFA in patients with sIBM. Data from 3 small, noninterventional, observational studies were analyzed. Several measures of physical function were included to assess validity. Reliability (Cronbach alpha, test-retest intraclass correlations), construct validity (correlations, analyses of variance), and responsiveness (effect size estimates) were evaluated. Cronbach alphas (range=0.86-0.91) and test-retest reliability (0.91) were highly satisfactory. Correlations with other measures provided evidence of convergent validity. sIBM patients able to walk without assistive devices scored significantly better on the sIFA (means=36.0-47.05) than those who require power mobility or wheelchairs (means=54.9-71.5), demonstrating the discriminating ability...
Sporadic inclusion body myositis is the most common inflammatory muscle disorder preferentially a... more Sporadic inclusion body myositis is the most common inflammatory muscle disorder preferentially affecting males over the age of 40 years. Progressive muscle weakness of the finger flexors and quadriceps muscles results in loss of independence with activities of daily living and eventual wheelchair dependence. Initial signs of disease are often overlooked and can lead to mis-or delayed diagnosis. The underlying cause of disease is unknown, and disease progression appears refractory to available treatment options. This review discusses the clinical presentation of inclusion body myositis and the current efforts in diagnosis, and focuses on the current state of research for both nonpharmacological and pharmacological treatment options for this patient group.
Objective: To continue evaluation of the long-term efficacy and safety of eteplirsen, a phosphoro... more Objective: To continue evaluation of the long-term efficacy and safety of eteplirsen, a phosphorodiamidate morpholino oligomer designed to skip DMD exon 51 in patients with Duchenne muscular dystrophy (DMD). Three-year progression of eteplirsen-treated patients was compared to matched historical controls (HC). Methods: Ambulatory DMD patients who were 7 years old and amenable to exon 51 skipping were randomized to eteplirsen (30/50mg/kg) or placebo for 24 weeks. Thereafter, all received eteplirsen on an open-label basis. The primary functional assessment in this study was the 6-Minute Walk Test (6MWT). Respiratory muscle function was assessed by pulmonary function testing (PFT). Longitudinal natural history data were used for comparative analysis of 6MWT performance at baseline and months 12, 24, and 36. Patients were matched to the eteplirsen group based on age, corticosteroid use, and genotype. Results: At 36 months, eteplirsen-treated patients (n 5 12) demonstrated a statistically significant advantage of 151m (p < 0.01) on 6MWT and experienced a lower incidence of loss of ambulation in comparison to matched HC (n 5 13) amenable to exon 51 skipping. PFT results remained relatively stable in eteplirsen-treated patients. Eteplirsen was well tolerated. Analysis of HC confirmed the previously observed change in disease trajectory at age 7 years, and more severe progression was observed in patients with mutations amenable to exon skipping than in those not amenable. The subset of patients amenable to exon 51 skipping showed a more severe disease course than those amenable to any exon skipping. Interpretation: Over 3 years of follow-up, eteplirsen-treated patients showed a slower rate of decline in ambulation assessed by 6MWT compared to untreated matched HC.
Children with many types of motor dysfunction have problems maintaining postural stability. Becau... more Children with many types of motor dysfunction have problems maintaining postural stability. Because maintenance of postural stability is an integral part of all movements, therapists evaluate and treat to improve postural stability in these children. This article reviews current pediatric assessment tools for postural stability and issues affecting testing this construct in children. The tests and measurements are classified according to their testing purpose and the National Center for Medical Rehabilitation Research disablement framework, focusing on the impairment and functional limitation dimensions. Postural stability is defined from a systems perspective with tests related to the sensory, motor, and biomechanical systems described. Reliability and validity information on the measurements is discussed. Relatively few measurements of postural stability in children are available that have acceptable reliability and validity documentation. Suggestions for research on test development in this area are discussed. [Westcott SL, Lowes LP, Richardson PK. Evaluation of postural stability in children: current theories and assessment tools.
DMD is a rare, degenerative, genetic disease that results in progressive muscle loss and prematur... more DMD is a rare, degenerative, genetic disease that results in progressive muscle loss and premature death and affects 1:5000 male births. Clinically manifest pulmonary dysfunction often occurs when DMD patients become non-ambulant and is preceded by subclinical deterioration of pulmonary function tests (PFTs). Specifically, MIP and MEP % predicted deteriorate by approximately 4 % per year between the ages of 8–19. Eteplirsen is an investigational drug designed to enable functional dystrophin production in boys who are amenable to skipping exon 51. When dosed for up to 120 weeks, stabilization of 6 min walk distance was demonstrated in a Phase 2b study. 12 boys were randomized 1:1:1 to 30/50 mg/kg or placebo. Upon completion of a 24-week double-blind, placebo-controlled phase, all patients were enrolled in an open-label extension and the placebo-treated patients initiated eteplirsen treatment. FVC, FVC % predicted, MIP, MEP and MIP and MEP % predicted were assessed every 12 to 24 weeks. For all 12 patients changes in function at Week 120 were examined from Week 1, and from last assessment pre-eteplirsen administration (Week 1 for 8 patients and Week 24 for 4 patients). One-sample t-test was used for statistical analysis. Reported here are the results for all 12 patients, including two patients who became non ambulant by Week 24. Median age at Week 120 was 12 years. The 120 week data for 5 of the 6 PFT parameters were not statistically different from baseline, with the exception of a statistically significant increase in MEP. Furthermore, individual patient values for all 12 patients continue to be in the age-adjusted normal ranges indicative of continued normal pulmonary function without the need for any ventilation assistance or respiratory failure. A PFT update after 3 years of treatment (Week 144) will be provided. Eteplirsen dosed for up to 120 weeks demonstrated stability on PFT measures contrary to a steady decline expected in DMD patients of this age.
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Papers by Linda Lowes