Longitudinal community walking activity in Duchenne muscular dystrophy.

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

Mutations in FKBP10, which result in Bruck syndrome and recessive forms of osteogenesis imperfecta, inhibit the hydroxylation of telopeptide lysines in bone collagen.

Although biallelic mutations in non-collagen genes account for <10% of individuals with osteogenesis imperfecta, the characterization of these genes has identified new pathways and potential interventions that could benefit even those with mutations in type I collagen genes. We identified mutations in FKBP10, which encodes the 65 kDa prolyl cis-trans isomerase, FKBP65, in 38 members of 21 families with OI. These include 10 families from the Samoan Islands who share a founder mutation. Of the mutations, three are missense; the remainder either introduce premature termination codons or create frameshifts both of which result in mRNA instability. In four families missense mutations result in loss of most of the protein. The clinical effects of these mutations are short stature, a high incidence of joint contractures at birth and progressive scoliosis and fractures, but there is remarkable variability in phenotype even within families. The loss of the activity of FKBP65 has several effects: type I procollagen secretion is slightly delayed, the stabilization of the intact trimer is incomplete and there is diminished hydroxylation of the telopeptide lysyl residues involved in intermolecular cross-link formation in bone. The phenotype overlaps with that seen with mutations in PLOD2 (Bruck syndrome II), which encodes LH2, the enzyme that hydroxylates the telopeptide lysyl residues. These findings define a set of genes, FKBP10, PLOD2 and SERPINH1, that act during procollagen maturation to contribute to molecular stability and post-translational modification of type I procollagen, without which bone mass and quality are abnormal and fractures and contractures result.

Mutations in PPIB (cyclophilin B) delay type I procollagen chain association and result in perinatal lethal to moderate osteogenesis imperfecta phenotypes.

Recessive mutations in the cartilage-associated protein (CRTAP), leucine proline-enriched proteoglycan 1 (LEPRE1) and peptidyl prolyl cis-trans isomerase B (PPIB) genes result in phenotypes that range from lethal in the perinatal period to severe deforming osteogenesis imperfecta (OI). These genes encode CRTAP (encoded by CRTAP), prolyl 3-hydroxylase 1 (P3H1; encoded by LEPRE1) and cyclophilin B (CYPB; encoded by PPIB), which reside in the rough endoplasmic reticulum (RER) and can form a complex involved in prolyl 3-hydroxylation in type I procollagen. CYPB, a prolyl cis-trans isomerase, has been thought to drive the prolyl-containing peptide bonds to the trans configuration needed for triple helix formation. Here, we describe mutations in PPIB identified in cells from three individuals with OI. Cultured dermal fibroblasts from the most severely affected infant make some overmodified type I procollagen molecules. Proα1(I) chains are slow to assemble into trimers, and abnormal procollagen molecules concentrate in the RER, and bind to protein disulfide isomerase (PDI) and prolyl 4-hydroxylase 1 (P4H1). These findings suggest that although CYPB plays a role in helix formation another effect is on folding of the C-terminal propeptide and trimer formation. The extent of procollagen accumulation and PDI/P4H1 binding differs among cells with mutations in PPIB, CRTAP and LEPRE1 with the greatest amount in PPIB-deficient cells and the least in LEPRE1-deficient cells. These findings suggest that prolyl cis-trans isomerase may be required to effectively fold the proline-rich regions of the C-terminal propeptide to allow proα chain association and suggest an order of action for CRTAP, P3H1 and CYPB in procollagen biosynthesis and pathogenesis of OI.

Amplicon Sequencing Minimal Information (ASqMI): Quality and Reporting Guidelines for Actionable Calls in Biodefense Applications.

BACKGROUND: Accurate, high-confidence data is critical for assessing potential biothreat incidents. In a biothreat event, false-negative and -positive results have serious consequences. Worst case scenarios can result in unnecessary shutdowns or fatalities at an exorbitant monetary and psychological cost, respectively. Quantitative PCR assays for agents of interest have been successfully used for routine biosurveillance. Recently, there has been increased impetus for adoption of amplicon sequencing (AS) for biosurveillance because it enables discrimination of true positives from near-neighbor false positives, as well as broad, simultaneous detection of many targets in many pathogens in a high-throughput scheme. However, the high sensitivity of AS can lead to false positives. Appropriate controls and workflow reporting can help address these challenges. OBJECTIVES: Data reporting standards are critical to data trustworthiness. The standards presented herein aim to provide a framework for method quality assessment in biodetection. METHODS: We present a set of standards, Amplicon Sequencing Minimal Information (ASqMI), developed under the auspices of the AOAC INTERNATIONAL Stakeholder Program on Agent Detection Assays for making actionable calls in biosurveillance applications. In addition to the first minimum information guidelines for AS, we provide a controls checklist and scoring scheme to assure AS run quality and assess potential sample contamination. RESULTS: Adoption of the ASqMI guidelines will improve data quality, help track workflow performance, and ultimately provide decision makers confidence to trust the results of this new and powerful technology. CONCLUSION: AS workflows can provide robust, confident calls for biodetection; however, due diligence in reporting and controls are needed. The ASqMI guideline is the first AS minimum reporting guidance document that also provides the means for end users to evaluate their workflows to improve confidence. HIGHLIGHTS: Standardized reporting guidance for actionable calls is critical to ensuring trustworthy data.

Long-term outcome of hamstring lengthening versus transfer and the role of biceps femoris lengthening in patients with spastic diplegia and dynamic knee flexion in gait.

Background: Orthopedic treatment of flexed-knee gait consists of hamstring lengthening along with surgery at other levels. Transfer of the semitendinosus (hamstring transfer) was introduced to avoid increase of anterior pelvic tilt as well as reduce risk of recurrence. Methods: We retrospectively assessed children with spastic cerebral palsy and flexed-knee gait pre-operatively, 1 year post-operatively, and at a minimum of 7 years post-operatively. Results: The 39 patients were a mean 9.4 ± 3.4 years at the time of surgery, 20 subjects underwent hamstring transfer, and 19 subjects had hamstring lengthening with mean follow-up 9.1 years. Passive range of motion improved initially, but regressed at long term. Dynamic minimum knee flexion in stance decreased in both groups at the first post-operative study, and was maintained at final follow-up in 64-67% of patients. There was a small increase in anterior pelvic tilt at the 1-year follow-up which subsequently decreased to less than pre-operative in the hamstring lengthening group but remained mildly increased (5°) in the hamstring transfer group at final follow-up. Success in correcting stance knee flexion of the entire group was 69% of the Gross Motor Function Classification System grades I and II and 60% of the Gross Motor Function Classification System grade III subjects. Gait profile Score and sagittal knee Gait Variable Score both showed clinically important improvement after surgery and was mostly maintained long term for both groups. Lateral hamstring lengthening was beneficial in more severe patients, with minimal risk of adverse effects. Conclusion: Hamstring surgery as part of single event multi-level surgery (SEMLS) is effective in correcting flexed-knee gait in 60%-70% of patients with minimal effect on anterior pelvic tilt. There was no added advantage to hamstring transfer. Biceps Femoris lengthening may be beneficial and without significant additional risk. Level of evidence: level III.

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

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

Single laboratory validation of a microsatellite marker-based method in tomato variety identification.

The objective of this study was to develop a systematic and flexible method for assembling multiplex simple sequence repeat marker panels for high-throughput genome analysis in the tomato, Solanum lycopersicum, for varietal identification and to demonstrate the technical viability of these genetic markers for use in the enforcement of U.S. Department of Agriculture marketing order-based identity preservation programs. GeneMapper, a semiautomated software tool, was used for designing multiplex panels, allele identification, and polymorphism pattern evaluation of diverse tomato cultivars. Semiautomated genotyping was performed on a set of 12 microsatellite markers providing genome-wide coverage of the tomato chromosomes. Microsatellites were detected with fluorescently labeled primers grouped into five multiplex panels, and each primer pair was assessed in replicated trials for reliability of allele size estimates. Allele sizes for each locus were compared, and a database for 34 tomato varieties was developed. The microsatellite marker set identified distinct allelic peaks and unique genetic fingerprints for each of the studied tomato varieties. A "blind testing" exercise with UglyRipe and Vintage Ripe tomato varieties, using the above set of markers and database, further established the usefulness of these microsatellite markers for tomato commodity marketing order enforcement.

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

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

Varus derotation osteotomy for the treatment of hip subluxation and dislocation in GMFCS level III to V patients with unilateral hip involvement. Follow-up at skeletal maturity.

PURPOSE: Hip displacement is common in children with cerebral palsy (CP). The risk of hip displacement is related to gross motor function level as graded with the Gross Motor Function Classification System (GMFCS). Most clinicians agree that surgical treatment is indicated for progressive hip subluxation in patients with CP. However, it is unclear whether unilateral bony surgery and musculotenduous release is effective in cases in which the contralateral hip is well seated. The purpose of this study is to describe the fate of the original and the contralateral hip of severely involved patients with CP, GMFCS III to V, with unilateral hip subluxation or dislocation treated by unilateral femoral osteotomy with or without pelvic osteotomy along with unilateral or bilateral soft tissue release when the contralateral hip was well seated followed to skeletal maturity. METHODS: A continuous group of GMFCS III to V CP patients with unilateral hip subluxation or dislocation who underwent soft tissue release (adductor and iliopsoas) and unilateral intertrochanteric varus, rotation and shortening osteotomy with or without pelvic osteotomy are included. All patients were clinically and radiologically followed from the time of presentation until skeletal maturity. RESULTS: Twenty-seven children and adolescents with GMFCS level III, IV, and V met the inclusion criteria. Two patients (7.4%) were GMFCS III, 5 (18.5%) were GMFCS IV and 20 (74.1%) GMFCS V. The male:female ratio was almost 1 (13 boys and 14 girls). At the time of chart and radiograph review, the average age of this patient group was 20.4 years (range: 14 to 25 y). Twelve patients (44%) required subsequent bony surgical management of the contralateral hip for subluxation or dislocation after the index procedure. Initially, in all cases there was pelvic obliquity with the operative side higher, which reversed in cases in which the contralateral hip deteriorated, and did not reverse when the contralateral hip remained stable. Nine of them were treated with femoral varus osteotomy alone and 3 underwent a combination of femoral and pelvic osteotomy. Three of these 12 (25%) patients had revision of the first hip and bony correction of the contralateral hip. Age at surgery did not seem to have a significant effect on maintaining reduction or in preventing the contralateral hip to deteriorate. CONCLUSIONS: The rates of recurrence of the original hip and contralateral hip subluxation and dislocation after unilateral bony surgery in GMFCS III to V spastic patients are higher than those of other earlier series. However, in this series patients were followed until skeletal maturity. It is prudent to warn families of the possibility of long-term subluxation or dislocation of the original hip and development of the hip dysplasia requiring surgery on the contralateral side. Consideration should be given to adductor and iliopsoas release and bony surgery on the contralateral side in a GMFCS level III to V child undergoing surgery for hip displacement, even when the hip seem radiologically normal. If unilateral bony surgery is carried out, close radiological follow-up of both hips is recommended. It also seems that unilateral hip surgery alters the forces maintaining pelvic alignment, which can lead to destabilization of the contralateral hip. LEVEL OF EVIDENCE: Case series. Level IV.

Efficacy of corticosteroid in decreasing scoliosis and extending time to loss of ambulation in a single clinic: an effectiveness trial.

PURPOSE: Pharmacologic doses of corticosteroid (CS) have been shown to ameliorate the progression of Duchenne muscular dystrophy (DMD) preserving strength, pulmonary function and ambulation as well as reducing the incidence of scoliosis. However, there are serious side effects of CS, which may impact dose tolerance. The purpose of this study was to compare the magnitude of positive CS effects on patients in our clinic to those reported in the literature. METHODS: We retrospectively reviewed medical records and radiographs of 142 DMD patients who were seen between 1st January 1991 and 31st December 2017. RESULTS: In total, 101 boys met study inclusion criteria. Of these 32 were steroid naïve, 37 took the recommended dose (standard of care, SOC) of Prednisone or Deflazacort, and 32 took a lower dose (LD). Following initiation of CS, both treatment groups showed an increase in weight velocity and decrease in linear growth velocity. Although there was a trend to later loss of ambulation (LOA) in the SOC group relative to the naïve group by one year, this was not significant, however, a small subgroup of boys on Deflazacort showed a 3.4 year later LOA than the naïve group. The incidence of scoliosis was reduced from 69% in the naïve, to 41% in the LD and 47% in the SOC group. CONCLUSIONS: Although there was a reduction in the incidence of scoliosis, it was not as robust as seen elsewhere. Many published studies have inadequate data on scoliosis probably due to the lack of inclusion of orthopaedists in the study group. LEVEL OF EVIDENCE: IV.

Variability and minimum detectable change for walking energy efficiency variables in children with cerebral palsy.

For individuals with neuromuscular disorders, the assessment of walking energy efficiency is useful as a clinical outcome measure. Issues surrounding data collection methodology, normalization of the data, and variability and clinical utility of energy efficiency data preclude universal application. This study examined the variability and the clinical utility of velocity, energy efficiency index (EEI), gross cost, and net nondimensional cost (NNcost) in children and adolescents with spastic diplegic cerebral palsy (CP) in Gross Motor Function Classification System (GMFCS) levels I to III. The energy efficiency of walking was evaluated in 23 children and adolescents (12 males, 11 females, mean age 11y 3mo [SD 3y 5mo]; range 7-17y). Day-to-day variability was similar for all energy efficiency variables, with no significant differences in magnitude of variability between GMFCS levels. Correlations between EEI and gross cost and EEI and NNcost were fairly good (r=0.65, p<0.001, and r=0.74, p<0.001 respectively). However, only gross cost and NNcost discriminated between GMFCS levels in children with CP. Gross cost required the greatest amount of change to be considered clinically significant, whereas NNcost and EEI required a similar amount of change. For cohorts of children with CP who are evaluated over time, NNcost is the best normalization method as it reduces the variability between participants of different ages, height, and weight while evaluating only the amount of energy used to ambulate.

Orthopaedic manifestations of congenital myotonic dystrophy during childhood and adolescence.

BACKGROUND: Congenital myotonic dystrophy (CMD) is a dominantly inherited disorder manifested in childhood by muscle weakness which can be profound at birth, but which progressively improves over the first few years. Congenital myotonic dystrophy represents the severe end of the spectrum of myotonic dystrophy, which in milder cases may not be diagnosed until adulthood. The goal of the study was to identify and quantitate the musculoskeletal deformities which may significantly affect the function of children with CMD. METHODS: A retrospective chart and radiograph review was performed after Institutional Review Board approval for all cases of myotonic dystrophy from 1987 to 2004 followed at a children's specialty orthopaedic hospital. Inclusion criteria were either a conclusive testing for CMD by gene testing, electromyography, and/or muscle biopsy in the child or parent and the presence of a typical clinical picture. Skeletal manifestations were classified by body segment (upper extremity, hand, spine, hip, lower extremity, foot) and by the type of deformity. Surgical procedures and outcomes were also documented. RESULTS: Thirty children and adolescents met the inclusion criteria. The male/female ratio was 1 (15 boys and 15 girls). In 27 cases, the mother transmitted the disease, and in 2 cases, the father transmitted the disease; in one case, it was impossible to reconstitute the family history of the child who was adopted. The mean age at onset of gait was 29 months. Twenty-two (73%) out of 30 children underwent surgery for lower extremity-, foot-, or spinal-related deformities. The mean follow-up was 11.4 years (range, 3-20 years).No contractures or deformities were observed in the upper extremities. Spinal deformities affected 9 patients (30%), and 3 of these required surgery. These spinal deformities when present usually had an early onset and included thoracolumbar scoliosis as well as kyphoscoliosis. Problems at the level of the hips and knee were infrequent and included only 2 patients who had unilateral hip abduction contracture and 1 patient who had significant fixed knee flexion contracture. Congenital clubfoot occurred in 5 patients (17%) and generally responded well after posteromedial release and recurrence occurred in only one case. Developmental equinus and equinovarus exclusive of clubfoot affected 7 patients (23%), 70% of whom required surgery. Outcome after Achilles tendon lengthening was positive, and many of the children began walking soon after the Achilles lengthening, and recurrence did not occur. CONCLUSIONS: Child with CMD are at high risk for musculoskeletal deformities of the spine and lower extremities. In our experience, correction and improved function were likely after surgery. LEVEL OF EVIDENCE: Retrospective study; level IV.

Iliopsoas tenotomy at the lesser trochanter versus at the pelvic brim in ambulatory children with cerebral palsy.

BACKGROUND: Progressive hip flexion deformity is a common problem in ambulatory children with spastic cerebral palsy, causing static and dynamic deformity. The iliopsoas muscle is recognized as a major deforming force in the development of this problem. Many clinicians address this problem by lengthening the iliopsoas, either in an intramuscular location at the pelvic brim or by complete tenotomy at the lesser trochanter. The goal of this study was to compare the outcomes of patients with ambulatory cerebral palsy who had intramuscular lengthening at the pelvic brim to those who underwent complete release of the iliopsoas tendon at the level of the lesser trochanter. METHODS: Twenty patients were included in the study, 11 of whom had iliopsoas release at the lesser trochanter (group 1) and 9 of whom had intramuscular lengthening at the pelvic brim (group 2). All patients had physical examinations, plus kinematic and kinetic analyses in our gait laboratory before and 1 year after surgery. RESULTS: Hip flexion contracture was decreased significantly only in group 1, although there was a trend of decrease in group 2. There was a significant increase in maximum hip extension in terminal stance and a reciprocal decrease in maximum swing phase hip flexion in group 1, with a similar trend that did not reach significance in group 2. Stride length increased significantly in both groups. There was no significant change in power generation of hip flexion during the swing phase in either group. CONCLUSIONS: We found improved static and dynamic parameters of hip extension after iliopsoas lengthening and did not detect any adverse kinematic or kinetic change in hip function after surgery. The improvement was more robust in the group who underwent release at the lesser trochanter. Because there are no adverse effects of iliopsoas release from the lesser trochanter and the improvement in hip extension is greater, this approach should be considered in ambulatory patients with spastic diplegia when a hip flexor weakening procedure is considered. LEVEL OF EVIDENCE: Comparative cohort study, level III, case-control study.

Respiratory Management of the Patient With Duchenne Muscular Dystrophy.

In 2010, Care Considerations for Duchenne Muscular Dystrophy, sponsored by the Centers for Disease Control and Prevention, was published in Lancet Neurology, and in 2018, these guidelines were updated. Since the publication of the first set of guidelines, survival of individuals with Duchenne muscular dystrophy has increased. With contemporary medical management, survival often extends into the fourth decade of life and beyond. Effective transition of respiratory care from pediatric to adult medicine is vital to optimize patient safety, prognosis, and quality of life. With genetic and other emerging drug therapies in development, standardization of care is necessary to accurately assess treatment effects in clinical trials. This revision of respiratory recommendations preserves a fundamental strength of the original guidelines: namely, reliance on a limited number of respiratory tests to guide patient assessment and management. A progressive therapeutic strategy is presented that includes lung volume recruitment, assisted coughing, and assisted ventilation (initially nocturnally, with the subsequent addition of daytime ventilation for progressive respiratory failure). This revision also stresses the need for serial monitoring of respiratory muscle strength to characterize an individual's respiratory phenotype of severity as well as provide baseline assessments for clinical trials. Clinical controversies and emerging areas are included.

American College of Chest Physicians consensus statement on the respiratory and related management of patients with Duchenne muscular dystrophy undergoing anesthesia or sedation.

This statement on the management of patients with Duchenne muscular dystrophy (DMD) undergoing procedural sedation or general anesthesia represents the consensus opinion of a multidisciplinary panel convened under the auspices of the American College of Chest Physicians. Expert recommendations on this subject are needed for several reasons. First, patients with DMD have an increased risk of complications when they undergo sedation or general anesthesia. In addition, due to improved cardiopulmonary therapies, patients with DMD are experiencing an unprecedented duration of survival. As a result, it is more common for them to require procedures involving sedation or general anesthesia. The risks related to anesthesia and sedation for DMD patients include potentially fatal reactions to inhaled anesthetics and certain muscle relaxants, upper airway obstruction, hypoventilation, atelectasis, congestive heart failure, cardiac dysrhythmias, respiratory failure, and difficulty weaning from mechanical ventilation. This statement includes advice regarding the highly interrelated areas of respiratory, cardiac, GI, and anesthetic management of patients with DMD undergoing general anesthesia or procedural sedation. The statement is intended to aid clinicians involved in the care of patients with DMD and to be a resource for other stakeholders in this field, including patients and their families. It is an up-to-date summary of medical literature regarding this topic and identifies areas in need of future research.

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

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

Stair locomotion in children with spastic hemiplegia: the impact of three different ankle foot orthosis (AFOs) configurations.

The purpose of this study was to investigate the impact of three different ankle foot orthoses (AFO) configurations on the function and kinematics of stair locomotion in children with spastic hemiplegia. Nineteen children were evaluated barefoot and with a hinged, posterior leaf spring (PLS) and solid AFO during stair ascent and descent. Stair specific items from the Pediatric Evaluation of Disability Inventory (PEDI) were used to evaluate function, while a motion measurement system was used to evaluate kinematics. The PEDI revealed no significant differences between AFOs and barefoot, although a greater percentage of children were able to keep up with their peers while wearing a hinged AFO. At the ankle, the hinged AFO provided the greatest amount of dorsiflexion during stance. All AFOs reduced plantarflexion in comparison to barefoot. The results of this study indicate that for children with spastic hemiplegia the use of an AFO did not impair stair ambulation.

Treatment of spastic diplegia in patients with cerebral palsy.

Appropriate treatment, which includes orthopaedic surgery, physical and occupational therapy, recreational therapy, orthotics, and utilization of assistive devices, will improve the functional outcomes of children with cerebral palsy. Medical modalities such as intramuscular injections of botulinum toxin, and constant intrathecal administration of Baclofen via an implanted pump may also be of benefit. There is a defined set of orthopaedic surgical procedures that can enhance function, and the challenge for the surgeon is to identify which combination of procedures is appropriate for each individual patient and at what point during development to implement them. Some surgeons prefer to wait until patients are older (8-10 years) and perform all of their surgical interventions in one sitting. We, however, favor a different approach wherein surgical procedures are done as indicated during childhood development to enhance function and allow further improvement of motor skills. We refer to this approach as 'Staged Multilevel Interventions in the Lower Extremity' or 'SMILE'. This paper will discuss the rationale for this approach and our recommendations regarding the indications and timing of surgical interventions, as well as techniques and outcomes as reported in the literature.