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Abstract Background The interface between research and policymaking in low-income countries is highly complex. The ability of health systems research to influence policy processes in such settings face numerous challenges. Successful analysis of the research-policy interface in these settings requires understanding of contextual factors as well as key influences on the interface. Future Health Systems (FHS): Innovations for Equity is a consortium conducting research in six countries in Asia and Africa. One of the three cross-country research themes of the consortium is analysis of the relationship between research (evidence) and policy making, especially their impact on the poor; insights gained in the initial conceptual phase of FHS activities can inform the global knowledge pool on this subject. Discussion This paper provides a review of the research-policy interface in low-income countries and proposes a conceptual framework, followed by directions for empirical approaches. First, four developmental perspectives are considered: social institutional factors; virtual versus grassroots realities; science-society relationships; and construction of social arrangements. Building on these developmental perspectives three research-policy interface entry points are identified: 1. Recognizing policy as complex processes; 2. Engaging key stakeholders: decision-makers, providers, scientists, and communities; and 3. Enhancing accountability. A conceptual framework with three entry points to the research-policy interface – policy processes; stakeholder interests, values, and power; and accountability – within a context provided by four developmental perspectives is proposed. Potential empirical approaches to the research-policy interface are then reviewed. Finally, the value of such innovative empirical analysis is considered. Conclusion The purpose of this paper is to provide the background, conceptual framework, and key research directions for empirical activities focused on the research-policy interface in low income settings. The interface can be strengthened through such analysis leading to potential improvements in population health in low-income settings. Health system development cognizant of the myriad factors at the research-policy interface can form the basis for innovative future health systems.

Biallelic pathogenic variants in the gene encoding nebulin (NEB) are a known cause of congenital myopathy. We present two brothers with congenital myopathy and compound heterozygous variants (NC_000002.12:g.151692086G>T; NM_001271208.2: c.2079C>A; p.(Cys693Ter) and NC_000002.12:g.151533439T>C; NM_001271208.2:c.21522+3A>G) in NEB. Transcriptomic sequencing on affected individual muscles revealed that the extended splice variant c.21522+3A>G causes exon 144 skipping. Nebulin isoforms containing exon 144 are known to be mutually exclusive with isoforms containing exon 143, and these isoforms are differentially expressed during development and in adult skeletal muscles. Affected individuals' MRI patterns of muscle involvement were compared with the known pattern of relative abundance of these two isoforms in muscle. We propose that the pattern of muscle involvement in these affected individuals better fits the distribution of exon 144-containing isoforms in muscle than with previously published MRI findings in NEB-related disease due to other variants. Our report introduces disease pathogenesis and manifestation as a result of alteration of isoform distributions in muscle., Competing Interests: Declaration of interests The authors declare no competing interests., (Published by Elsevier Inc.)

Background and Objectives: Omigapil is a small molecule which inhibits the GAPDH-Siah1-mediated apoptosis pathway. Apoptosis is a pathomechanism underlying the congenital muscular dystrophy subtypes LAMA2-related dystrophy (LAMA2-RD) and COL6-related dystrophy (COL6-RD). Studies of omigapil in the (dy w /dy w ) LAMA2-RD mouse model demonstrated improved survival, and studies in the (dy 2J /dy 2J ) LAMA2-RD mouse model and the (Col6a1 -/- ) COL6-RD mouse model demonstrated decreased apoptosis., Methods: A phase 1 open-label, sequential group, ascending oral dose, cohort study of omigapil in patients with LAMA2-RD or COL6-RD ages 5-16 years was performed (1) to establish the pharmacokinetic (PK) profile of omigapil at a range of doses, (2) to evaluate the safety and tolerability of omigapil at a range of doses, and (3) to establish the feasibility of conducting disease-relevant clinical assessments. Patients were enrolled in cohorts of size 4, with each patient receiving 4 weeks of vehicle run-in and 12 weeks of study drug (at daily doses ranging from 0.02 to 0.08 mg/kg). PK data from each cohort were analyzed before each subsequent dosing cohort was enrolled. A novel, adaptive dose-finding method (stochastic approximation with virtual observation recursion) was used to allow for dose escalation/reduction between cohorts based on PK data., Results: Twenty patients were enrolled at the NIH (LAMA2-RD: N = 10; COL6-RD: N = 10). Slightly greater than dose-proportional increases in systemic exposure to omigapil were seen at doses 0.02-0.08 mg/kg/d. The dose which achieved patient exposure within the pre-established target area under the plasma concentration-vs-time curve (AUC 0-24h ) range was 0.06 mg/kg/d. In general, omigapil was safe and well tolerated. No consistent changes were seen in the disease-relevant clinical assessments during the duration of the study., Discussion: This study represents the thus far only clinical trial of a therapeutic small molecule for LAMA2-RD and COL6-RD, completed with an adaptive trial design to arrive at dose adjustments. The trial met its primary end point and established that the PK profile of omigapil is suitable for further development in pediatric patients with LAMA2-RD or COL6-RD, the most common forms of congenital muscular dystrophy. While within the short duration of the study disease-relevant clinical assessments did not demonstrate significant changes, this study establishes the feasibility of performing interventional clinical trials in these rare disease patient populations., Classification of Evidence: This study provides Class IV evidence of omigapil in a dose-finding phase 1 study., Trial Registration Information: Clinical Trials NCT01805024., Competing Interests: A.R. Foley, P. Yun, M.E. Leach, S. Neuhaus, G. Averion, Y. Hu, L.H. Hayes, S. Donkervoort, M. Jain, M. Waite, R. Parks, D.X. Bharucha-Goebel, O.H. Mayer, Y. Zou, M. Fink, J. DeCoster, C. Mendoza, C. Arévalo, and K. Cheung report no disclosures relevant to the manuscript; R. Hausmann was an employee and a shareholder of Santhera Pharmaceuticals at the time of this study; D. Petraki was an employee of Santhera Pharmaceuticals at the time of this study; C.G. Bönnemann was the site principal investigator for this study sponsored by Santhera Pharmaceuticals. Go to Neurology.org/NG for full disclosures., (Written work prepared by employees of the Federal Government as part of their official duties is, under the U.S. Copyright Act, a “work of the United States Government” for which copyright protection under Title 17 of the United States Code is not available. As such, copyright does not extend to the contributions of employees of the Federal Government.)

Collagen VI-related dystrophies (COL6-RDs) manifest with a spectrum of clinical phenotypes, ranging from Ullrich congenital muscular dystrophy (UCMD), presenting with prominent congenital symptoms and characterised by progressive muscle weakness, joint contractures and respiratory insufficiency, to Bethlem muscular dystrophy, with milder symptoms typically recognised later and at times resembling a limb girdle muscular dystrophy, and intermediate phenotypes falling between UCMD and Bethlem muscular dystrophy. Despite clinical and immunohistochemical features highly suggestive of COL6-RD, some patients had remained without an identified causative variant in COL6A1 , COL6A2 or COL6A3 . With combined muscle RNA-sequencing and whole-genome sequencing we uncovered a recurrent, de novo deep intronic variant in intron 11 of COL6A1 (c.930+189C>T) that leads to a dominantly acting in-frame pseudoexon insertion. We subsequently identified and have characterised an international cohort of forty-four patients with this COL6A1 intron 11 causative variant, one of the most common recurrent causative variants in the collagen VI genes. Patients manifest a consistently severe phenotype characterised by a paucity of early symptoms followed by an accelerated progression to a severe form of UCMD, except for one patient with somatic mosaicism for this COL6A1 intron 11 variant who manifests a milder phenotype consistent with Bethlem muscular dystrophy. Characterisation of this individual provides a robust validation for the development of our pseudoexon skipping therapy. We have previously shown that splice-modulating antisense oligomers applied in vitro effectively decreased the abundance of the mutant pseudoexon-containing COL6A1 transcripts to levels comparable to the in vivo scenario of the somatic mosaicism shown here, indicating that this therapeutic approach carries significant translational promise for ameliorating the severe form of UCMD caused by this common recurrent COL6A1 causative variant to a Bethlem muscular dystrophy phenotype.

Biallelic pathogenic variants in the gene encoding nebulin ( NEB ) are a known cause of congenital myopathy. We present two individuals with congenital myopathy and compound heterozygous variants (NM_001271208.2: c.2079C>A; p.(Cys693Ter) and c.21522+3A>G ) in NEB. Transcriptomic sequencing on patient muscle revealed that the extended splice variant c.21522+3A>G causes exon 144 skipping. Nebulin isoforms containing exon 144 are known to be mutually exclusive with isoforms containing exon 143, and these isoforms are differentially expressed during development and in adult skeletal muscles. Patients MRIs were compared to the known pattern of relative abundance of these two isoforms in muscle. We propose that the pattern of muscle involvement in these patients better fits the distribution of exon 144-containing isoforms in muscle than with previously published MRI findings in NEB -related disease due to other variants. To our knowledge this is the first report hypothesizing disease pathogenesis through the alteration of isoform distributions in muscle., Competing Interests: Declaration of interests The authors have no conflicts of interest to declare

Purpose: We sought to delineate a multisystem disorder caused by recessive cysteine-rich with epidermal growth factor-like domains 1 (CRELD1) gene variants., Methods: The impact of CRELD1 variants was characterized through an international collaboration utilizing next-generation DNA sequencing, gene knockdown, and protein overexpression in Xenopus tropicalis, and in vitro analysis of patient immune cells., Results: Biallelic variants in CRELD1 were found in 18 participants from 14 families. Affected individuals displayed an array of phenotypes involving developmental delay, early-onset epilepsy, and hypotonia, with about half demonstrating cardiac arrhythmias and some experiencing recurrent infections. Most harbored a frameshift in trans with a missense allele, with 1 recurrent variant, p.(Cys192Tyr), identified in 10 families. X tropicalis tadpoles with creld1 knockdown displayed developmental defects along with increased susceptibility to induced seizures compared with controls. Additionally, human CRELD1 harboring missense variants from affected individuals had reduced protein function, indicated by a diminished ability to induce craniofacial defects when overexpressed in X tropicalis. Finally, baseline analyses of peripheral blood mononuclear cells showed similar proportions of immune cell subtypes in patients compared with healthy donors., Conclusion: This patient cohort, combined with experimental data, provide evidence of a multisystem clinical syndrome mediated by recessive variants in CRELD1., Competing Interests: Conflict of Interest Two authors report part ownership of startup companies unrelated to this work: Qiyas Higher Health (Saquib A. Lakhani) and Victory Genomics (Saquib A. Lakhani and Mustafa K. Khokha). Kirsty McWalter is an employee of GeneDx. Kimberly Nugent is currently an employee of Cooper Surgical. Bryan Mak is currently an employee of Genome Medical. All other authors declare no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To accurately categorize the phenotypes of individuals with collagen VI-related dystrophies (COL6-RDs) during the first years of life to predict long-term motor function and pulmonary function, to provide phenotype-specific anticipatory care, and to improve clinical trial readiness., Methods: This retrospective, multicenter, international study analyzed the relationship of long-term motor and pulmonary function with the initial maximal motor ability achieved in individuals with COL6-RD., Results: We studied 119 patients with COL6-RD from Spain (n = 54) and the United States (n = 65). The early maximal motor milestones of ability to rise from the floor unassisted and ability to climb 4 steps without holding onto a railing demonstrated reliability in distinguishing between 3 COL6-RD phenotypic subgroups: (1) Ullrich congenital muscular dystrophy, (2) intermediate COL6-RD, and (3) Bethlem myopathy. Long-term motor function and pulmonary function are strongly correlated with the maximal motor ability achieved during the first years of life. Maximal motor capacity can predict other disease-relevant events such as the age at loss of ambulation and the need for the initiation of nocturnal noninvasive ventilation., Conclusion: This work proposes a prospective phenotypic classification for COL6-RDs that will enable an accurate prediction of a patient's COL6-RD phenotype during the first years of life. The ability to establish a patient's COL6-RD phenotypic classification early will enable a more accurate prognosis of future motor and pulmonary function, thus improving anticipatory clinical care, and it will be instrumental in aiding the design of future clinical trials by allowing early stratification of trial cohorts., (© 2021 American Academy of Neurology.)

Background: Only a few small studies have previously reported episodes of hypoglycemia in children with neuromuscular diseases; however, there has been no broader investigation into the occurrence of hypoglycemia in children with congenital muscle disease (CMD)., Methods: Pediatric patients enrolled in the CMD International Registry (CMDIR) with a history of hypoglycemia were included in this retrospective review. Hypoglycemic episodes and associated clinical and biochemical characteristics were characterized., Results: Ten patients with CMD (5 with LAMA2-related muscular dystrophy) reported at least one episode of hypoglycemia beginning at an average age of 3.5 years. Predominant symptoms included altered mental status and nausea/vomiting, and laboratory studies demonstrated metabolic acidosis and ketonuria, consistent with ketotic hypoglycemia., Conclusion: Patients with CMD may have an increased risk of hypoglycemia during fasting, illness, or stress due to their relatively low muscle mass and hence, paucity of gluconeogenic substrate. Clinicians should therefore maintain a high index of suspicion for hypoglycemia in this high-risk patient population and caregivers should routinely be trained to recognize and treat hypoglycemia.

MSTO1 encodes a cytosolic mitochondrial fusion protein, misato homolog 1 or MSTO1. While the full genotype-phenotype spectrum remains to be explored, pathogenic variants in MSTO1 have recently been reported in a small number of patients presenting with a phenotype of cerebellar ataxia, congenital muscle involvement with histologic findings ranging from myopathic to dystrophic and pigmentary retinopathy. The proposed underlying pathogenic mechanism of MSTO1-related disease is suggestive of impaired mitochondrial fusion secondary to a loss of function of MSTO1. Disorders of mitochondrial fusion and fission have been shown to also lead to mitochondrial DNA (mtDNA) depletion, linking them to the mtDNA depletion syndromes, a clinically and genetically diverse class of mitochondrial diseases characterized by a reduction of cellular mtDNA content. However, the consequences of pathogenic variants in MSTO1 on mtDNA maintenance remain poorly understood. We present extensive phenotypic and genetic data from 12 independent families, including 15 new patients harbouring a broad array of bi-allelic MSTO1 pathogenic variants, and we provide functional characterization from seven MSTO1-related disease patient fibroblasts. Bi-allelic loss-of-function variants in MSTO1 manifest clinically with a remarkably consistent phenotype of childhood-onset muscular dystrophy, corticospinal tract dysfunction and early-onset non-progressive cerebellar atrophy. MSTO1 protein was not detectable in the cultured fibroblasts of all seven patients evaluated, suggesting that pathogenic variants result in a loss of protein expression and/or affect protein stability. Consistent with impaired mitochondrial fusion, mitochondrial networks in fibroblasts were found to be fragmented. Furthermore, all fibroblasts were found to have depletion of mtDNA ranging from 30 to 70% along with alterations to mtDNA nucleoids. Our data corroborate the role of MSTO1 as a mitochondrial fusion protein and highlight a previously unrecognized link to mtDNA regulation. As impaired mitochondrial fusion is a recognized cause of mtDNA depletion syndromes, this novel link to mtDNA depletion in patient fibroblasts suggests that MSTO1-deficiency should also be considered a mtDNA depletion syndrome. Thus, we provide mechanistic insight into the disease pathogenesis associated with MSTO1 mutations and further define the clinical spectrum and the natural history of MSTO1-related disease.

Objective: Comprehensive clinical characterization of congenital titinopathy to facilitate diagnosis and management of this important emerging disorder., Methods: Using massively parallel sequencing we identified 30 patients from 27 families with 2 pathogenic nonsense, frameshift and/or splice site TTN mutations in trans. We then undertook a detailed analysis of the clinical, histopathological and imaging features of these patients., Results: All patients had prenatal or early onset hypotonia and/or congenital contractures. None had ophthalmoplegia. Scoliosis and respiratory insufficiency typically developed early and progressed rapidly, whereas limb weakness was often slowly progressive, and usually did not prevent independent walking. Cardiac involvement was present in 46% of patients. Relatives of 2 patients had dilated cardiomyopathy. Creatine kinase levels were normal to moderately elevated. Increased fiber size variation, internalized nuclei and cores were common histopathological abnormalities. Cap-like regions, whorled or ring fibers, and mitochondrial accumulations were also observed. Muscle magnetic resonance imaging showed gluteal, hamstring and calf muscle involvement. Western blot analysis showed a near-normal sized titin protein in all samples. The presence of 2 mutations predicted to impact both N2BA and N2B cardiac isoforms appeared to be associated with greatest risk of cardiac involvement. One-third of patients had 1 mutation predicted to impact exons present in fetal skeletal muscle, but not included within the mature skeletal muscle isoform transcript. This strongly suggests developmental isoforms are involved in the pathogenesis of this congenital/early onset disorder., Interpretation: This detailed clinical reference dataset will greatly facilitate diagnostic confirmation and management of patients, and has provided important insights into disease pathogenesis. Ann Neurol 2018;83:1105-1124., (© 2018 American Neurological Association.)

Introduction: Electrical impedance myography (EIM) is a noninvasive electrophysiological technique that characterizes muscle properties through bioimpedance. We compared EIM measurements to function, strength, and disease severity in a population with congenital muscular dystrophy (CMD)., Methods: Forty-one patients with CMD, either collagen 6 related disorders (COL6-RD; n = 21) or laminin α-2-related disorders (LAMA2-RD; n = 20), and 21 healthy pediatric controls underwent 2 yearly EIM exams. In the CMD cohorts, EIM was compared with functional and strength measurements., Results: Both CMD cohorts exhibited change over time and had correlation with disease severity. The 50-kHZ phase correlated well with function and strength in the COL6-RD cohort but not in the LAMA2-RD cohort., Discussion: EIM is a potentially useful measure in clinical studies with CMD because of its sensitivity to change over a 1-year period and correlation with disease severity. For COL6-RD, there were also functional and strength correlations. Muscle Nerve 57: 54-60, 2018., (© 2017 Wiley Periodicals, Inc.)

Collagen prolyl 4-hydroxylases (C-P4Hs) play a central role in the formation and stabilization of the triple helical domain of collagens. P4HA1 encodes the catalytic α(I) subunit of the main C-P4H isoenzyme (C-P4H-I). We now report human bi-allelic P4HA1 mutations in a family with a congenital-onset disorder of connective tissue, manifesting as early-onset joint hypermobility, joint contractures, muscle weakness and bone dysplasia as well as high myopia, with evidence of clinical improvement of motor function over time in the surviving patient. Similar to P4ha1 null mice, which die prenatally, the muscle tissue from P1 and P2 was found to have reduced collagen IV immunoreactivity at the muscle basement membrane. Patients were compound heterozygous for frameshift and splice site mutations leading to reduced, but not absent, P4HA1 protein level and C-P4H activity in dermal fibroblasts compared to age-matched control samples. Differential scanning calorimetry revealed reduced thermal stability of collagen in patient-derived dermal fibroblasts versus age-matched control samples. Mutations affecting the family of C-P4Hs, and in particular C-P4H-I, should be considered in patients presenting with congenital connective tissue/myopathy overlap disorders with joint hypermobility, contractures, mild skeletal dysplasia and high myopia., (Published by Oxford University Press 2017. This work is written by US Government employees and is in the public domain in the US.)

Mutations in ACTA1 cause a group of myopathies with expanding clinical and histopathological heterogeneity. We describe three patients with severe ACTA1-related myopathy who have muscle fiber cytoplasmic bodies but no classic nemaline rods. Patient 1 is a five-year-old boy who presented at birth with severe weakness and respiratory failure, requiring mechanical ventilation. Whole exome sequencing identified a heterozygous c.282C>A (p.Asn94Lys) ACTA1 mutation. Patients 2 and 3 were twin boys with hypotonia, severe weakness, and respiratory insufficiency at birth requiring mechanical ventilation. Both died at 6 months of age. The same heterozygous c.282C>A (p.Asn94Lys) ACTA1 mutation was identified by whole exome sequencing. We conclude that clinically severe ACTA1-related myopathy can present with muscle morphological findings suggestive of cytoplasmic body myopathy in the absence of definite nemaline rods. The Asn94Lys mutation in skeletal muscle sarcomeric α-actin may be linked to this histological appearance. These novel ACTA1 cases also illustrate the successful application of whole exome sequencing in directly arriving at a candidate genetic diagnosis in patients with unexpected phenotypic and histologic features for a known neuromuscular gene., (Copyright © 2017. Published by Elsevier B.V.)

Congenital muscular dystrophy (CMD) comprises a rare group of genetic muscle diseases that present at birth or early during infancy. Two common subtypes of CMD are collagen VI-related muscular dystrophy (COL6-RD) and laminin alpha 2-related dystrophy (LAMA2-RD). Traditional outcome measures in CMD include gross motor and mobility assessments, yet significant motor declines underscore the need for valid upper extremity motor assessments as a clinical endpoint. This study validated a battery of upper extremity measures in these two CMD subtypes for future clinical trials. For this cross-sectional study, 42 participants were assessed over the same 2-5 day period at the National Institutes of Health Clinical Center. All upper extremity measures were correlated with the Motor Function Measure 32 (MFM32). The battery of upper extremity assessments included the Jebsen Taylor Hand Function Test, Quality of Upper Extremity Skills Test (QUEST), hand held dynamometry, goniometry, and MyoSet Tools. Spearman Rho was used for correlations to the MFM32. Pearson was performed to correlate the Jebsen, QUEST, hand-held dynamometry, goniometry and the MyoSet Tools. Correlations were considered significant at the 0.01 level (2-tailed). Significant correlations were found between both the MFM32 and MFM Dimension 3 only (Distal Motor function) and the Jebsen, QUEST, MyoGrip and MyoPinch, elbow flexion/extension ROM and myometry. Additional correlations between the assessments are reported. The Jebsen, the Grasp and Dissociated Movements domains of the QUEST, the MyoGrip and the MyoPinch tools, as well as elbow ROM and myometry were determined to be valid and feasible in this population, provided variation in test items, and assessed a range of difficulty in CMD. To move forward, it will be of utmost importance to determine whether these upper extremity measures are reproducible and sensitive to change over time., (Copyright © 2016 Elsevier B.V. All rights reserved.)

A quality improvement project to reduce paediatric prescribing errors was carried out in a London teaching hospital between June 2013 and March 2014. It involved paediatric medical and surgical wards and a paediatric intensive care unit. A multi professional team of 'prescribing champions' was formed. Baseline audit identified high prescribing error rate. Prescribing standards were taught through workshops and 'prescribing test'. Feedback of weekly sampling and 'star chart game' led to an initial improvement of prescribing errors which was not sustained. Qualitative feedback showed increased knowledge and empowerment of multi-professional stakeholders., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Hereditary spastic paraplegias are a clinically and genetically heterogeneous group of disorders characterized by lower extremity spasticity and weakness. Recently, the first de novo mutations in KIF1A were identified in patients with an early-onset severe form of complicated hereditary spastic paraplegia. We report two additional patients with novel de novo mutations in KIF1A, hereby expanding the genetic spectrum of KIF1A-related hereditary spastic paraplegia. Both children presented with spastic paraplegia and additional findings of optic nerve atrophy, structural brain abnormalities, peripheral neuropathy, cognitive/language impairment, and never achieved ambulation. In particular, we highlight the progressive nature of cerebellar involvement as captured on sequential magnetic resonance images (MRIs), thus linking the neurodegenerative and spastic paraplegia phenotypes. Exome sequencing in patient 1 and patient 2 identified novel heterozygous missense mutations in KIF1A at c.902G>A (p.R307Q) and c.595G>A (p.G199 R), respectively. Therefore, our report contributes to expanding the genotypic and phenotypic spectrum of hereditary spastic paraplegia caused by mutations in KIF1A., Competing Interests: The authors declare no conflict of interest., (© The Author(s) 2016.)

Collagen 6-related dystrophies and myopathies (COL6-RD) are a group of disorders that form a wide phenotypic spectrum, ranging from severe Ullrich congenital muscular dystrophy, intermediate phenotypes, to the milder Bethlem myopathy. Both inter- and intrafamilial variable expressivity are commonly observed. We present clinical, immunohistochemical, and genetic data on four COL6-RD families with marked intergenerational phenotypic heterogeneity. This variable expression seemingly masquerades as anticipation is due to parental mosaicism for a dominant mutation, with subsequent full inheritance and penetrance of the mutation in the heterozygous offspring. We also present an additional fifth simplex patient identified as a mosaic carrier. Parental mosaicism was confirmed in the four families through quantitative analysis of the ratio of mutant versus wild-type allele (COL6A1, COL6A2, and COL6A3) in genomic DNA from various tissues, including blood, dermal fibroblasts, and saliva. Consistent with somatic mosaicism, parental samples had lower ratios of mutant versus wild-type allele compared with the fully heterozygote offspring. However, there was notable variability of the mutant allele levels between tissues tested, ranging from 16% (saliva) to 43% (fibroblasts) in one mosaic father. This is the first report demonstrating mosaicism as a cause of intrafamilial/intergenerational variability of COL6-RD, and suggests that sporadic and parental mosaicism may be more common than previously suspected., (© 2014 WILEY PERIODICALS, INC.)

Objective: To develop and validate an English version of the Neuromuscular (NM)-Score, a classification for patients with NM diseases in each of the 3 motor function domains: D1, standing and transfers; D2, axial and proximal motor function; and D3, distal motor function., Design: Validation survey., Setting: Patients seen at a medical research center between June and September 2013., Participants: Consecutive patients (N=42) aged 5 to 19 years with a confirmed or suspected diagnosis of congenital muscular dystrophy., Interventions: Not applicable., Main Outcome Measures: An English version of the NM-Score was developed by a 9-person expert panel that assessed its content validity and semantic equivalence. Its concurrent validity was tested against criterion standards (Brooke Scale, Motor Function Measure [MFM], activity limitations for patients with upper and/or lower limb impairments [ACTIVLIM], Jebsen Test, and myometry measurements). Informant agreement between patient/caregiver (P/C)-reported and medical doctor (MD)-reported NM scores was measured by weighted kappa., Results: Significant correlation coefficients were found between NM scores and criterion standards. The highest correlations were found between NM-score D1 and MFM score D1 (ρ=-.944, P<.0001), ACTIVLIM (ρ=-.895, P<.0001), and hip abduction strength by myometry (ρ=-.811, P<.0001). Informant agreement between P/C-reported and MD-reported NM scores was high for D1 (κ=.801; 95% confidence interval [CI], .701-.914) but moderate for D2 (κ=.592; 95% CI, .412-.773) and D3 (κ=.485; 95% CI, .290-.680). Correlation coefficients between the NM scores and the criterion standards did not significantly differ between P/C-reported and MD-reported NM scores., Conclusions: Patients and physicians completed the English NM-Score easily and accurately. The English version is a reliable and valid instrument that can be used in clinical practice and research to describe the functional abilities of patients with NM diseases., (Copyright © 2014 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.)

Duchenne muscular dystrophy (DMD) is caused by mutations in Dystrophin and affects 1 in 3600-6000 males. It is characterized by progressive weakness leading to loss of ambulation, respiratory insufficiency, cardiomyopathy, and scoliosis. We describe the unusual phenotype of 3 patients with skeletal dysplasias in whom an additional diagnosis of DMD was later established. Two unrelated boys presented with osteogenesis imperfecta due to point mutations in COL1A1 and were both subsequently found to have a 1 bp frameshift deletion in the Dystrophin gene at age 3 and age 15 years, respectively. The third patient had a diagnosis of pseudoachondroplasia caused by a mutation in the COMP gene and was found to have a deletion of exons 48-50 in Dystrophin at age 9. We discuss the atypical presentation caused by the concomitant presence of 2 conditions affecting the musculoskeletal system, emphasizing aspects that may confound the presentation of a well-characterized disease like DMD. Additional series of patients with DMD and a secondary inherited condition are necessary to establish the natural history in this "double trouble" population. The recognition and accurate diagnosis of patients with two independent genetic disease processes is essential for management, prognosis, genetic risk assessment, and discussion regarding potential therapeutic interventions., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Objective: Relatively minor abusive injuries can precede severe physical abuse in infants. Our objective was to determine how often abused infants have a previous history of "sentinel" injuries, compared with infants who were not abused., Methods: Case-control, retrospective study of 401, <12-month-old infants evaluated for abuse in a hospital-based setting and found to have definite, intermediate concern for, or no abuse after evaluation by the hospital-based Child Protection Team. A sentinel injury was defined as a previous injury reported in the medical history that was suspicious for abuse because the infant could not cruise, or the explanation was implausible., Results: Of the 200 definitely abused infants, 27.5% had a previous sentinel injury compared with 8% of the 100 infants with intermediate concern for abuse (odds ratio: 4.4, 95% confidence interval: 2.0-9.6; P < .001). None of the 101 nonabused infants (controls) had a previous sentinel injury (P < .001). The type of sentinel injury in the definitely abused cohort was bruising (80%), intraoral injury (11%), and other injury (7%). Sentinel injuries occurred in early infancy: 66% at <3 months of age and 95% at or before the age of 7 months. Medical providers were reportedly aware of the sentinel injury in 41.9% of cases., Conclusions: Previous sentinel injuries are common in infants with severe physical abuse and rare in infants evaluated for abuse and found to not be abused. Detection of sentinel injuries with appropriate interventions could prevent many cases of abuse.

Objectives/hypothesis: To compare prehematopoietic stem cell transplantation (SCT) sinus computed tomography (CT) scans to post-SCT sinus CT scans and to evaluate the relationship between pre-SCT sinus CT scans and the incidence of otolaryngology consultation after SCT., Study Design: Retrospective chart review., Methods: Charts of 228 adult SCT patients from January 2003 to June 2009 with pre-SCT sinus CT scans were reviewed. Data gathered included diagnosis, type of SCT, otolaryngology referral requests, and rhinosinusitis management. Pre- and post-SCT sinus CT scans were scored using the staging system introduced by Lund and Mackay., Results: Two hundred thirty-nine SCTs were performed on the 228 patients included in this study. No disease was identified on 25.1% of pre-SCT CT scans, mild sinus inflammation was identified on 60.7% of scans, 11.3% had moderate inflammation, and 2.9% had severe inflammation. Pre-SCT scans were found to be predictive of post-SCT CT scans. A significant proportion of patients demonstrated worsening of their Lund-Mackay score post-SCT. Pre-SCT CT scores had no predictive ability for otolaryngology consultations., Conclusions: Pre-SCT CT scan scores are associated with post-SCT scan scores; disease severity on CT may worsen following SCT and may be useful for stratifying patients into surgical versus non-surgical candidates. Further study is needed to outline the benefit of sinus surgery in these patients., (Copyright © 2012 The American Laryngological, Rhinological, and Otological Society, Inc.)

Purpose: Elbow flexion posture, caused by spasticity of the muscles on the anterior surface of the elbow, is the most common elbow deformity seen in patients with cerebral palsy. This study retrospectively evaluated early results of 2 surgical interventions for elbow flexion deformities based on degree of contracture. We hypothesized that by guiding surgical treatment to degree of preoperative contracture, elbow extension and flexion posture angle at ambulation could be improved while preserving maximum flexion., Methods: Eighty-six patients (90 elbows) were treated for elbow spasticity due to cerebral palsy. Seventy-one patients (74 elbows) were available for follow-up. Fifty-seven patients with fixed elbow contractures less than 45° were surgically treated with a partial elbow muscle lengthening, which included partial lengthening of the biceps and brachialis and proximal release of the brachioradialis. Fourteen patients (17 elbows) with fixed elbow contractures ≥ 45° had a more extensive full elbow release, with biceps z-lengthening, partial brachialis myotomy, and brachioradialis proximal release., Results: Age at surgery averaged 10 years (range, 3-20 y) for partial lengthening and 14 years (range, 5-20 y) for full elbow release. Follow-up averaged 22 months (range, 7-144 mo) for partial lengthening and 18 months (range, 6-51 mo) for full elbow release. Both groups achieved meaningful improvement in flexion posture angle at ambulation, active and passive extension, and total range of motion. Elbow flexion posture angle at ambulation improved by 57° and active extension increased 17° in the partial lengthening group, with a 4° loss of active flexion. In the full elbow release group, elbow flexion posture angle at ambulation improved 51° and active extension improved 38°, with a loss of 19° of active flexion., Conclusions: Surgical treatment of spastic elbow flexion in cerebral palsy can improve deformity. We obtained excellent results by guiding the surgical intervention by the amount of preoperative elbow contracture., Type of Study/level of Evidence: Therapeutic IV., (Copyright © 2012 American Society for Surgery of the Hand. Published by Elsevier Inc. All rights reserved.)

Objective: To analyze malpractice litigation trends related to the administration of corticosteroids and the reported complications., Study Design: Retrospective., Setting: Tertiary medical center., Subjects and Methods: The WESTLAW database was reviewed from March 1996 to November 2008. Data were compiled on the demographics of the defendant, plaintiff, expert witness specialty, allegation, complication, indication for steroids, verdict, and judgment., Results: Eighty-three cases met inclusion criteria and were selected for review. The most common conditions for which steroids were prescribed were pain (23%), asthma or another pulmonary condition (20%), a dermatologic condition (18%), a nondermatologic autoimmune condition (17%), and allergies (6%). Allegation of negligent use was the most common reason for a suit being filed (65%), followed by lack of proper informed consent (36%), failure to diagnose or misdiagnosis (22%), multiple allegations (25%), and wrongful death (4%). Verdicts for the defendant predominated (59%), whereas 24 cases (29%) were found for the plaintiff, and 10 cases (12%) settled out of court. The range of monetary awards was from $25,000 to $8.1 million. Complications reported were often multiple and included avascular necrosis (39%), mood changes (16%), visual complaints (14%), and infectious complications (14%). Three cases involved otolaryngologists., Conclusion: Although other specialties were more often involved in suits, otolaryngologists frequently prescribe corticosteroids and must be diligent in explaining potential side effects of steroids. The informed consent process, documentation, and close monitoring of patients are critical to avoid potential litigation.

Surface plasmon resonance was employed to establish a quantitative assay for recombinant FVIII (rFVIII) products using rFVIII as standard. The anti-FVIII monoclonal antibody ESH4 was immobilized onto a carboxymethyldextran surface. A range of rFVIII concentrations were injected over the surface and the binding response enhanced by the addition of a further monoclonal antibody ESH8. Validation using National Institute of Biological Standards and Controls (NIBSC) sixth International rFVIII concentrate standard gave inter- and intra-assay coefficient of variations (CVs) of 7.5 and 3.68% respectively for ESH4-rFVIII binding alone. Enhancement of the binding signal by secondary addition of ESH8 produced inter- and intra-assay CVs of 2.75 and 1.5%. The ESH4 immobilized chip was found to retain binding capacity following regeneration for at least 75 cycles. The assay was found to be unsuitable for quantitation of plasma derived FVIII product but may prove useful for monitoring of rFVIII production.