Matthew B Dobbs

Washington University in St. Louis, San Luis, Missouri, United States

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Publications (133)426.94 Total impact

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    ABSTRACT: Background: Deletions of the HOXC gene cluster result in variable phenotypes in mice, but have been rarely described in humans. Objective: To report chromosome 12q13.13 microdeletions ranging from 13 to 175 kb and involving the 5' HOXC genes in four families, segregating congenital lower limb malformations, including clubfoot, vertical talus and hip dysplasia. Methods: Probands (N=253) with clubfoot or vertical talus were screened for point mutations and copy number variants using multiplexed direct genomic selection, a pooled BAC targeted capture approach. SNP genotyping included 1178 probands with clubfoot or vertical talus and 1775 controls. Results: The microdeletions share a minimal non-coding region overlap upstream of HOXC13, with variable phenotypes depending upon HOXC13, HOXC12 or the HOTAIR lncRNA inclusion. SNP analysis revealed HOXC11 p.Ser191Phe segregating with clubfoot in a small family and enrichment of HOXC12 p.Asn176Lys in patients with clubfoot or vertical talus (rs189468720, p=0.0057, OR=3.8). Defects in limb morphogenesis include shortened and overlapping toes, as well as peroneus muscle hypoplasia. Finally, HOXC and HOXD gene expression is reduced in fibroblasts from a patient with a 5' HOXC deletion, consistent with previous studies demonstrating that dosage of lncRNAs alters expression of HOXD genes in trans. Conclusions: Because HOXD10 has been implicated in the aetiology of congenital vertical talus, variation in its expression may contribute to the lower limb phenotypes occurring with 5' HOXC microdeletions. Identification of 5' HOXC microdeletions highlights the importance of transcriptional regulators in the aetiology of severe lower limb malformations and will improve their diagnosis and management.
    No preview · Article · Jan 2016 · Journal of Medical Genetics
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    ABSTRACT: Adolescent idiopathic scoliosis (AIS) is a complex inherited spinal deformity whose etiology has been elusive. While common genetic variants are associated with AIS, they explain only a small portion of disease risk. To explore the role of rare variants in AIS susceptibility, exome sequence data of 391 severe AIS cases and 843 controls of European ancestry were analyzed using a pathway burden analysis in which variants are first collapsed at the gene level then by Gene Ontology terms. Novel nonsynonymous/splice-site variants in extracellular matrix genes were significantly enriched in AIS cases compared to controls (P=6×10(-9), OR=1.7, CI=1.4-2.0). Specifically, novel variants in musculoskeletal collagen genes were present in 32% (126/391) of AIS cases compared to 17% (146/843) of in-house controls and 18% (780/4300) of EVS controls (P=1×10(-9), OR=1.9, CI=1.6-2.4). Targeted resequencing of six collagen genes replicated this association in combined 919 AIS cases (P=3x10(-12), OR=2.2, CI=1.8-2.7) and revealed a highly significant single-gene association with COL11A2 (P=6x10(-9), OR=3.8, CI=2.6-7.2). Importantly, AIS cases harbor mainly non-glycine missense mutations and lack the clinical features of monogenic musculoskeletal collagenopathies. Overall, our study reveals a complex genetic architecture of AIS in which a polygenic burden of rare variants across extracellular matrix genes contributes strongly to risk.
    Full-text · Article · Nov 2015 · Human Molecular Genetics
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    ABSTRACT: Adolescent idiopathic scoliosis (AIS) is the most common form of structural spinal deformities that have a radiological lateral Cobb angle — a measure of spinal curvature — of ≥10°. AIS affects between 1% and 4% of adolescents in the early stages of puberty and is more common in young women than in young men. The condition occurs in otherwise healthy individuals and currently has no recognizable cause. In the past few decades, considerable progress has been made towards understanding the clinical patterns and the three-dimensional pathoanatomy of AIS. Advances in biomechanics and technology and their clinical application, supported by limited evidence-based research, have led to improvements in the safety and outcomes of surgical and non-surgical treatments. However, the definite aetiology and aetiopathogenetic mechanisms that underlie AIS are still unclear. Thus, at present, both the prevention of AIS and the treatment of its direct underlying cause are not possible.
    Full-text · Article · Sep 2015
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    ABSTRACT: Background: Despite being recognized as the gold standard in isolated clubfoot treatment, the Ponseti casting method has yielded variable results. Few studies have directly compared common predictors of treatment failure between institutions with high versus low failure rates. Questions/purposes: We asked: (1) is the provider's rigid adherence to the Ponseti method associated with a lower likelihood of unplanned clubfoot surgery, and (2) at the institution that did not adhere rigidly to Ponseti's principles, are any demographic or treatment-related factors associated with increased likelihood of unplanned clubfoot surgery? Methods: After institutional review board approval, a consecutive series of patients with a diagnosis of isolated clubfoot who underwent treatment between January 2003 and December 2007 were identified. At Institution 1, 91 of 133 patients met the eligibility criteria and were followed for a minimum of 2 years compared with 58 of 58 patients at Institution 2. At Institution 1, 16 providers managed care using a conservative casting approach based on the Ponseti method. However, treatment was adapted by the provider(s). At Institution 2, one orthopaedic surgeon managed care with strict adherence to the Ponseti method. Surgical indications at both institutions included the presence of a persistent equinovarus foot position while standing. A chart review was used to collect data related to proportion of patients undergoing unplanned additional treatment for deformity recurrences after Ponseti casting, demographics, and treatment patterns. Results: The proportion of subjects who underwent unplanned major surgical intervention was greater (odds ratio [OR], 51.1; 95% CI, 6.8-384.0; p < 0.001) at Institution 1 (60 of 131, 47%) compared with Institution 2 (two of 91, 2%). There was no difference (p = 0.200) in the proportion of patients who underwent additional casting, repeat tendo Achilles lengthening, and/or anterior tibialis tendon transfer only (minor recurrence) at Institution 1 (nine of 131, 7%) compared with Institution 2 (11 of 91, 13%). At Institution 1, an increase in the number of revision casts (multiple vs no casts, hazard ratio [HR] = 3.9; 95% CI, 2.0-7.6; p < 0.001) and an increase in the number of cast-related complications (multiple vs no complications, HR = 2.8; 95% CI, 1.2-6.7; p = 0.019) were associated with increased risk of major surgery in the multivariate analysis. Conclusions: Rigid commitment to the Ponseti method in the conservative treatment of patients with isolated clubfoot was associated with a lower risk of subsequent unplanned surgical intervention. In addition, clubfoot treatment programs that use a care model that prioritizes continuity in care and dedication to the Ponseti method may decrease the proportion of patients who undergo unplanned surgical intervention. Level of evidence: Level III, therapeutic study.
    No preview · Article · Sep 2015 · Clinical Orthopaedics and Related Research
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    ABSTRACT: Introduction: Coalition resection can restore motion, and improve pain in patients with talocalcaneal coalitions (TCCs) and an aligned foot. However, there is some debate regarding appropriate treatment of patients with associated valgus deformity. The purpose of this study was to present the outcomes and complications following surgical reconstruction, with or without coalition resection, in a series of patients with TCC and severe hindfoot valgus. Methods: Thirteen consecutive patients (14 feet) were evaluated. Eleven patients were male. Mean age was 14 years. Mean follow-up was 43.8 months. Seven patients (8 feet) underwent simultaneous resection of the coalition and reconstruction, and 6 patients (6 feet) isolated reconstruction. The talar-first metatarsal angle, the talar-horizontal angle, and calcaneal pitch were measured preoperatively and postoperatively. Clinical evaluation was made according to the American Orthopaedic Foot and Ankle Society ankle-hindfoot score. Results: All radiographic values improved significantly and were within the normal ranges postoperatively. The average American Orthopaedic Foot and Ankle Society ankle-hindfoot score had improved from 45 to 98 points (P<0.001) in the group of simultaneous resection and reconstruction, and from 60 to 92.3 points (P=0.002) in the group of isolated reconstruction. All patients were asymptomatic at the last follow-up and were satisfied with the procedure. Discussion: Surgical reconstruction with or without coalition resection can achieve significant functional and radiographic improvements, and symptoms relief in selected patients with TCCs and severe valgus deformity. Level of evidence: Level IV-therapeutic study.
    No preview · Article · Sep 2015 · Journal of pediatric orthopedics
  • Mark Miller · Matthew B Dobbs
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    ABSTRACT: Congenital vertical talus is a rare foot deformity. If left untreated, it causes significant disability, including pain and functional limitations. Although the etiology of vertical talus is likely heterogeneous, recent evidence strongly supports a genetic cause linking it to genes expressed during early limb development. Traditional management for vertical talus involves extensive surgeries that are associated with significant short- and long-term complications. A minimally invasive approach that relies on serial manipulation and casting to achieve most of the correction has been shown to produce excellent short-term results with regard to clinical and radiographic correction in both isolated and nonisolated cases of vertical talus. Although long-term studies are needed, achieving correction without extensive surgery may lead to more flexible and functional feet, much as Ponseti method has done for clubfeet. Copyright 2015 by the American Academy of Orthopaedic Surgeons.
    No preview · Article · Sep 2015 · The Journal of the American Academy of Orthopaedic Surgeons
  • Justin S Yang · Matthew B Dobbs
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    ABSTRACT: BACKGROUND: The most common historical treatment method for congenital vertical talus is extensive soft-tissue release surgery. A minimally invasive treatment approach that relies primarily on serial cast correction was introduced almost ten years ago, with promising early results. The purpose of this study was to assess the long-term outcome of patients with congenital vertical talus managed with the minimally invasive technique and compare them with a cohort treated with extensive soft-tissue release surgery.
    No preview · Article · Aug 2015 · The Journal of Bone and Joint Surgery
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    ABSTRACT: Background: Scoliosis is a feature of several genetic disorders that are also associated with aortic aneurysm, including Marfan syndrome, Loeys-Dietz syndrome, and type-IV Ehlers-Danlos syndrome. Life-threatening complications of aortic aneurysm can be decreased through early diagnosis. Genetic screening formutations in populations at risk, such as patients with adolescent idiopathic scoliosis, may improve recognition of these disorders. Methods: The coding regions of five clinically actionable genes associated with scoliosis (COL3A1, FBN1, TGFBR1, TGFBR2, and SMAD3) and aortic aneurysm were sequenced in 343 adolescent idiopathic scoliosis cases. Gene variants that had minor allele frequencies of < 0.0001 or were present in human disease mutation databases were identified. Variants were classified as pathogenic, likely pathogenic, or variants of unknown significance. Results: Pathogenic or likely pathogenic mutations were identified in 0.9% (three) of 343 adolescent idiopathic scoliosis cases. Two patients had pathogenic SMAD3 nonsense mutations consistent with type-III Loeys-Dietz syndrome and one patient had a pathogenic FBN1 mutation with subsequent confirmation of Marfan syndrome. Variants of unknown significance in COL3A1 and FBN1 were identified in 5.0% (seventeen) of 343 adolescent idiopathic scoliosis cases. Six FBN1 variants were previously reported in patients with Marfan syndrome, yet were considered variants of unknown significance based on the level of evidence. Variants of unknown significance occurred most frequently in FBN1 and were associated with greater curve severity, systemic features of Marfan syndrome, and joint hypermobility. Conclusions: Clinically actionable pathogenic mutations in genes associated with adolescent idiopathic scoliosis and aortic aneurysm are rare in patients with adolescent idiopathic scoliosis who are not suspected of having these disorders, although variants of unknown significance are relatively common.
    Full-text · Article · Apr 2015 · The Journal of Bone and Joint Surgery
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    ABSTRACT: Patients ask two main questions when considering an orthopaedic reconstruction: (1) Does it work? And (2) will it last? We have devoted a great deal of space on the Editorial and Spotlight pages of Clinical Orthopaedics and Related Research® to the question of efficacy, and we have considered its importance in many areas.How big of a difference is a patient likely to detect [5]?Have we overlooked women as we design laboratory and clinical research studies [7]?And what is the difference between efficacy and safety[6]?By comparison, the question of durability may have gotten short shrift. For decades now, our specialty—and our Journal—have relied on the now-ubiquitous Kaplan-Meier method of estimating survivorship [4]. This approach is superior to crude survivorship calculations since the Kaplan-Meier estimator adjusts for patients whose status cannot be determined because they have not failed as of the end of the study, or because they have been lost to followup. Two generations (or mor ...
    Full-text · Article · Feb 2015 · Clinical Orthopaedics and Related Research
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    ABSTRACT: Adolescent idiopathic scoliosis (AIS) is the most common form of structural spinal deformities that have a radiological lateral Cobb angle — a measure of spinal curvature — of ≥10o. AIS affects between 1% and 4% of adolescents in the early stages of puberty and is more common in young women than in young men. The condition occurs in otherwise healthy individuals and currently has no recognizable cause. In the past few decades, considerable progress has been made towards understanding the clinical patterns and the three-dimensional pathoanatomy of AIS. Advances in biomechanics and technology and their clinical application, supported by limited evidence-based research, have led to improvements in the safety and outcomes of surgical and non-surgical treatments. However, the definite aetiology and aetiopathogenetic mechanisms that underlie AIS are still unclear. Thus, at present, both the prevention of AIS and the treatment of its direct underlying cause are not possible.
    Full-text · Article · Jan 2015
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    ABSTRACT: Idiopathic scoliosis occurs in 3% of individuals and has an unknown etiology. The objective of this study was to identify rare variants that contribute to the etiology of idiopathic scoliosis, using exome sequencing in a multigenerational family with idiopathic scoliosis. Exome sequencing was completed for three members of this multigenerational family with idiopathic scoliosis, resulting in the identification of a variant in the HSPG2 gene as a potential contributor to the phenotype. The HSPG2 gene was sequenced in a separate cohort of 100 unrelated individuals affected with idiopathic scoliosis, and was also examined in an independent idiopathic scoliosis population. The exome sequencing and subsequent bioinformatics filtering resulted in 16 potentially damaging and rare coding variants. One of these variants, p.Asn786Ser, is located in the HSPG2 gene. The variant p.Asn786Ser is also over-represented in a larger cohort of idiopathic scoliosis cases compared to a control population (p=0.024). Furthermore, we identified additional rare HSPG2 variants that are predicted to be damaging in two independent cohorts of individuals with idiopathic scoliosis. The HSPG2 gene encodes for a ubiquitous multifunctional protein within the extracellular matrix in which loss of function mutation are known to result in a musculoskeletal phenotype in both mouse and humans. Based on these results, we conclude that rare variants in the HSPG2 gene potentially contribute to the idiopathic scoliosis phenotype in a subset of patients with idiopathic scoliosis. Further studies must be completed to confirm the effect of the HSPG2 gene on the idiopathic scoliosis phenotype. Copyright © 2014 Author et al.
    Full-text · Article · Dec 2014 · G3-Genes Genomes Genetics
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    ABSTRACT: Clubfoot treatment commonly fails and often results in impaired quality of life. An understanding of the soft-tissue abnormalities associated with both treatment-responsive and treatment-resistant clubfoot is important to improving the diagnosis of clubfoot, the prognosis for patients, and treatment.
    No preview · Article · Aug 2014 · The Journal of Bone and Joint Surgery
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    ABSTRACT: Adolescent idiopathic scoliosis (AIS) is a complex genetic disorder that causes spinal deformity in approximately 3% of the population. Candidate gene, linkage, and genome-wide association studies have sought to identify genetic variation that predisposes individuals to AIS, but the genetic basis remains unclear. Copy number variants are associated with several isolated skeletal phenotypes, but their role in AIS, to our knowledge, has not been assessed. We determined the frequency of recurrent copy number rearrangements, chromosome aneuploidy, and rare copy number variants in patients with AIS. Between January 2010 and August 2014, we evaluated 150 patients with isolated AIS and spinal curvatures measuring 10A degrees or greater, and 148 agreed to participate. Genomic copy number analysis was performed on patients and 1079 control subjects using the Affymetrix(A (R)) Genome-wide Human SNP Array 6.0. After removing poor quality samples, 143 (97%) patients with AIS were evaluated for copy number variation. We identified a duplication of chromosome 1q21.1 in 2.1% (N = 3/143) of patients with AIS, which was enriched compared with 0.09% (N = 1/1079) of control subjects (p = 0.0057) and 0.07% (N = 6/8329) of a large published control cohort (p = 0.0004). Other notable findings include trisomy X, which was identified in 1.8% (N = 2/114) of female patients with AIS, and rearrangements of chromosome 15q11.2 and 16p11.2 that previously have been associated with spinal phenotypes. Finally, we report rare copy number variants that will be useful in future studies investigating candidate genes for AIS. Copy number variation and chromosomal aneuploidy may contribute to the pathogenesis of adolescent idiopathic scoliosis. Chromosomal microarray may reveal clinically useful abnormalities in some patients with AIS.
    Full-text · Article · Jul 2014 · Clinical Orthopaedics and Related Research
  • Laurene A Sweet · Lindsey M Oʼneill · Matthew B Dobbs
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    ABSTRACT: The purpose of this report is to explore assessment and serial casting intervention for painful rigid flatfoot deformities with vertical talus in an adolescent girl with hereditary spastic paraplegia who was nonambulatory. The participant's right foot underwent 2 phases of casting with correction first toward hindfoot inversion and then dorsiflexion. Because of a vertical talus, her left foot required an intermediate casting toward plantar flexion, inversion, and forefoot adduction prior to casting toward dorsiflexion. The patient improved despite the underlying progressive neuromuscular disorder. Pain ameliorated and she returned to supported standing and transfers. Spasticity decreased bilaterally and the flexibility of her foot deformities improved to allow orthotic fabrication in subtalar neutral. Results were maintained at 12 and 16 months. Individualized multiphase serial casting requires further investigation with patients such as those with hereditary spastic paraplegia.
    No preview · Article · Jun 2014 · Pediatric physical therapy: the official publication of the Section on Pediatrics of the American Physical Therapy Association
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    ABSTRACT: Adolescent idiopathic scoliosis (AIS) causes spinal deformity in 3% of children. Despite a strong genetic basis, few genes have been associated with AIS and the pathogenesis remains poorly understood. In a genome-wide rare variant burden analysis using exome sequence data, we identified fibrillin-1 (FBN1) as the most significantly associated gene with AIS. Based on these results, FBN1 and a related gene, fibrillin-2 (FBN2), were sequenced in a total of 852 AIS cases and 669 controls. In individuals of European ancestry, rare variants in FBN1 and FBN2 were enriched in severely affected AIS cases (7.6%) compared with in-house controls (2.4%) (OR = 3.5, P = 5.46 × 10−4) and Exome Sequencing Project controls (2.3%) (OR = 3.5, P = 1.48 × 10−6). Scoliosis severity in AIS cases was associated with FBN1 and FBN2 rare variants (P = 0.0012) and replicated in an independent Han Chinese cohort (P = 0.0376), suggesting that rare variants may be useful as predictors of curve progression. Clinical evaluations revealed that the majority of AIS cases with rare FBN1 variants do not meet diagnostic criteria for Marfan syndrome, though variants are associated with tall stature (P = 0.0035) and upregulation of the transforming growth factor beta pathway. Overall, these results expand our definition of fibrillin-related disorders to include AIS and open up new strategies for diagnosing and treating severe AIS.
    Full-text · Article · May 2014 · Human Molecular Genetics
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    ABSTRACT: Adolescent idiopathic scoliosis (AIS) is a common rotational deformity of the spine that presents in children worldwide, yet its etiology is poorly understood. Recent genome-wide association studies (GWAS) have identified a few candidate risk loci. One locus near the chromosome 10q24.31 LBX1 gene (OMIM #604255) was originally identified by a GWAS of Japanese subjects and replicated in additional Asian populations. To extend this result, and to create larger AIS cohorts for the purpose of large-scale meta-analyses in multiple ethnicities, we formed a collaborative group called the International Consortium for Scoliosis Genetics (ICSG). Here, we report the first ICSG study, a meta-analysis of the LBX1 locus in six Asian and three non-Asian cohorts. We find significant evidence for association of this locus with AIS susceptibility in all nine cohorts. Results for seven cohorts containing both genders yielded P=1.22×10-43 for rs11190870, and P=2.94×10-48 for females in all nine cohorts. Comparing the regional haplotype structures for three populations, we refined the boundaries of association to a ∼25 kb block encompassing the LBX1 gene. The LBX1 protein, a homeobox transcription factor that is orthologous to the Drosophila ladybird late gene, is involved in proper migration of muscle precursor cells, specification of cardiac neural crest cells, and neuronal determination in developing neural tubes. Our results firmly establish the LBX1 region as the first major susceptibility locus for AIS in Asian and non-Hispanic white groups, and provide a platform for larger studies in additional ancestral groups.
    No preview · Article · Apr 2014 · Journal of Medical Genetics
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    ABSTRACT: Clubfoot is a common congenital birth defect with complex inheritance patterns. Currently, the genetic and morphological basis of clubfoot is poorly understood. To identify genetic risk factors associated with clubfoot, we performed a genome-wide association study of common genetic variants. The DNA of 396 isolated clubfoot patients and 1000 controls of European descent was genotyped for >600 000 single nucleotide polymorphisms (SNP) using the Affymetrix 6.0 array. Replication was performed with an independent cohort of 370 isolated clubfoot cases and 363 controls of European descent. Strongest evidence for an association of clubfoot was found with an intergenic SNP on chromosome 12q24.31 between NCOR2 and ZNF664 (rs7969148, OR=0.58, p=1.25×10(-5)) that was significant on replication (combined OR=0.63, p=1.90×10(-7)). Additional suggestive SNPs were identified near FOXN3, SORCS1 and MMP7/TMEM123 that also confirmed on replication. Our study suggests a potential role for common genetic variation in several genes that have not previously been implicated in clubfoot pathogenesis.
    Full-text · Article · Mar 2014 · Journal of Medical Genetics
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    Full-text · Article · Nov 2013 · Clinical Orthopaedics and Related Research
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    Full-text · Article · Sep 2013 · Clinical Orthopaedics and Related Research
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    ABSTRACT: Background The role of bracing in patients with adolescent idiopathic scoliosis who are at risk for curve progression and eventual surgery is controversial. Methods We conducted a multicenter study that included patients with typical indications for bracing due to their age, skeletal immaturity, and degree of scoliosis. Both a randomized cohort and a preference cohort were enrolled. Of 242 patients included in the analysis, 116 were randomly assigned to bracing or observation, and 126 chose between bracing and observation. Patients in the bracing group were instructed to wear the brace at least 18 hours per day. The primary outcomes were curve progression to 50 degrees or more (treatment failure) and skeletal maturity without this degree of curve progression (treatment success). ResultsThe trial was stopped early owing to the efficacy of bracing. In an analysis that included both the randomized and preference cohorts, the rate of treatment success was 72% after bracing, as compared with 48% after observation (propensity-score-adjusted odds ratio for treatment success, 1.93; 95% confidence interval [CI], 1.08 to 3.46). In the intention-to-treat analysis, the rate of treatment success was 75% among patients randomly assigned to bracing, as compared with 42% among those randomly assigned to observation (odds ratio, 4.11; 95% CI, 1.85 to 9.16). There was a significant positive association between hours of brace wear and rate of treatment success (P<0.001). Conclusions Bracing significantly decreased the progression of high-risk curves to the threshold for surgery in patients with adolescent idiopathic scoliosis. The benefit increased with longer hours of brace wear. (Funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases and others; BRAIST ClinicalTrials.gov number, NCT00448448.)
    Full-text · Article · Sep 2013 · New England Journal of Medicine

Publication Stats

3k Citations
426.94 Total Impact Points

Institutions

  • 2001-2015
    • Washington University in St. Louis
      • Department of Orthopaedic Surgery
      San Luis, Missouri, United States
  • 2002-2010
    • Shriners Hospitals for Children
      Tampa, Florida, United States
  • 2007
    • Barnes Jewish Hospital
      San Luis, Missouri, United States
  • 2000-2006
    • University of Iowa
      • Department of Orthopaedics and Rehabilitation
      Iowa City, IA, United States
  • 1999-2000
    • University of Iowa Children's Hospital
      Iowa City, Iowa, United States