Introduction/Aims
There is considerable heterogenicity in clinical outcomes in Duchenne muscular dystrophy (DMD). The aim of this study was to assess whether dystrophin gene (DMD) pathogenic variant ...location influences upper or lower extremity motor function outcomes in a large prospective cohort.
Methods
We used longitudinal timed and quantitative motor function measurements obtained from 154 boys with DMD over a 10‐y period by the Cooperative International Neuromuscular Research Group Duchenne Natural History Study (CINRG‐DNHS) to understand how the trajectories of motor function differ based on proximal versus distal DMD pathogenic variants. Proximal variants were defined as located proximal to 5′ DMD intron 44, and distal variants as those including nucleotides 3′ DMD including intron 44. Distal DMD variants are predicted to alter the expression of short dystrophin isoforms (Dp140, Dp116, and Dp71). We compared various upper extremity and lower extremity motor function measures in these two groups, after adjusting for total lifetime corticosteroid use.
Results
The time to loss‐of‐ambulation and timed motor function measurements of both upper and lower limbs over a 10‐y period were comparable between boys with proximal (n = 53) and distal (n = 101) DMD pathogenic variants. Age had a significant effect on several motor function outcomes. Boys younger than 7 y of age (n = 49) showed gain in function whereas boys 7 y and older (n = 71) declined, regardless of dystrophin pathogenic variant location.
Discussion
The longitudinal decline in upper and lower motor function is independent of proximal versus distal location of DMD pathogenic variants.
Objective
We studied the effects of LTBP4 and SPP1 polymorphisms on age at loss of ambulation (LoA) in a multiethnic Duchenne muscular dystrophy (DMD) cohort.
Methods
We genotyped SPP1 rs28357094 and ...LTBP4 haplotype in 283 of 340 participants in the Cooperative International Neuromuscular Research Group Duchenne Natural History Study (CINRG‐DNHS). Median ages at LoA were compared by Kaplan–Meier analysis and log‐rank test. We controlled polymorphism analyses for concurrent effects of glucocorticoid corticosteroid (GC) treatment (time‐varying Cox regression) and for population stratification (multidimensional scaling of genome‐wide markers).
Results
Hispanic and South Asian participants (n = 18, 41) lost ambulation 2.7 and 2 years earlier than Caucasian subjects (p = 0.003, <0.001). The TG/GG genotype at SPP1 rs28357094 was associated to 1.2‐year‐earlier median LoA (p = 0.048). This difference was greater (1.9 years, p = 0.038) in GC‐treated participants, whereas no difference was observed in untreated subjects. Cox regression confirmed a significant effect of SPP1 genotype in GC‐treated participants (hazard ratio = 1.61, p = 0.016). LTBP4 genotype showed a direction of association with age at LoA as previously reported, but it was not statistically significant. After controlling for population stratification, we confirmed a strong effect of LTBP4 genotype in Caucasians (2.4 years, p = 0.024). Median age at LoA with the protective LTBP4 genotype in this cohort was 15.0 years, 16.0 for those who were treated with GC.
Interpretation
SPP1 rs28357094 acts as a pharmacodynamic biomarker of GC response, and LTBP4 haplotype modifies age at LoA in the CINRG‐DNHS cohort. Adjustment for GC treatment and population stratification appears crucial in assessing genetic modifiers in DMD. Ann Neurol 2015;77:684–696
Objectives/Hypothesis
Our objectives were to investigate pediatric cochlear implantation (PCI) across representative states within the United States and analyze any geographical differences in age, ...median household income, race, insurance, and total medical charges.
Study Design
Cross‐sectional.
Methods
Data from children (aged 0.5–18 years) who received cochlear implantation surgery were collected from the 2011 State Ambulatory Surgery and Services Databases from California (CA), Florida (FL), Maryland (MD), New York (NY), and Kentucky (KY) as a part of the Healthcare Cost and Utilization Project. We performed data analysis using a combination of Kruskal‐Wallis and Wilcoxon rank sum tests, as well as nominal logistic regression.
Results
Five hundred twelve cases of PCI were performed during 2011 across the five states. The overall mean and median age of implantation were 5.6 years and 4 years, respectively. There was no statistical difference in age of implantation across states (P = .85). However, there were statistical differences in primary payer (P < .001), median household income quartiles of patients who received an implant (P < .006), race (P < .001), and total median hospital charges for four of the states, with the exception of CA (P < .001).
Conclusions
Age of PCI appears to be similar across the five states in cross‐sectional analysis. Geographic variations in charges, payer, race, and median household income occur with statistical significance in PCI. Further analysis of contributing factors at each state level may help elucidate the root cause of these disparities and improve and justify a uniform approach to healthcare delivery and standards of care.
Level of Evidence
4. Laryngoscope, 128:954–958, 2018
Objectives
1) To analyze clinical outcomes of children stratified by ultrasound into three diagnoses: acute tonsillitis, peritonsillar phlegmon, and abscess; and 2) To compare clinical outcomes and ...financial impact between children who underwent ultrasound protocol to those who did not.
Study Design
Retrospective analysis between two cohorts: ultrasound protocol group and control group.
Methods
Children with peritonsillar abscess (PTA) diagnosed in the emergency department (ED) were enrolled during a 2‐year period for transcervical ultrasound evaluation of bilateral tonsillar fossae. Data from a cohort of patients with PTA prior to ultrasound screening were also collected from retrospective chart review. Outcome variables were analyzed using multivariate logistic regression.
Results
Seventy‐eight children (mean 12.3 years) were enrolled in the ultrasound protocol, compared to 101 children (mean 13.6 years) evaluated using traditional methods of examination and/or computed tomography (CT) imaging. Demographics between the two groups were not significantly different.
Only one‐third of patients presumed to have PTA by ED staff had ultrasound findings consistent with abscess. Overall treatment failure rate was 8%, requiring readmission or surgical intervention for abscess. Length of stay, surgical drainage, and radiation exposure from CT scans were reduced significantly in the ultrasound group (P < 0.006). Differences in readmission rates and mean charges between the two groups did not reach significance.
Conclusion
Peritonsillar abscess is a common infection in the pediatric population, but diagnosis can be challenging. Transcervical ultrasound is a safe, cost‐effective, and accurate modality to help stratify patients into medical and surgical treatment arms.
Level of Evidence
3b. Laryngoscope, 127:1924–1929, 2017
Duchenne muscular dystrophy (DMD) exhibits substantial variability in rates of disease progression and response to treatment. This has hindered treatment development and complicated interpretation of ...drug effects in clinical trials.
We hypothesized that a multivariate combination of early-age clinical outcome measurements can explain differential disease progression.
Data on boys with DMD (ages 4-<10 years), both treated with steroidal anti-inflammatories and untreated, were obtained from CINRG Duchenne Natural History Study (n = 209) and vamorolone VBP15-002/003/LTE (n = 46) studies. Velocities from three timed function tests (TFTs; stand from supine, run/walk 10 meters, and climb 4 stairs) were simultaneously modeled in a longitudinal latent class analysis.
Three classes of differentially progressing early age DMD motor trajectories were identified. Quicker decline/progression was associated with lower baseline TFT velocities, earlier loss of ability to finish a TFT, and lower predicted velocities. Earlier substantial steroid exposure was associated with greater TFT velocities while the moderate progression class was observed to have the largest difference in performance between boys treated early with steroids vs. not. Sample size calculations with the class showing the largest treatment response showed a large reduction in required sample size as compared to using summaries from all participants. Gene mutations were also investigated in post-hoc analyses, with mutations near the beginning of the DMD gene (Dp427 absent and Dp140/Dp71 present) found to be enriched in the slowest progressing class.
This study provides insight into the variation in DMD progression through a latent class analysis. Our findings show class-related trajectories of motor outcomes and pharmacological response to corticosteroids, and suggest that enrichment strategies and/or subgroup analyses could be considered further in design of therapeutic interventions in DMD.
Introduction/Aims
There is debate about whether and to what extent either respiratory or cardiac dysfunction occurs in patients with dysferlinopathy. This study aimed to establish definitively ...whether dysfunction in either system is part of the dysferlinopathy phenotype.
Methods
As part of the Jain Foundation's International Clinical Outcome Study (COS) for dysferlinopathy, objective measures of respiratory and cardiac function were collected twice, with a 3‐y interval between tests, in 188 genetically confirmed patients aged 11–86 y (53% female). Measures included forced vital capacity (FVC), electrocardiogram (ECG), and echocardiogram (echo).
Results
Mean FVC was 90% predicted at baseline, decreasing to 88% at year 3. FVC was less than 80% predicted in 44 patients (24%) at baseline and 48 patients (30%) by year 3, including ambulant participants. ECGs showed P‐wave abnormalities indicative of delayed trans‐atrial conduction in 58% of patients at baseline, representing a risk for developing atrial flutter or fibrillation. The prevalence of impaired left ventricular function or hypertrophy was comparable to that in the general population.
Discussion
These results demonstrate clinically significant respiratory impairment and abnormal atrial conduction in some patients with dysferlinopathy. Therefore, we recommend that annual or biannual follow‐up should include FVC measurement, enquiry about arrhythmia symptoms and peripheral pulse palpation to assess cardiac rhythm. However, periodic specialist cardiac review is probably not warranted unless prompted by symptoms or abnormal pulse findings.
We performed an observational, natural history study of males with in‐frame dystrophin gene deletions causing Becker muscular dystrophy (BMD). A prospective natural history study collected ...longitudinal medical, strength, and timed function assessments. Eighty‐three participants with genetically confirmed BMD were enrolled (age range 5.6–75.4 years). Lower extremity function and the percentage of participants who retained ambulation declined across the age span. The largest single group of participants had in‐frame deletions that corresponded to an out‐of‐frame deletion treated with an exon 45 skip to restore the reading frame. This group of 54 participants showed similarities in baseline motor functional assessments when compared to the group of all others in the study. A prospective natural history cohort with in‐frame dystrophin gene deletions offers the potential to contribute to clinical trial readiness for BMD and to analyze therapeutic benefit of exon skipping for Duchenne muscular dystrophy.
Summary
Background
Blood transfusions in patients with adolescent idiopathic scoliosis after fusion have been associated with increased morbidity, mortality, and cost.
Objective
The aim of this study ...was to evaluate the association between implementation of blood–conservation strategies within the perioperative surgical home on transfusion rates for patients with adolescent idiopathic scoliosis undergoing spinal fusion.
Methods
Two hundred and thirteen patients (44 preperioperative surgical home, 169 postperioperative surgical home) who underwent posterior spine fusion for adolescent idiopathic scoliosis between 23 June 2014, and 30 July 2017, were enrolled in this case control study. The perioperative surgical home implemented in March 2015 involved evidence–based perioperative interventions to create a standardized clinical pathway including judicious use of crystalloid management, restrictive transfusion strategy, routine use of cell saver, and standardized administration of anti‐fibrinolytics. The primary outcome was odds of perioperative transfusion. Secondary outcomes included volumes of crystalloid, albumin, cell saver, packed red blood cells as well as calculated blood loss. Other variables that were documented included antibrinolytic total dose, mean arterial pressure, temperature, laboratory values, intrathecal morphine dosing, and surgical time. Statistical methods included t test and logistic regression.
Results
For the postperioperative surgical home, the odds of perioperative transfusion were 0.30 (95% CI 0.13‐0.70), as compared to preperioperative surgical home. In terms of secondary outcomes, calculated blood loss was significantly lower in the postperioperative surgical home patients (27.0 mL/kg preperioperative surgical home vs 22.8 mL/kg postperioperative surgical home; mean difference = −0.24 −0.44, −0.04). Although no difference was noted in the amount of intraoperative cell saver or albumin administered, a reduction was noted in mean intraoperative crystalloid given postperioperative surgical home (41.4 mL/kg ± 20.4 mL/kg preperioperative surgical home vs 28.0 mL/kg ± 13.7 mL/kg postperioperative surgical home; log mean difference = 0.37 95% CI 0.21‐0.53, P < 0.001). Postperioperative surgical home patients also had a significantly higher temperature nadir (mean difference = −0.47 95% CI −0.70 to −0.23; P < 0.001), received a significantly higher total anti‐fibrinolytic dose (mean difference = −3939 95% CI −5364 to −2495; P < 0.001), and were exposed to shorter surgical times (mean difference = 0.72 95% CI 0.36‐1.09; P < 0.001).
Conclusions
Implementation of blood–conservation strategies as part of a perioperative surgical home for patients with adolescent idiopathic scoliosis undergoing posterior spine fusion resulted in significant decrease in perioperative blood transfusions.
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