DMD genotypes and motor function in Duchenne muscular dystrophy

Background and ObjectivesClinical trials of genotype-targeted treatments in Duchenne muscular dystrophy (DMD) tra-ditionally compare treated patients with untreated patients with the same DMD genotype class.This avoids confounding of drug efficacy by genotype effects but also shrinks the pool of eligiblecontrols, increasing challenges for trial enrollment in this already rare disease. To evaluate thesuitability of genotypically unmatched controls in DMD, we quantified effects of genotype classon 1-year changes in motor function endpoints used in clinical trials.MethodsMore than 1,600 patient-years of follow-up (>700 patients) were studied from 6 real-world/natural history data sources (UZ Leuven, PRO-DMD-01 shared by CureDuchenne, iMDEX,North Star UK, Cincinnati Children’s Hospital Medical Center, and the DMD Italian Group),with genotypes classified as amenable to skipping exons 44, 45, 51, or 53, or other skippable,nonsense, and other mutations. Associations between genotype class and 1-year changes inNorth Star Ambulatory Assessment total score (DNSAA) and in 10-m walk/run velocity(D10MWR) were studied in each data source with and without adjustment for baselineprognostic factors.ResultsThe studied genotype classes accounted for approximately 2% of variation in DNSAA outcomesafter 12 months, whereas other prognostic factors explained >30% of variation in large datasources. Based on a meta-analysis across all data sources, pooled effect estimates for the studiedskip-amenable mutation classes were all small in magnitude (1-year follow up), smaller than clinically important differences in NSAA, and were preciselyestimated with standard errors Functional Genomics of Muscle, Nerve and Brain Disorder

Adaptive Hearing Aid Benefit in Children With Mild/Moderate Hearing Loss:A Registered, Double-Blind, Randomized Clinical Trial

Objectives: We completed a registered double-blind randomized control trial to compare acclimatization to two hearing aid fitting algorithms by experienced pediatric hearing aid users with mild to moderate hearing loss. We hypothesized that extended use (up to 13 months) of an adaptive algorithm with integrated directionality and noise reduction, OpenSound Navigator (OSN), would result in improved performance on auditory, cognitive, academic, and caregiver- or self-report measures compared with a control, omnidirectional algorithm (OMNI). Design: Forty children aged 6 to 13 years with mild to moderate/severe symmetric sensorineural hearing loss completed this study. They were all experienced hearing aid users and were recruited through the Cincinnati Children’s Hospital Medical Center Division of Audiology. The children were divided into 20 pairs based on similarity of age (within 1 year) and hearing loss (level and configuration). Individuals from each pair were randomly assigned to either an OSN (experimental) or OMNI (control) fitting algorithm group. Each child completed an audiology evaluation, hearing aid fitting using physically identical Oticon OPN hearing aids, follow-up audiological appointment, and 2 research visits up to 13 months apart. Research visit outcome measures covered speech perception (in quiet and in noise), novel grammar and word learning, cognition, academic ability, and caregiver report of listening behaviors. Analysis of outcome differences between visits, groups, ages, conditions and their interactions used linear mixed models. Between 22 and 39 children provided useable data for each task. Results: Children using the experimental (OSN) algorithm did not show any significant performance differences on the outcome measures compared with those using the control (OMNI) algorithm. Overall performance of all children in the study increased across the duration of the trial on word repetition in noise, sentence repetition in quiet, and caregivers’ assessment of hearing ability. There was a significant negative relationship between age at first hearing aid use, final Reading and Mathematical ability, and caregiver rated speech hearing. A significant positive relationship was found between daily hearing aid use and study-long change in performance on the Flanker test of inhibitory control and attention. Logged daily use of hearing aids related to caregiver rated spatial hearing. All results controlled for age at testing/evaluation and false discovery rate. Conclusions: Use of the experimental (OSN) algorithm neither enhanced nor reduced performance on auditory, cognitive, academic or caregiver report measures compared with the control (OMNI) algorithm. However, prolonged hearing aid use led to benefits in hearing, academic skills, attention, and caregiver evaluation

Adaptive Hearing Aid Benefit in Children With Mild/Moderate Hearing Loss : A Registered, Double-Blind, Randomized Clinical Trial

Objectives: We completed a registered double-blind randomized control trial to compare acclimatization to two hearing aid fitting algorithms by experienced pediatric hearing aid users with mild to moderate hearing loss. We hypothesized that extended use (up to 13 months) of an adaptive algorithm with integrated directionality and noise reduction, OpenSound Navigator (OSN), would result in improved performance on auditory, cognitive, academic, and caregiver- or self-report measures compared with a control, omnidirectional algorithm (OMNI).Design: Forty children aged 6 to 13 years with mild to moderate/severe symmetric sensorineural hearing loss completed this study. They were all experienced hearing aid users and were recruited through the Cincinnati Children’s Hospital Medical Center Division of Audiology. The children were divided into 20 pairs based on similarity of age (within 1 year) and hearing loss (level and configuration). Individuals from each pair were randomly assigned to either an OSN (experimental) or OMNI (control) fitting algorithm group. Each child completed an audiology evaluation, hearing aid fitting using physically identical Oticon OPN hearing aids, follow-up audiological appointment, and 2 research visits up to 13 months apart. Research visit outcome measures covered speech perception (in quiet and in noise), novel grammar and word learning, cognition, academic ability, and caregiver report of listening behaviors. Analysis of outcome differences between visits, groups, ages, conditions and their interactions used linear mixed models. Between 22 and 39 children provided useable data for each task.Results: Children using the experimental (OSN) algorithm did not show any significant performance differences on the outcome measures compared with those using the control (OMNI) algorithm. Overall performance of all children in the study increased across the duration of the trial on word repetition in noise, sentence repetition in quiet, and caregivers’ assessment of hearing ability. There was a significant negative relationship between age at first hearing aid use, final Reading and Mathematical ability, and caregiver rated speech hearing. A significant positive relationship was found between daily hearing aid use and study-long change in performance on the Flanker test of inhibitory control and attention. Logged daily use of hearing aids related to caregiver rated spatial hearing. All results controlled for age at testing/evaluation and false discovery rate.Conclusions: Use of the experimental (OSN) algorithm neither enhanced nor reduced performance on auditory, cognitive, academic or caregiver report measures compared with the control (OMNI) algorithm. However, prolonged hearing aid use led to benefits in hearing, academic skills, attention, and caregiver evaluation.</p