Rare EIF4A2 variants are associated with a neurodevelopmental disorder characterized by intellectual disability, hypotonia, and epilepsy.

Eukaryotic initiation factor-4A2 (EIF4A2) is an ATP-dependent RNA helicase and a member of the DEAD-box protein family that recognizes the 5' cap structure of mRNAs, allows mRNA to bind to the ribosome, and plays an important role in microRNA-regulated gene repression. Here, we report on 15 individuals from 14 families presenting with global developmental delay, intellectual disability, hypotonia, epilepsy, and structural brain anomalies, all of whom have extremely rare de novo mono-allelic or inherited bi-allelic variants in EIF4A2. Neurodegeneration was predominantly reported in individuals with bi-allelic variants. Molecular modeling predicts these variants would perturb structural interactions in key protein domains. To determine the pathogenicity of the EIF4A2 variants in vivo, we examined the mono-allelic variants in Drosophila melanogaster (fruit fly) and identified variant-specific behavioral and developmental defects. The fruit fly homolog of EIF4A2 is eIF4A, a negative regulator of decapentaplegic (dpp) signaling that regulates embryo patterning, eye and wing morphogenesis, and stem cell identity determination. Our loss-of-function (LOF) rescue assay demonstrated a pupal lethality phenotype induced by loss of eIF4A, which was fully rescued with human EIF4A2 wild-type (WT) cDNA expression. In comparison, the EIF4A2 variant cDNAs failed or incompletely rescued the lethality. Overall, our findings reveal that EIF4A2 variants cause a genetic neurodevelopmental syndrome with both LOF and gain of function as underlying mechanisms.

The maximum phonation time as marker for voice treatment efficacy: A network meta-analysis.

PURPOSE: There is a diversity in treatment approaches for voice therapy in which aerodynamic treatment effects between the approaches are lacking. The evidence of voice treatments on the maximum phonation time (MPT) was quantified using the statistical approach of a network meta-analysis (NMA). DATA SOURCES: Three databases and manual search from inception to November 2021 were evaluated. STUDY SELECTION: Studies were considered which were reports of randomised controlled/clinical trials (RCT) evaluating the efficacy of a specific voice therapy treatment using MPT as an outcome measure in adult participants with voice disorders. Studies were excluded if participants had been diagnosed with neurological-motor-speech disorders or who were vocally healthy. Furthermore, no medical, pharmacological, or technical instrumental treatments were used. DATA EXTRACTION AND SYNTHESIS: Preferred Reporting Items for systematic reviews and meta-analyses extension statement guidelines were followed. Two reviewers independently screened citations, extracted data, and assessed risk of bias using PEDro scale. Random effects model was used for meta-analysis. RESULTS: We identified finally 12 RCT studies (treatment groups n = 285, and control group without an intervention n = 62). Eight interventions were evaluated. The only effective intervention with a significant effect was vocal function exercises (VFE) (mean pre-post difference 6.16 s, 95% confidence interval, 1.18-11.13 s). CONCLUSIONS AND RELEVANCE: VFE effectively improved MPT from pre- to post-treatment in comparison with other voice interventions which were identified in the present NMA. Further high-quality intervention studies with large samples sizes, multidimensional measures, and homogeneous groups of dysphonia are needed to support evidence-based practice in laryngology.

Family Perspectives on Newborn Screening for X-Linked Adrenoleukodystrophy in California.

X-linked adrenoleukodystrophy (ALD) is caused by gene variants in the ABCD1 gene, resulting in a varied clinical spectrum. Males with ALD present with symptoms ranging from isolated adrenal insufficiency and slowly progressive myelopathy to severe cerebral demyelination. Females who are heterozygous for ALD typically develop milder symptoms by late adulthood. Treatment for adrenal insufficiency associated with ALD exists in the form of cortisol, and cerebral ALD may be treated with stem cell transplantation. Currently, there is no treatment for myelopathy. Since 2013, at least 14 states have added ALD to their newborn screening (NBS) panel, including California in 2016. We examined the impact of a positive NBS result for ALD on families in California. Qualitative interviews were conducted with mothers of 10 children who were identified via NBS for ALD. Interviews were transcribed verbatim and analyzed using thematic analysis by two coders. Mothers felt strongly that ALD should be included on California's NBS panel; however, many expressed concerns over their experience. Themes included stress at initial phone call, difficulty living with uncertainty, concerns regarding mental health support, and desire for more information on disease progression, treatments and clinical trials. Mothers exhibited diverse coping strategies, including relying on faith, information seeking, and maintaining hope. Mothers' recommendations for healthcare providers included: educating providers making the initial phone call, providing patient-friendly resources, offering information about ongoing research, and streamlining care coordination. Advice for parents of children with ALD focused on staying hopeful and appreciating the time they have with their children. As more states add ALD to their NBS panel, it is important to improve the current model to promote family resiliency and autonomy.

Doing More With Less: A Centralized Model for Fellowship Program Coordination.

BACKGROUND: Pediatrics fellowship programs typically are small, embedded in divisions, and vary in their approach to education. Program coordination usually falls to division administrators who operate in silos despite common requirements across programs, creating redundancy and inefficiency. OBJECTIVE: We examined the feasibility, acceptability, and impact of a centralized administrative model for pediatrics fellowship support at a large university-based institution. METHODS: In 2014, administrative support for the pediatrics fellowships at the University of California, San Francisco, was restructured from a model with division-level support to a centralized model. In the new model, a team of 6 full-time administrators supports 19 fellowship programs with a total of 80 fellows. The fellowship support team consists of 3 program coordinators, a data coordinator, a human resource coordinator, a team manager, and a faculty advisor. The team meets twice a month to discuss program issues and innovative ideas. Quarterly meetings are held with all coordinators and directors to discuss changes across fellowships and foster further collaboration. We surveyed program directors to examine the acceptability of the model and assessed its impact on finances and turnover. RESULTS: Of 19 eligible fellowship program directors, 15 (79%) completed the survey. The majority indicated that the new administrative model was "better" or "much better" than the prior model. The new model resulted in decreased costs (an estimated $250,000 per year in salary support) and lower staff turnover. CONCLUSIONS: Centralization of fellowship administration is feasible and offers substantial benefits for all stakeholders involved.