Pediatric randomized controlled trials (RCTs) inform decisions concerning the choice of interventions in children and adolescents. To enable the implementation of effective interventions, RCT reports need to provide adequate details on the elements, infrastructure, and delivery of these interventions. Using the 12-item Template for the Intervention Description and Replication (TIDieR) framework, an international team developed guidance for comprehensive reporting of trial interventions in pediatric RCT protocols and reports. We (1) identified initial pediatric considerations (PCs) and examples of good reporting using 50 recent pediatric RCT reports, (2) held an expert panel meeting, (3) conducted a Family Caregiver Workshop to discuss and get input on PCs, (4) compiled PCs and examples of good reporting, and (5) achieved consensus on final PCs and examples. Thirteen PCs reached consensus; they address how trial intervention materials were appropriate for the age and developmental stage of trial participants, which adjustments to enhance palatability of medications and acceptability of interventions were implemented, and how pediatric-specific dosing was determined. Consensus was also reached on accompanying good reporting exemplars. Presenting a minimum set of considerations pertinent to pediatric trial interventions, the TIDieR-Child & Adolescent Health (TIDieR-C) checklist can help trial authors and evidence end users comprehensively report and appraise tested interventions. It can be used with the pediatric-specific extensions of the Standard Protocol Items for Randomized Trials (SPIRIT) and Consolidated Standards of Reporting Trials (CONSORT): SPIRIT-Children & Adolescents and CONSORT-Children & Adolescents. Uptake of this guidance may lead to improved understanding, replicability, and implementation fidelity of effective trial interventions.

ABSTRACT Background Neural retina leucine zipper (NRL) is a crucial transcription factor that plays a key role in the development and differentiation of photoreceptor cells. A variant in this gene can cause a retinal phenotype known as Enhanced S cone Syndrome (ESCS). This study presents three novel autosomal recessive (ar) NRL variants and expands the clinical ophthalmic phenotype of NRL-associated retinopathy to include microphthalmia. Methods Investigations included electrodiagnostic testing, best corrected visual acuity (BCVA), optical coherence tomography (OCT), ultra-wide field autofluorescence (UWAF), fundus imaging, and visual fields. PubMed, Cochrane library and ClinVar database were used for literature search. Results Three patients (P1–3) from 2 different families with novel biallelic NRL variants were reported. P1 had novel homozygous likely-pathogenic NRL variant, p.(Glu86*). Genetic screening of both P2 and P3 identified a second and third novel heterozygous likely pathogenic variants, p.(Leu75Profs *19) and p.(Ser6Alafs *13). Multimodal imaging and functional studies in these patients were consistent with the classical features of ESCS with an additional feature of microphthalmia. Conclusion This study expands the genotype and phenotype of NRL-associated retinopathy and compares the ocular phenotype of our cohort with published NRL reports in the literature.

Rett syndrome (RTT, OMIM #312750) is a severe genetic, neurodevelopmental disorder, primarily affecting females, that occurs due to pathogenic variants in MECP2. Clinical features include loss of acquired developmental milestones, such as purposeful hand movements and communicative abilities and the onset of stereotypic hand movements. Mitochondrial dysfunction/impairment, and inflammation have been reported in individuals with RTT. Despite numerous clinical trials and medications thought to be disease-modifying, treatment often remains purely symptomatic. A significant impediment in determining treatment efficacy has been the lack of clinical biomarkers that correlate with disease state. Mitokines, such as fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15), have been established as biomarkers of cellular stress and mitochondrial dysfunction that may be of clinical utility for patients with RTT. We aimed to determine the suitability of these mitokines as biomarkers for RTT where we analysed their expression levels in blood samples from individuals with RTT as well as fromthe Mecp2T158A mouse model . Our data showed higher FGF21 and GDF15 levels in female Mecp2-deficient mice compared to their wild type littermates. Median FGF21 and GDF15 levels also trended higher in the affected human cohort compared to controls; however, these elevations did not reach statistical significance and appear to be correlated with sodium valproate therapy.