Generation and transcriptomic characterization of MIR137 knockout miniature pig model for neurodevelopmental disorders.

BACKGROUND: Neurodevelopmental disorders (NDD), such as autism spectrum disorders (ASD) and intellectual disorders (ID), are highly debilitating childhood psychiatric conditions. Genetic factors are recognized as playing a major role in NDD, with a multitude of genes and genomic regions implicated. While the functional validation of NDD-associated genes has predominantly been carried out using mouse models, the significant differences in brain structure and gene function between mice and humans have limited the effectiveness of mouse models in exploring the underlying mechanisms of NDD. Therefore, it is important to establish alternative animal models that are more evolutionarily aligned with humans. RESULTS: In this study, we employed CRISPR/Cas9 and somatic cell nuclear transplantation technologies to successfully generate a knockout miniature pig model of the MIR137 gene, which encodes the neuropsychiatric disorder-associated microRNA miR-137. The homozygous knockout of MIR137 (MIR137-/-) effectively suppressed the expression of mature miR-137 and led to the birth of stillborn or short-lived piglets. Transcriptomic analysis revealed significant changes in genes associated with neurodevelopment and synaptic signaling in the brains of MIR137-/- miniature pig, mirroring findings from human ASD transcriptomic data. In comparison to miR-137-deficient mouse and human induced pluripotent stem cell (hiPSC)-derived neuron models, the miniature pig model exhibited more consistent changes in critical neuronal genes relevant to humans following the loss of miR-137. Furthermore, a comparative analysis identified differentially expressed genes associated with ASD and ID risk genes in both miniature pig and hiPSC-derived neurons. Notably, human-specific miR-137 targets, such as CAMK2A, known to be linked to cognitive impairments and NDD, exhibited dysregulation in MIR137-/- miniature pigs. These findings suggest that the loss of miR-137 in miniature pigs affects genes crucial for neurodevelopment, potentially contributing to the development of NDD. CONCLUSIONS: Our study highlights the impact of miR-137 loss on critical genes involved in neurodevelopment and related disorders in MIR137-/- miniature pigs. It establishes the miniature pig model as a valuable tool for investigating neurodevelopmental disorders, providing valuable insights for potential applications in human research.

The use of ecological momentary assessment to evaluate real-world aided outcomes with children.

BACKGROUND: Ecological momentary assessment (EMA) methods allow for real-time, real-world survey data collection. Studies with adults have reported EMA as a feasible and valid tool in the measurement of real-world listening experience. Research is needed to investigate the use of EMA with children who wear hearing aids. OBJECTIVES: This study explored the implementation of EMA with children using a single-blinded repeated measures design to evaluate real-world aided outcome. METHODS: Twenty-nine children, aged 7-17, used manual program switching to access hearing aid programs, fitted according to Desired Sensation Level (DSL) version 5.0 child quiet and noise prescriptive targets. Aided outcome was measured using participant-triggered twice-daily EMA entries, across listening situations and hearing dimensions. RESULTS: Adherence to the EMA protocol by the children was high (82.4% compliance rate). Speech loudness, understanding and preference results were found to relate to both the hearing aid program and the listening situation. Aided outcomes related to prescription-based noise management were found to be highest in noisy situations. CONCLUSIONS: Mobile device-based EMA methods can be used to inform daily life listening experience with children. Prescription-based noise management was found to decrease perceived loudness in noisy, non-school environments; this should be evaluated in combination with hearing aid noise reductions features.

Road safety impact of Ontario street racing and stunt driving law.

OBJECTIVE: The purpose of this study was to conduct a process and outcome evaluation of the deterrent impact of Ontario's street racing and stunt driving legislation which came into effect on September 30, 2007, on collision casualties defined as injuries and fatalities. It was hypothesized that because males, especially young ones, are much more likely to engage in speeding, street racing and stunt driving, the new law would have more impact in reducing speeding-related collision casualties in males when compared to females. METHODS: Interrupted time series analysis with ARIMA modelling was applied to the monthly speeding-related collision casualties in Ontario for the period of January 1, 2002 to December 31, 2010, separately for young male drivers 16-25 years of age (primary intervention group), mature male drivers 26-65 years of age (secondary intervention group), young female drivers 16-25 years of age (primary comparison group) and mature female drivers 26-65 years of age (secondary comparison group). A covariate adjustment using non-speeding casualties was included. RESULTS: A significant intervention effect was found for young male drivers with, on average, 58 fewer collision casualties per month, but not for mature male drivers, when non-speeding casualties were controlled for. No corresponding effect was observed in either comparison (females) group. CONCLUSION: These findings indicate a reduction in speeding-related casualties among young males of 58 fewer casualties per month subsequent to the introduction of Ontario's street racing and stunt driving legislation and suggest the presence of a general deterrent effect.