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This thesis builds on the currently available literature on medical complications in achondroplasia, the most common skeletal dysplasia causing short stature in humans. Studies have reported the rates of medical investigations, complications, interventions, and service utilisation in achondroplasia. Limitations have been uncertain diagnosis, clarity of follow up, variable quality medical records, and reliance on self-reports therefore recall. Management of medical complications has evolved over time in line with American Academy of Pediatrics Guidelines, and there is a need for contemporary accounts of medical complications. Pharmaceutical therapies for achondroplasia are emerging, and this natural history data will assist in the evaluation of these. A retrospective cohort study of 108 participants was undertaken to address identified gaps in the literature. Rates of craniocervical stenosis, hydrocephalus, hearing impairment, sleep disordered breathing, lower limb malalignment, thoracolumbar kyphosis, symptomatic spinal stenosis, obesity, respiratory illness, and death were recorded. There was variability in the rates of complications in this cohort, compared with previous reports related to differences in population demographics, local practices, and changes in management over time. Recommendations for improving clinical practice include improved record keeping, incorporating new evidence into practice, improving the clinical management of some conditions, and improving data collection for rare and less studied complications. Recommendations for future research include the standardisation of prospective data collection across multiple sites, evaluation of medical complications in children treated with pharmaceutical therapists, and to better understand phenotypical differences in achondroplasia.

N-methyl-D-aspartate receptors (NMDARs) are excitatory ionotropic glutamate receptors expressed throughout the CNS, including in the spinal dorsal horn. The GluN2 subtypes of NMDAR subunit, which include GluN2A, GluN2B, and GluN2D in the dorsal horn, confer NMDARs with structural and functional variability, enabling heterogeneity in synaptic transmission and plasticity. Despite essential roles for NMDARs in physiological and pathological pain processing, the distribution and function of these specific GluN2 isoforms across dorsal horn laminae remain poorly understood. Surprisingly, there is a complete lack of knowledge of GluN2 expression in female rodents. We, therefore, investigated the relative expression of specific GluN2 variants in the dorsal horn of lumbar (L4/L5) spinal cord from both male and female rats. In order to detect synaptic GluN2 isoforms, we used pepsin antigen-retrieval to unmask these highly cross-linked protein complexes. We found that GluN2B and GluN2D are preferentially localized to the pain-processing superficial regions of the dorsal horn in males, while only GluN2B is predominantly localized to the superficial dorsal horn of female rats. The GluN2A subunit is diffusely localized to neuropil throughout the dorsal horn of both males and females, while GluN2B and GluN2D immunolabelling are found both in the neuropil and on the soma of dorsal horn neurons. Finally, we identified an unexpected enhanced expression of GluN2B in the medial division of the superficial dorsal horn, but in males only. These sex-specific localization patterns of GluN2-NMDAR subunits across dorsal horn laminae have significant implications for the understanding of divergent spinal mechanisms of pain processing.

OBJECTIVES: Cerebrovascular disease is among the top 10 causes of death in US children, but risk factors for mortality are poorly understood. Within an international registry, we identify predictors of in-hospital mortality after pediatric arterial ischemic stroke (AIS). METHODS: Neonates (0–28 days) and children (29 days– RESULTS: Fourteen of 915 neonates (1.5%) and 70 of 2273 children (3.1%) died during hospitalization. Of 48 cases with reported causes of death, 31 (64.6%) were stroke-related, with remaining deaths attributed to medical disease. In multivariable analysis, congenital heart disease (odds ratio [OR]: 3.88; 95% confidence interval [CI]: 1.23–12.29; P = .021), posterior plus anterior circulation stroke (OR: 5.36; 95% CI: 1.70–16.85; P = .004), and stroke presentation without seizures (OR: 3.95; 95% CI: 1.26–12.37; P = .019) were associated with in-hospital mortality for neonates. Hispanic ethnicity (OR: 3.12; 95% CI: 1.56–6.24; P = .001), congenital heart disease (OR: 3.14; 95% CI: 1.75–5.61; P < .001), and posterior plus anterior circulation stroke (OR: 2.71; 95% CI: 1.40–5.25; P = .003) were associated with in-hospital mortality for children. CONCLUSIONS: In-hospital mortality occurred in 2.6% of pediatric AIS cases. Most deaths were attributable to stroke. Risk factors for in-hospital mortality included congenital heart disease and posterior plus anterior circulation stroke. Presentation without seizures and Hispanic ethnicity were also associated with mortality for neonates and children, respectively. Awareness and study of risk factors for mortality represent opportunities to increase survival.

Supplemental material, Supplementary table for Children with post-stroke epilepsy have poorer outcomes one year after stroke by Christine K Fox, Lori C Jordan, Lauren A Beslow, Jennifer Armstrong, Mark T Mackay, Gabrielle deVeber and on behalf of the SIPS Investigators in International Journal of Stroke