Vitamin D has pleiotropic physiological actions including immune system regulation, in addition to its classical role in calcium homeostasis. Hormonal 1,25-dihydroxyvitamin D (1,25D) signals through the nuclear vitamin D receptor, and large-scale expression profiling has provided numerous insights into its diverse physiological roles. To obtain a comprehensive picture of vitamin D signaling, we analyzed raw data from 94 (80 human, 14 mouse) expression profiles of genes regulated by 1,25D or its analogs. This identified several thousand distinct genes directly or indirectly up- or downregulated in a highly cell-specific manner in human cells using a 1.5-fold cut-off. There was significant overlap of biological processes regulated in human and mouse but minimal intersection between genes regulated in each species. Disease ontology clustering confirmed roles for 1,25D in immune homeostasis in several human cell types, and analysis of canonical pathways revealed novel and cell-specific roles of vitamin D in innate immunity. This included cell-specific regulation of several components of NOD-like pattern recognition receptor signaling, and metabolic events controlling innate immune responses. Notably, 1,25D selectively enhanced catabolism of branched-chain amino acids (BCAAs) in monocytic cells. BCAA levels regulate the major metabolic kinase mTOR, and pretreatment with 1,25D suppressed BCAA-dependent activation of mTOR signaling. Furthermore, ablation of BCAT1 expression in monocytic cells blocked 1,25D-induced increases in autophagy marker LAMP1. In conclusion, the data generated represents a powerful tool to further understand the diverse physiological roles of vitamin D signaling and provides multiple insights into mechanisms of innate immune regulation by 1,25D.

Background: Newborn screening (NBS) identifies infants with severe, early-onset diseases, enabling early diagnosis and treatment. In Canada, decisions regarding disease inclusion in NBS programs occur at the provincial level, which leads to variability in patient care. We aimed to determine whether important differences exist in NBS programs across provinces and territories. Given that spinal muscular atrophy (SMA) is the most recent disease added to NBS programs, we hypothesized that its inclusion would show interprovincial variability and be more likely in provinces already screening for a greater number of diseases. Methods: We conducted a cross-sectional survey of all NBS labs in Canada to understand: 1) what conditions were included in their program; 2) what genetic-based testing was performed and; 3) if SMA was included. Results: All NBS programs (N = 8) responded to this survey by June 2022. There was a 2.5-fold difference in the number of conditions screened (N = 14 vs N = 36) and a 9-fold difference in the number of conditions screened by gene-based testing. Only nine conditions were common to all provincial NBS programs. NBS for SMA was performed in four provinces at the time of our survey, with BC recently becoming the fifth province to add SMA to their NBS on October 1, 2022. Currently, 72% of Canadian newborns are screened for SMA at birth. Conclusion: Although healthcare in Canada is universal, its decentralization gives rise to regional differences in NBS programs which creates inequity in the treatment, care, and potential outcomes of affected children across provincial jurisdictions.

Background Post-hemorrhagic ventricular dilatation (PHVD) is a serious complication of intraventricular hemorrhage (IVH) in preterm newborns and is associated with significant impairments. The natural evolution of PHVD and developmental implications of spontaneous resolution are not well established. Objectives To investigate the natural evolution of PHVD and compare neurodevelopmental impairments in newborns with (1) spontaneous resolution of PHVD; (2) persistent PHVD and (3) PHVD who underwent neurosurgical intervention. Design/Methods We conducted a multicenter retrospective cohort study of 5238 newborns born at ≤34 weeks’ gestational age (GA) admitted to two tertiary Neonatal Intensive Care Units (NICU) between 2012 and 2020. Head ultrasounds (HUS) of 476 newborns with IVH grade ≥2 were reviewed to identify PHVD, defined as ventricular index (VI) >97th centile (p97) for GA and anterior horn width (AHW) >6mm on any HUS in the first 6 weeks of life. Newborns with PHVD were divided into three groups, Group 1: newborns with spontaneous resolution of PHVD, defined as the regression of both lateral ventricles below the VI and AHW thresholds, Group 2: newborns with persistent PHVD absent neurosurgical intervention and Group 3: newborns who underwent any neurosurgical intervention. Neurodevelopmental outcomes at 18 months corrected, obtained through chart review, were compared. Results Of 108 newborns with PHVD, 88 survived to NICU discharge (mean GA 28.4 weeks, SD 2.8; median age at PHVD diagnosis 8.0 days, IQR 5.0-12.8). Overall, 34/88 (38.6%) newborns had spontaneous resolution of PHVD (Group 1). The median time between PHVD diagnosis and spontaneous resolution was 14.0 days (IQR 6.8-32.3) (Figure). In Group 3, the median time between PHVD diagnosis and the first neurosurgical intervention was 14.0 days (IQR 7.0-23.0). Group 1 had significantly smaller maximal VI (1.8, 3.4, and 11.1mm above p97, p<0.001) and AHW (7.2, 10.8, and 20.3mm, p<0.001) than Groups 2 and 3, respectively, and were less likely to have bilateral PHVD (OR 0.47, 95% CI 0.33-0.67) than Group 3. Neurodevelopmental outcome data at 18 month were available for 53/88 (60.2%) survivors (Table). Group 1 had lower rates of cerebral palsy (17.4% vs 45.8%; p=0.037), global developmental delay (17.4% vs 50.0%; p=0.018), epilepsy (4.3% vs 29.2%; p=0.048) and involvement of ≥3 allied health professionals (34.8% vs 70.8%; p=0.013) compared to Group 3. Conclusion Newborns with PHVD without spontaneous resolution are at higher risk for significant neurodevelopmental impairments despite neurosurgical interventions, which may be due to more prominent ventricular dilatation. Strategies aimed at mitigating the burden of impairments in patients without spontaneous resolution are needed.

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