Citations

Background and Objectives The genetic basis of adult-onset multiple sclerosis (MS) is well-studied, but less is known about pediatric-onset MS (pedMS), comprising approximately 5% of all MS onsets. Mendelian randomization (MR) studies have demonstrated evidence for a causal association between MS and both 25-hydroxyvitamin D [25(OH)D] serum levels and genetic variation related to vitamin D receptor (VDR) binding. The objective was to identify whether VDR binding variants (VDR-BVs) previously implicated in adult-onset MS were associated with pedMS using genetic instrumental variables (GIVs). Methods Using previously identified VDR-BVs to construct individual GIVs with two-sample MR, we investigated associations with pedMS in 725 cases and 592 controls of European ancestry from the US Network of Pediatric MS Centers. Associations between each VDR-BV and pedMS were estimated using logistic regression adjusting for the first three genome-wide principal components. A significant interaction between a VDR-BV and 25(OH)D GIV provided evidence for a causal association unbiased by pleiotropy. Results One VDR-BV, rs2531804, previously associated with adult-onset MS, was also significantly associated with pedMS after multiple testing correction. Discussion This study is the first to use VDR-BVs from previous MR studies to demonstrate causal differences in VDR binding at a locus contributing to pedMS susceptibility.

Abstract We conducted a national survey of current pediatric infectious diseases (PID) fellows and PID fellowship graduates from the past 10 years to assess satisfaction with existing PID initial certifying exam preparatory materials. Satisfaction with existing resources was low. The most desired new resource was additional board-style questions.

Importance Nontraumatic subarachnoid hemorrhage (SAH) represents the third most common stroke type with unique etiologies, risk factors, diagnostics, and treatments. Nevertheless, epidemiological studies often cluster SAH with other stroke types leaving its distinct burden estimates obscure. Objective To estimate the worldwide burden of SAH. Design, Setting, and Participants Based on the repeated cross-sectional Global Burden of Disease (GBD) 2021 study, the global burden of SAH in 1990 to 2021 was estimated. Moreover, the SAH burden was compared with other diseases, and its associations with 14 individual risk factors were investigated with available data in the GBD 2021 study. The GBD study included the burden estimates of nontraumatic SAH among all ages in 204 countries and territories between 1990 and 2021. Exposures SAH and 14 modifiable risk factors. Main Outcomes and Measures Absolute numbers and age-standardized rates with 95% uncertainty intervals (UIs) of SAH incidence, prevalence, mortality, and disability-adjusted life-years (DALYs) as well as risk factor–specific population attributable fractions (PAFs). Results In 2021, the global age-standardized SAH incidence was 8.3 (95% UI, 7.3-9.5), prevalence was 92.2 (95% UI, 84.1-100.6), mortality was 4.2 (95% UI, 3.7-4.8), and DALY rate was 125.2 (95% UI, 110.5-142.6) per 100 000 people. The highest burden estimates were found in Latin America, the Caribbean, Oceania, and high-income Asia Pacific. Although the absolute number of SAH cases increased, especially in regions with a low sociodemographic index, all age-standardized burden rates decreased between 1990 and 2021: the incidence by 28.8% (95% UI, 25.7%-31.6%), prevalence by 16.1% (95% UI, 14.8%-17.7%), mortality by 56.1% (95% UI, 40.7%-64.3%), and DALY rate by 54.6% (95% UI, 42.8%-61.9%). Of 300 diseases, SAH ranked as the 36th most common cause of death and 59th most common cause of DALY in the world. Of all worldwide SAH-related DALYs, 71.6% (95% UI, 63.8%-78.6%) were associated with the 14 modeled risk factors of which high systolic blood pressure (population attributable fraction [PAF] = 51.6%; 95% UI, 38.0%-62.6%) and smoking (PAF = 14.4%; 95% UI, 12.4%-16.5%) had the highest attribution. Conclusions and Relevance Although the global age-standardized burden rates of SAH more than halved over the last 3 decades, SAH remained one of the most common cardiovascular and neurological causes of death and disabilities in the world, with increasing absolute case numbers. These findings suggest evidence for the potential health benefits of proactive public health planning and resource allocation toward the prevention of SAH.

Abstract Hypoplastic left heart syndrome (HLHS) is the most lethal congenital heart disease (CHD). The pathogenesis of HLHS is poorly understood, and due to the likely oligogenic complexity of the disease, definitive HLHS-causing genes have not yet been identified. Postulating impaired cardiomyocyte proliferation as a likely important contributing mechanism to HLHS pathogenesis, and we conducted a genome-wide siRNA screen to identify genes affecting proliferation of human iPSC-derived cardiomyocytes (hPSC-CMs). This yielded ribosomal protein (RP) genes as the most prominent class of effectors of CM proliferation. In parallel, whole genome sequencing and rare variant filtering of a cohort of 25 HLHS proband-parent trios with poor clinical outcome revealed enrichment of rare variants of RP genes. In addition, in a familial CHD case we identified a rare, predicted-damaging promoter variant affecting RPS15A that was shared between the HLHS proband and a distant relative with CHD. Functional testing with an integrated multi-model system approach reinforced the idea that RP genes are major regulators of cardiac growth and proliferation, thus potentially contributing to the hypoplastic phenotype observed in HLHS patients. Cardiac knockdown (KD) of RP genes with promoter or coding variants (RPS15A, RPS17, RPL26L1, RPL39, RPS15) reduced proliferation in generic hPSC-CMs and caused malformed hearts, heart-loss or even lethality in Drosophila. In zebrafish, diminished rps15a function caused reduced CM numbers, heart looping defects, or weakened contractility, while reduced rps17 or rpl39 function caused reduced ventricular size or systolic atrial dysfunction of the atrium, respectively. Importantly, genetic interactions between RPS15A and core cardiac transcription factors TBX5 in CMs, Drosocross, pannier and tinman in flies, and tbx5 and nkx2-7 (nkx2-5 paralog) in fish, support a specific role for RP genes in heart development. Furthermore, RPS15A KD-induced heart/CM proliferation defects were significantly attenuated by p53 KD in both hPSC- CMs and zebrafish, and by Hippo activation (YAP/yorkie overexpression) in developing fly hearts. Based on these findings, we conclude that RP genes play novel critical roles in cardiogenesis and constitute an emerging class of gene candidates likely involved in HLHS and other CHDs.

Abstract Introduction Moyamoya is characterized by idiopathic, progressive, large intracranial arterial steno-occlusion, affecting the anterior circulation of the brain. Common presentations include strokes, seizures, and headaches, which have been associated with poor sleep quality and sleep disorders in the general population. However, to our knowledge, sleep quality has not been previously investigated in Moyamoya disease. The aim of this study was to characterize self-reported sleep quality, sleepiness, sleep disorder diagnoses in patients with Moyamoya syndrome, and to explore possible association between sleep disturbance and quality of life in these patients. Methods We analyzed consecutive patients with Moyamoya evaluated at our institution who completed the Pittsburgh Sleep Quality Index (PSQI) and the Epworth Sleepiness Scale (ESS). We also abstracted the Patient-Reported Outcomes Measurement Information System (PROMIS) to measure person-centered physical, mental and social wellbeing. Results We studied 23 patients with mean age 41.8 ± 12.1 years old having disease duration of 3 ± 4.4 years. 15 (65.2%) had ischemic strokes. Mean total PSQI score was 6.9 ± 2.9, and 17 (73.9%) had poor sleep quality (PSQI>5). Mean sleep efficiency was reduced at 80 ± 17%. Although Median ESS was 6 (IQR 3.25 – 8), most patients (91.3%) reported at least mild daytime dysfunction (Component 7≥1). Mean PSQI component scores (0 – 3 severity, 3 is worse) were 1.29 ± 0.62 (subjective quality), 1.1 ± 0.73 (sleep latency), 1.04 ± 0.83 (sleep duration), 0.87 ± 1.01 (sleep efficiency), 1.22 ± 0.52 (sleep disturbances), 0.3 ± 0.88 (sleep medication), and 1.1 ± 0.52 (daytime dysfunction). The total PSQI score was positively correlated with PROMIS score (r=0.47, p=0.044). Only one patient was diagnosed with obstructive sleep apnea and three with chronic insomnia. Conclusion Poor sleep quality appears to be a frequent problem in patients with Moyamoya disease. Sleep disturbance severity was similar to previous findings in clinical stroke populations. The apparent mismatch between subjective sleep disturbance and sleep disorder diagnoses suggest that sleep disorders are likely underdiagnosed in Moyamoya patients. The relationship between PSQI and PROMIS scores suggests that sleep disturbance may significantly affect quality of life in these patients. Support (if any)

In 2007, the Bárány Society embarked on a project to establish definitions of vestibular syndromes and disorders based on best available evidence, referred to as the International Classification of Vestibular Disorders (ICVD). Since then, numerous publications providing consensus-driven diagnostic criteria for vestibular symptoms, syndromes, and disorders have been published. Here, we reflect on the rationale for developing the ICVD as well as its subsequent achievements, challenges, and outlook. In this summary of the work of the ICVD to date, the authors will focus on practical aspects to help improve the utility and applicability of these diagnostic criteria moving forward.

ABSTRACT Evidence indicates that the integrity of in utero development influences late life healthy or unhealthy aging; however, specific links between them are unclear. Histone chaperone HIRA is thought to play a role in both life stages, and here, we explore this role using the murine pigmentary system by investigating and comparing the effects of its lineage‐specific knockout, either conditionally during embryogenesis or postnatally. Embryonic knockout of Hira in tyrosinase+ neural crest‐derived lineages, including melanoblasts, led to reduced melanoblast numbers during embryogenesis, with single‐cell RNA sequencing analysis indicating evidence of lineage‐specificity defects. This was supported in an in vitro model using melb‐a melanoblasts in which Hira knockdown affected lineage identity and melanoblast differentiation potential, with ATAC‐seq data indicating a role of HIRA in orchestrating chromatin accessibility. Interestingly, however, newborn Hira knockout mice had wild type numbers of differentiated melanocytes, albeit functionally defective, as demonstrated by very mild hypopigmentation of the first hair coat, increased melanocyte telomere‐associated DNA damage foci, and impaired response to proliferative challenge. Moreover, as they aged, mice with embryonic melanoblast Hira knockout displayed marked defects in melanocyte stem cell maintenance and premature hair graying. Importantly, this phenotype was not observed after postnatal inducible knockout, indicating an essential role for HIRA at embryonic stages that is transmitted to adulthood, rather than a direct postnatal requirement within the pigmentary system. This genetic model shows that HIRA function during early development lays a foundation for maintaining lineage identity and subsequent maintenance of adult tissue‐specific stem cells during aging.