Faculty Bibliography

BACKGROUND/UNASSIGNED:The potential for impaired sleep due to pain or discomfort can be a concern for adherence to nighttime bracing when treating clubfoot. The primary aim of our study was to compare sleep efficiency in young children wearing a nighttime foot abduction orthosis (FAO) to that of a matched control group. Secondary aims included the comparison of total sleep time, number of night wakings, and number of parental interventions between groups. METHODS/UNASSIGNED:< .05. RESULTS/UNASSIGNED:There were no significant differences in sleep efficiency, total sleep time, or number of night wakings. There were slightly more nighttime interventions for parents of children with clubfeet compared to controls. CONCLUSIONS/UNASSIGNED:Sleep metrics of young children undergoing Ponseti-style FAO bracing are not significantly different from those of matched controls. KEY CONCEPTS/UNASSIGNED:(1)Autovideosomnography using the Nanit infant monitor was utilized to measure sleep/wake patterns in 25 clubfoot patients undergoing Ponseti-style boots and bar treatment and 75 matched controls.(2)Clubfoot patients undergoing Ponseti-style boots and bar treatment did not have any significant differences across sleep efficiency, total sleep time, total time awake or number of night wakings compared to controls.(3)As brace tolerance and consistent adherence to a nighttime bracing regimen are essential to prevent recurrent clubfoot, caregivers and physicians may be reassured that clubfoot bracing will not significantly impact a child's sleep. LEVEL OF EVIDENCE/UNASSIGNED:Level II.

The ability to shift focus within three-dimensional space depends on vergence eye movements, which are impaired in ≤40% of individuals with neurodegenerative disorders. Although foundational studies in monkeys have identified neural correlates of vergence in the midbrain, a translational gap persists, leaving the neural basis of vergence dysfunction in humans poorly understood. Through voxel-wise analyses in 66 humans and 19 monkeys with midbrain lesions, we link vergence dysfunction causally to a region rostral to the superior colliculus and centred on the nucleus of the posterior commissure (NPC). Connectivity analyses across species identified a brain circuit linking the NPC to the visual pretectum and midbrain premotor hubs, regions capable of integrating the visual input and motor output necessary for vergence control. Collectively, these findings provide a neuroanatomical basis for vergence dysfunction and demonstrate how lesion mapping can bridge fundamental insights from animal models with clinical observations in humans.

BACKGROUND:Increased chronological age correlates with reduced relapse rates and increased disability in multiple sclerosis (MS). Biological age may better capture ageing's impact on MS and might accelerate due to MS itself. Establishing accelerated biological ageing in adults is complicated by normal ageing and comorbidities. Telomere length, a well-recognised biological ageing marker, is shortened in adults with MS and associated with disability. Demonstrating accelerated biological ageing in paediatric-onset MS (POMS) would strengthen the hypothesis that MS drives premature biological ageing. This study aimed to determine if telomere length differs in POMS compared to age-similar healthy controls. METHODS:We performed a cross-sectional case-control study of whole blood samples and clinical data from The US Network of Pediatric MS Centers. Real-time quantitative PCR measured telomere length, expressed as a telomere to somatic DNA ratio (T/S ratio). T/S ratio was compared between cases and age-similar healthy controls using multivariate regression analysis adjusting for chronological age, sex, race, ethnicity, tobacco exposure, socioeconomic status and body mass index. RESULTS:We analysed 300 POMS cases and 200 controls. The unadjusted mean T/S ratios were 1.66 (SD 0.32) for cases and 1.71 (SD 0.29) for controls (mean difference -0.05, 95% CI -0.10 to 0.01, p=0.08). After adjusting for key covariables with face validity, POMS participants had a mean 0.086 shorter T/S ratio than controls (95% CI 0.015 to 0.157, p=0.018). CONCLUSIONS:POMS participants demonstrated shorter telomeres than age-similar controls in a multivariable model adjusting for sociodemographic variables, suggesting that MS may contribute to accelerated biological ageing.

BACKGROUND:Multiple sclerosis (MS) and neurosarcoidosis (NS) can present as similar neuro-radiologic syndromes. Neither disease has pathognomonic clinical or laboratory findings and differentiating between them may be challenging. We hypothesized that cerebrospinal fluid (CSF) immune cell profiles, including CD4/CD8 cell ratio and proportion of B cells, might help to distinguish NS from MS. METHODS:Patients with probable or definite NS who were evaluated at the NYU MS Comprehensive Care Center (New York) and had CSF flow cytometry done as part of diagnostic workup were matched by age, sex, and race/ethnicity to MS patients with available CSF flow cytometry. All patients who received immunomodulatory therapy within 3 months of lumbar puncture were excluded. Flow cytometry was performed using BD FACSCanto™ and FACSCanto™ II Cell Analyzers (BDBiosciences, San Jose, CA) and manually verified by a hematopathologist. Group comparisons were made with an unpaired two-tailed Student's t-test, Chi-square test, or Wilcoxon rank sum test, as appropriate; p < 0.05 was considered significant. RESULTS:, p < 0.0001) and protein levels (101.2 ± 88.9 mg/dL vs. 35.7 ± 19.6, p = 0.003), while MS patients had more CSF-restricted oligoclonal bands (7.7 ± 5.3 vs. 1.7 ± 2.4, p < 0.00042). No differences were found in CSF glucose concentrations or IgG indices. Proportions of all immune cells in CSF were similar in NS and MS, including the CD4/CD8 ratio and percentages of B cells. CONCLUSION/CONCLUSIONS:Clinically available CSF flow cytometry immune profiles do not offer added discriminatory value for differentiating NS from MS. More granular immunophenotyping may be needed to improve diagnostic precision.

IMPORTANCE/UNASSIGNED:Millions of children worldwide are experiencing prolonged symptoms after SARS-CoV-2 infection, yet social risk factors for developing long COVID are largely unknown. As child health is influenced by the environment in which they live and interact, adverse social determinants of health (SDOH) may contribute to the development of pediatric long COVID. OBJECTIVE/UNASSIGNED:To identify whether adverse SDOH are associated with increased odds of long COVID in school-aged children and adolescents in the US. DESIGN, SETTING, AND PARTICIPANTS/UNASSIGNED:This cross-sectional analysis of a multicenter, longitudinal, meta-cohort study encompassed 52 sites (health care and community settings) across the US. School-aged children (6-11 years; n = 903) and adolescents (12-17 years; n = 3681) with SARS-CoV-2 infection history were included. Those with an unknown date of first infection, history of multisystem inflammatory syndrome in children, or symptom surveys with less than 50% of questions completed were excluded. Participants were recruited via health care systems, long COVID clinics, fliers, websites, social media campaigns, radio, health fairs, community-based organizations, community health workers, and existing research cohorts from March 2022 to August 2024, and surveys were completed by caregivers between March 2022 and August 2024. EXPOSURE/UNASSIGNED:Twenty-four individual social determinant of health factors were grouped into 5 Healthy People 2030 domains: economic stability, social and community context, caregiver education access and quality, neighborhood and built environment, and health care access and quality. Latent classes were created within each domain and used in regression models. MAIN OUTCOMES AND MEASURES/UNASSIGNED:Presence of long COVID using caregiver-reported, symptom-based, age-specific research indices. RESULTS/UNASSIGNED:The mean (SD) age among 4584 individuals included in this study was 14 (3) years, and 2330 (51%) of participants were male. The number of latent classes varied by domain; the reference group was the class with the least adversity. In unadjusted analyses, most classes in each domain were associated with higher odds of long COVID. After adjusting for many factors, including age group, sex, timing of infection, referral source, and other social determinant of health domains, economic instability characterized by difficulty covering expenses, poverty, receipt of government assistance, and food insecurity were associated with an increased risk of having long COVID (class 2 adjusted odds ratio [aOR], 1.57; 95% CI, 1.18-2.09; class 4 aOR, 2.39; 95% CI, 1.73-3.30); economic instability without food insecurity (class 3) was not (aOR, 0.93; 95% CI, 0.70-1.23). Poorer social and community context (eg, high levels of discrimination and low social support) was also associated with long COVID (aOR, 2.17; 95% CI, 1.77-2.66). Sensitivity analyses stratified by age group and adjusted for race and ethnicity did not alter or attenuate these results. CONCLUSIONS AND RELEVANCE/UNASSIGNED:In this study, economic instability that included food insecurity and poor social and community context were associated with greater odds of pediatric long COVID. Those with food security, despite experiencing other economic challenges, did not have greater odds of long COVID. Further study is needed to determine if addressing SDOH factors can decrease the rate of pediatric long COVID.

BACKGROUND/UNASSIGNED:Outdoor navigation poses significant challenges for people with blindness or low vision, yet the role of gaze behaviour in supporting mobility remains underexplored. Fully sighted individuals typically adopt consistent scanning strategies, whereas those with visual impairments rely on heterogeneous adaptations shaped by residual vision and experience. METHODS/UNASSIGNED:We conducted a comparative eye-tracking study of fully sighted, low vision, blind, and fully blind participants navigating outdoor routes. Using a wearable eye tracker, we quantified fixation counts, fixation rate, fixation area, direction, peak fixation location, and walking speed. RESULTS/UNASSIGNED:Walking speed declined systematically with worsening vision. Fixation count increased with greater impairment, reflecting slower travel times and more frequent sampling. Fixation rate differed across groups, though between-group differences were generally not significant between most groups. Fixation spatial coverage decreased along the continuum of vision loss. Fixation patterns were most consistent in the fully sighted group. Peak fixation locations were centred in fully sighted participants but shifted outward and became more variable with impairment. CONCLUSION/UNASSIGNED:Gaze strategies during navigation form a graded continuum across vision groups, with fully sighted and fully blind participants at opposite poles and low vision and blind groups spanning the middle. Visual acuity alone does not predict functional gaze use, as rehabilitation experience and adaptive strategies strongly shape behaviour. These findings highlight the need for personalised rehabilitation and assistive technologies, with residual gaze patterns offering insight into mobility capacity and training opportunities for safer navigation.IMPLICATIONS FOR REHABILITATIONDistinct Residual Vision Patterns: This research reveals that residual vision patterns differ significantly, with fully sighted individuals exhibiting a consistent fixation pattern while low vision participants show more varied strategies during navigation.Highly Individualised Gaze Behaviours: Low vision participants demonstrate highly individualised gaze behaviours, indicating that a one-size-fits-all approach is inadequate for effective rehabilitation.Tailored Assistive Solutions: Assistive technologies and rehabilitation programs should be designed to address these unique, individualised needs, providing personalised feedback and training to enhance mobility and safety.

OBJECTIVE:Cervical artery dissection (CeAD) may be limited to the extracranial extradural space or extend to the intradural space. Intradural extension can potentially increase the risk of stroke and subarachnoid hemorrhage. However, the factors associated with intradural extension and its impact on clinical outcome remain unclear. METHODS:This was a secondary analysis of the STOP-CAD observational, multi-center study. Patients with CeAD and intradural extension (CeADid) were compared with those with pure CeAD extradural dissections (CeADed) using multiple regression analyses. RESULTS:Of 4,023 patients with CeAD, 534 (13.3%) had CeADid. In comparison to patients with CeADed, those with CeADid more often had clinical overt stroke or transient ischemic attack (TIA) at presentation, acute infarcts on imaging, a vertebral artery affected, and severe stenosis of the involved vessel (p < 0.001 for all). In contrast, carotid involvement and complete occlusions were more frequent in patients with CeADed (p < 0.001 for both). CeADid was associated with a shift in the distribution of scores on the modified Rankin Scale (mRS) toward worse functional outcome (odds ratio [OR] = 0.76, 95% confidence interval [CI] = 0.62-0.92) but the odds for favorable outcomes (mRS = 0-2) did not differ between the groups after appropriate adjustments on multivariate analysis. CeADid was independently associated with higher mortality at 180 days on multivariate analysis (adjusted OR = 2.84, 95% CI = 1.50-5.38). INTERPRETATION/CONCLUSIONS:CeADid is associated with more severe clinical presentation, a shift toward less favorable outcomes, and higher mortality rates. These findings suggest that CeADid may represent a high-risk type of CeAD. ANN NEUROL 2026.

The Stroke Treatment Academic Industry Roundtable convened a workshop regarding artificial intelligence (AI) and innovative clinical trial designs during the Stroke Treatment Academic Industry Roundtable XIII meeting on March 28, 2025. This forum brought together stroke physicians and researchers, and industry representatives to discuss the current use and future opportunities for AI and novel trial designs in acute stroke trials. AI already plays a substantial role in the treatment of acute stroke with regards to imaging but is poised to have a much larger impact in clinical care and research trials over the coming years. The quality and understanding of the data are used to train the AI, the human element needed to ensure training is successful, and the clinician and trialist at the bedside, the humans "in the loop," will be necessary to maximize AI's effectiveness in clinical practice and trials. Platform trials address multiple scientific questions in an area of medicine simultaneously within the same trial structure by sharing controls across multiple interventions. While platform trials increase efficiency and potentially decrease the time needed to answer important clinical scientific questions, they also can introduce complexity to standard workflows. Future acute ischemic stroke clinical trials should incorporate elements of pragmatic and patient-centered trial design when possible. Pragmatic trials aim to assess the effectiveness of treatments when they are implemented into routine clinical care rather than under idealized conditions. AI models and platform, pragmatic, and patient-centered trial designs are new tools to answer important clinical questions, but understanding how they work, their best uses, and their limitations is critical for accelerating successful new treatments for stroke.

IMPORTANCE/UNASSIGNED:Neuroscientific, epidemiological, and electronic health record studies implicate herpes simplex virus (HSV) as potentially etiological for Alzheimer disease (AD). OBJECTIVE/UNASSIGNED:To compare the efficacy and adverse effects of valacyclovir vs placebo in participants with early symptomatic AD and HSV seropositivity (HSV-1 or HSV-2). DESIGN, SETTING, AND PARTICIPANTS/UNASSIGNED:This randomized clinical trial included adults with a clinical diagnosis of probable AD or a clinical diagnosis of mild cognitive impairment with positive biomarkers for AD, a positive serum antibody test (IgG or IgM) for HSV-1 or HSV-2, and a Mini-Mental State Examination score of 18 to 28. The trial was conducted at 3 US outpatient clinics specializing in memory disorders. Recruitment occurred from January 2018 to May 2022; the last follow-up occurred in September 2024. INTERVENTION/UNASSIGNED:Either 4 g/d of valacyclovir (n = 60) or matching placebo (n = 60). MAIN OUTCOMES AND MEASURES/UNASSIGNED:The primary outcome was least-squares mean (LSM) change at 78 weeks in the 11-item Alzheimer's Disease Assessment Scale Cognitive (ADAS-Cognitive) Subscale score (range, 0-70; higher scores indicate greater impairment). The secondary outcomes were LSM change in the Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) Scale score; LSM change in the 18F-florbetapir amyloid positron emission tomography (PET) standardized uptake value ratio (SUVR; higher scores indicate higher amyloid levels) for 6 brain regions (medial orbitofrontal, anterior cingulate, parietal lobe, posterior cingulate, temporal lobe, and precuneus); and LSM change in 18F-MK-6240 tau PET medial temporal SUVR (higher scores indicate higher tau levels) for 4 brain regions (amygdala, hippocampus, entorhinal, and parahippocampus). The frequency of adverse events was the safety outcome. RESULTS/UNASSIGNED:Of the 120 participants (mean age, 71.4 [SD, 8.6] years; 55% were female), 93 (77.5%) completed the trial. At 78 weeks, the LSM change in the 11-item ADAS-Cognitive Subscale score was 10.86 (95% CI, 8.80 to 12.91) in the valacyclovir group vs 6.92 (95% CI, 4.88 to 8.97) in the placebo group, indicating greater cognitive worsening with valacyclovir than placebo (between-group difference, 3.93 [95% CI, 1.03 to 6.83]; P = .01). The LSM change in the ADCS-ADL Scale score at 78 weeks was -13.78 (95% CI, -17.00 to -10.56) in the valacyclovir group vs -10.16 (95% CI, -13.37 to -6.96) in the placebo group (between-group difference, -3.62 [95% CI, -8.16 to 0.93]). At 78 weeks, the LSM change in the 18F-florbetapir amyloid PET SUVR was 0.03 (95% CI, -0.04 to 0.10) in the valacyclovir group vs 0.01 (95% CI, -0.06 to 0.08) in the placebo group (between-group difference, 0.02 [95% CI, -0.08 to 0.12]). The LSM change in the 18F-MK-6240 tau PET medial temporal SUVR at 78 weeks was 0.07 (95% CI, -0.06 to 0.19) in the valacyclovir group vs -0.04 (95% CI, -0.15 to 0.07) in the placebo group (between-group difference, 0.11 [95% CI, -0.06 to 0.28]). The most common adverse events were elevated serum creatinine level (5 participants [8.3%] in the valacyclovir group vs 2 participants [3.3%] in the placebo group) and COVID-19 infection (3 [5%] vs 2 [3.3%], respectively). CONCLUSIONS AND RELEVANCE/UNASSIGNED:Valacyclovir was not efficacious with cognitive worsening for the primary outcome and it is not recommended to treat individuals with early symptomatic AD and HSV seropositivity. TRIAL REGISTRATION/UNASSIGNED:ClinicalTrials.gov Identifier: NCT03282916.

Polyaminopathies are a recently described family of rare genetic neurodevelopmental disorders. Polyaminopathies disrupt the biosynthesis of the primary polyamines: putrescine, spermidine, and spermine. Snyder-Robinson syndrome results from hemizygous loss-of-function variants in the spermine synthase (SMS) gene, resulting in decreased or complete loss of spermine synthase enzyme activity. Bachmann-Bupp syndrome results from heterozygous gain-of-function variants in the ornithine decarboxylase 1 (ODC1) gene, resulting in increased ornithine decarboxylase enzyme activity. Faundes-Banka syndrome results from heterozygous loss-of-function variants in the eukaryotic translation initiation factor 5A (EIF5A) gene, impairing eIF5A protein function. DHPS (deoxyhypusine synthase) deficiency is an autosomal recessive disease and results from bi-allelic hypomorphic variants in the deoxyhypusine synthase (DHPS) gene, which results in reduced deoxyhypusine synthase enzyme activity. Finally, DOHH (deoxyhypusine hydroxylase) disorder is an autosomal recessive disorder caused by bi-allelic loss-of-function variants in the deoxyhypusine hydroxylase (DOHH) gene, which causes decreased deoxyhypusine hydroxylase enzyme activity. Snyder-Robinson syndrome was first described in 1969, while the other four syndromes have only been identified in the past 7 years. A comprehensive phenotypic and genotypic description of these five syndromes is needed. We review the clinical and genetic features of these five polyaminopathies to create an inclusive clinical resource. A systematic keyword search strategy was used to identify all published cases in PubMed, Web of Science, and Scopus databases. The five known syndromes associated with the polyamine pathway share many similar clinical phenotypes, and yet patients with each syndrome present with distinctive syndromic features. This review will serve as a valuable resource for clinicians diagnosing and caring for patients with these rare polyaminopathies.