Faculty Bibliography

Gliomas are a major cause of cancer-related deaths in adolescents and young adults (AYAs; ages 15-39 years). Different molecular alterations drive gliomas in children and adults, leading to distinct biology and clinical consequences, but the implications of pediatric- versus adult-type alterations in AYAs are unknown. Our population-based analysis of 1,456 clinically and molecularly characterized gliomas in patients aged 0-39 years addresses this gap. Pediatric-type alterations were found in 31% of AYA gliomas and conferred superior outcomes compared to adult-type alterations. AYA low-grade gliomas with specific RAS-MAPK alterations exhibited senescence, tended to arise in different locations and were associated with superior outcomes compared to gliomas in children, suggesting different cellular origins. Hemispheric IDH-mutant, BRAF p.V600E and FGFR-altered gliomas were associated with the risk of malignant transformation, having worse outcomes with increased age. These insights into gliomagenesis may provide a rationale for earlier intervention for certain tumors to disrupt the typical behavior, leading to improved outcomes.

Seizures occur in 20-45% of patients with cerebral arteriovenous malformations (AVMs) and can potentially influence their quality of life. Some studies have suggested risk factors influencing their development, but the evidence is limited to small cohorts. To analyze seizure presentation and factors influencing seizure development in patients with cerebral AVMs using a multi-institutional consortium. Retrospective multicenter registry from multiple centers in North America and Europe of patients aged 1 to 89 years who had undergone any intervention for brain AVMs between January 2010 and December 2023. Demographics, functional assessment (modified Rankin Scale; mRS), and AVM characteristics, were evaluated to assess for relationship with seizures using a multivariate generalized linear mixed-effects model. 1,005 AVM patients were analyzed; the median age was 42, 73% had a baseline mRS ≤ 2. The median nidus size was 2.2 cm, and most AVMs were Spetzler-Martin grade II (37%). Seizure was the presenting symptom in 237 patients (24%). After adjusting for significant variables, patient-specific factors associated with seizures were younger age (OR 0.99, CI95% 0.98-1), male sex (OR 1.65, CI95% 1.18-2.30), and smoking history (OR 1.69, CI95% 1.17-2.44). AVM-specific factors associated with seizures included rupture status (OR 0.42, CI95% 0.30-0.61); eloquent cortex (OR 1.61, CI95% 1.13-2.29); frontal (OR 1.54, CI95% 1.01-2.35), temporal (OR 1.93, CI95% 1.26-2.96) and parietal (OR 1.71 CI95% 1.08-2.71) location; larger nidal size (OR = 1.23, CI95% 1.08-1.39), and superficial draining vein location (OR 1.86, CI95% 1.15-3.01). In this multicenter consortium, after controlling for significant variables, the incidence of AVM-related seizures was associated with younger age, male sex, smoking history, larger AVMs, eloquent locations, and AVMs in the frontal, temporal, and parietal cortices. Conversely, rupture status, deep venous drainage, and cerebellar locations were negatively associated with seizures.

OBJECTIVE:Dravet syndrome (DS) is a severe developmental and epileptic encephalopathy caused by SCN1A haploinsufficiency in the majority of cases. Caregivers of adults with DS often complain about the loss of previously acquired skills. We set out to explore these perceptions and determine whether abnormalities reported were detectable in validated tests. We also investigated possible correlations between symptoms, age, and exposure to sodium channel blockers (SCBs). METHODS:This cross-sectional, multicenter study used the Vineland Adaptive Behavior Scales, 3rd edition (raw scores) for behavior analyses and Moss-Psychiatric Assessment Schedules checklist to screen for psychiatric symptoms. The Social Communication Questionnaire screened for social communication deficits. Parkinsonian features were evaluated with the modified Unified Parkinson's Disease Rating Scale. For gait evaluation, we validated the use of home videos, using instrumental gait analysis in a subgroup of patients, and then used the home videos for the remainder. RESULTS:A total of 92 patients were enrolled (age range = 18-51 years, mean = 27.93 ± 8.59 years). Sixty percent of caregivers observed a decline in previously acquired skills, including intelligence, speech, interaction with others, ability to climb stairs and walk without support, and hand coordination. Adaptive skills, parkinsonian symptoms, and gait were worse in older patients and those exposed to SCBs for longer periods of time. Fourteen percent of patients screened positive for affective disorders, 11.6% for dementia, and 10.5% for a psychotic disorder. Fifty-three percent screened positive for social communication deficits. SIGNIFICANCE/CONCLUSIONS:This is the largest group of adults with DS to be systematically evaluated. They had severe nonseizure symptoms. Older age and longer use of SCBs were associated with worse adaptive skills, gait, and parkinsonism. Some older adults screened positive for depression and dementia. Caregivers identified functional decline in activities of daily living (ADLs). Taken together, the risk of dementia, parkinsonian gait, and decline in ability to perform previously mastered ADLs support that some adults with DS may be developing a neurodegenerative disorder.

BACKGROUND AND OBJECTIVES/OBJECTIVE:The aim of this study was to identify distinct inflammatory response subtypes in patients with c-NORSE by analyzing their cytokine profiles. Insights into underlying mechanisms were sought to understand the pathophysiology and guide personalized therapies to improve patient outcomes. METHODS:Sixty-two patients with c-NORSE were included. A comprehensive panel of 96 cytokines was analyzed in serum samples. Patients were clustered based on their cytokine profiles using the Louvain algorithm, an unsupervised graph-based clustering method. The identified clusters of patients were compared regarding cytokine levels and clinical features. Protein pathway analysis was used to explore the biological relevance of the inflammatory markers within each cluster. Patients with c-NORSE were compared with control patients (n = 18) and patients with other forms of refractory SE (n = 45). RESULTS:Compared with controls, patients with c-NORSE exhibited significant differences in 33 cytokines. Pathway analysis revealed dysregulations in chemotaxis and neutrophil recruitment and migration, highlighting the importance of innate immunity in patients with c-NORSE. Within the c-NORSE cohort, 3 clusters of patients emerged: cluster A, lacking specific inflammatory markers; cluster B, with a much stronger innate-immunity cytokine-driven inflammatory response compared with clusters A and C; and cluster C, defined by dysregulated autoimmune processes. Notably, patients in cluster B showed a statistically significant elevation of innate immune-related proinflammatory cytokines associated with leukocyte recruitment and degranulation. By contrast, those in cluster C showed activation of Janus kinase signal transducer and activator of transcription (JAK-STAT) pathways, suggesting autoimmune mechanisms. Patients in clusters B and C demonstrated varied responses to immunotherapies, with cluster C patients showing favorable outcomes after multiple immunotherapies. DISCUSSION/CONCLUSIONS:The identification of distinct inflammatory subgroups in c-NORSE suggests that variations in the underlying immune mechanisms contribute to differential treatment responses. These findings underscore the importance of personalized therapeutic strategies, potentially targeting specific inflammatory pathways, to optimize clinical outcomes in this challenging condition.

Since the first antiseizure medication (ASM) was introduced in 1857, more than 30 medications have been approved by the United States Food and Drug Administration (FDA) for the treatment of epilepsy. However, limitations in efficacy and tolerability have led to one-third of patients suffering from uncontrolled seizures. Recent advances in genetics, disease modeling, high-throughput target-based and phenotype-based screening, study design, and identification of novel mechanisms of action or routes of delivery have resulted in more than 200 therapeutics currently under development in the epilepsy pipeline. This study discusses near-to-market drugs in advanced clinical development, with select drugs in earlier stages. Background regarding mechanisms, animal studies, pharmacokinetics, pharmacodynamics, efficacy, tolerability, and safety data are provided for each drug when available.

IMPORTANCE/UNASSIGNED:The profile of gastrointestinal (GI) tract outcomes associated with the postacute and chronic phases of COVID-19 in children and adolescents remains unclear. OBJECTIVE/UNASSIGNED:To investigate the risks of GI tract symptoms and disorders during the postacute (28-179 days after documented SARS-CoV-2 infection) and the chronic (180-729 days after documented SARS-CoV-2 infection) phases of COVID-19 in the pediatric population. DESIGN, SETTING, AND PARTICIPANTS/UNASSIGNED:This retrospective cohort study was performed from March 1, 2020, to September 1, 2023, at 29 US health care institutions. Participants included pediatric patients 18 years or younger with at least 6 months of follow-up. Data analysis was conducted from November 1, 2023, to February 29, 2024. EXPOSURES/UNASSIGNED:Presence or absence of documented SARS-CoV-2 infection. Documented SARS-CoV-2 infection included positive results of polymerase chain reaction analysis, serological tests, or antigen tests for SARS-CoV-2 or diagnosis codes for COVID-19 and postacute sequelae of SARS-CoV-2. MAIN OUTCOMES AND MEASURES/UNASSIGNED:GI tract symptoms and disorders were identified by diagnostic codes in the postacute and chronic phases following documented SARS-CoV-2 infection. The adjusted risk ratios (ARRs) and 95% CI were determined using a stratified Poisson regression model, with strata computed based on the propensity score. RESULTS/UNASSIGNED:The cohort consisted of 1 576 933 pediatric patients (mean [SD] age, 7.3 [5.7] years; 820 315 [52.0%] male). Of these, 413 455 patients had documented SARS-CoV-2 infection and 1 163 478 did not; 157 800 (13.6%) of those without documented SARS-CoV-2 infection had a complex chronic condition per the Pediatric Medical Complexity Algorithm. Patients with a documented SARS-CoV-2 infection had an increased risk of developing at least 1 GI tract symptom or disorder in both the postacute (8.64% vs 6.85%; ARR, 1.25; 95% CI, 1.24-1.27) and chronic (12.60% vs 9.47%; ARR, 1.28; 95% CI, 1.26-1.30) phases compared with patients without a documented infection. Specifically, the risk of abdominal pain was higher in COVID-19-positive patients during the postacute (2.54% vs 2.06%; ARR, 1.14; 95% CI, 1.11-1.17) and chronic (4.57% vs 3.40%; ARR, 1.24; 95% CI, 1.22-1.27) phases. CONCLUSIONS AND RELEVANCE/UNASSIGNED:In this cohort study, the increased risk of GI tract symptoms and disorders was associated with the documented SARS-CoV-2 infection in children or adolescents during the postacute or chronic phase. Clinicians should note that lingering GI tract symptoms may be more common in children after documented SARS-CoV-2 infection than in those without documented infection.

Understanding the effects of solid boundaries on turbulent fluctuations remains a long-standing challenge. Available data on mean-square fluctuations in these flows show apparent contradiction with classical scaling. We had earlier proposed an alternative model based on the principle of bounded dissipation. Despite its putative success, a conclusive outcome requires much higher Reynolds numbers than are available at present, or can be expected to be available in the near future. However, the model can be validated satisfactorily even within the Reynolds number range already available by considering high-order moments and their distributions in the wall-normal direction. Expressions for high-order moments of streamwise velocity fluctuation [Formula: see text] are derived in the form [Formula: see text], where the superscript [Formula: see text] indicates the wall unit normalization, and brackets stand for averages over time and the homogeneous plane normal to the wall, [Formula: see text] is an integer, [Formula: see text] and [Formula: see text] are constants independent of the friction Reynolds number [Formula: see text], and [Formula: see text] is the distance away from the wall, normalized by the flow thickness [Formula: see text]. In particular, [Formula: see text] according to the "linear q-norm Gaussian" process, where [Formula: see text] and [Formula: see text] are flow-independent constants. Excellent agreement is found between this formula and the available data in boundary layers, pipes, and channels for [Formula: see text]. For fixed [Formula: see text], the present formulation leads to the bounded state [Formula: see text] as [Formula: see text]. This work demonstrates the success of the present model in describing the behavior of fluctuations in wall flows.