Faculty Bibliography

BACKGROUND AND OBJECTIVES/UNASSIGNED:Exposure to repetitive head impacts (RHI) is linked to the development of chronic traumatic encephalopathy (CTE), which can only be diagnosed at post-mortem. The presence of a cavum septum pellucidum (CSP) is a common finding in post-mortem studies of confirmed CTE and in neuroimaging studies of individuals exposed to RHI. This study examines CSP in living former American football players, investigating its association with RHI exposure, traumatic encephalopathy syndrome (TES) diagnosis, and provisional levels of certainty for CTE pathology. METHODS/UNASSIGNED:Data from the DIAGNOSE CTE Research Project were used to compare the presence and ratio of CSP in former American football players (n = 175), consisting of former college (n = 58) and former professional players (n = 117), and asymptomatic unexposed controls without RHI exposure (n = 55). We further evaluated potential associations between CSP measures and cumulative head impact index (CHII) measures (frequency, linear acceleration, and rotational force), a TES diagnosis (yes/no), and a provisional level of certainty for CTE pathology (suggestive, possible, and probable). RESULTS/UNASSIGNED:Former American football players exhibited a higher CSP presence and ratio than unexposed asymptomatic controls. Among player subgroups, professional players showed a greater CSP ratio than former college players and unexposed asymptomatic controls. Among all football players, CHII rotational forces correlated with an increased CSP ratio. No significant associations were found between CSP measures and diagnosis of TES or provisional levels of certainty for CTE pathology. DISCUSSION/UNASSIGNED:This study confirms previous findings, highlighting a greater prevalence of CSP and a greater CSP ratio in former American football players compared with unexposed asymptomatic controls. In addition, former professional players showed a greater CSP ratio than college players. Moreover, the relationship between estimates of CHII rotational forces and CSP measures suggests that cumulative frequency and strength of rotational forces experienced in football are associated with CSP. However, CSP does not directly correlate with TES diagnosis or provisional levels of certainty for CTE, indicating that it may be a consequence of RHI associated with rotational forces. Further research, especially longitudinal studies, is needed for confirmation and to explore changes over time.

OBJECTIVE:The CDKL5 Clinical Severity Assessment (CCSA) is a comprehensive, content-validated measurement tool capturing the diverse challenges of cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD), a genetically caused developmental epileptic encephalopathy (DEE). The CCSA is divided into clinician-reported (CCSA-Clinician) and caregiver-reported (CCSA-Caregiver) assessments. The aim of this study was to evaluate the factor structure of these measures through confirmatory factor analysis (CFA) and evaluate their validity and reliability. METHODS:Participants were recruited from the International CDKL5 Clinical Research Network to take part in an in-clinic CCSA-Clinician evaluation (n = 148) and/or complete the CCSA-Caregiver questionnaire (n = 198). CFA was used to determine domains, and factor loadings and validity were assessed. For the CCSA-Clinician, inter-rater reliability was assessed by nine CDD experienced clinicians via 14 pre-recorded evaluations. Eight clinicians re-viewed and re-scored the videos after 4 weeks to evaluate intra-rater reliability. The CCSA-Caregiver was completed on a second occasion by 34 caregivers after 2-4 weeks to assess test-retest reliability. RESULTS:CFA resulted in three domains for the CCSA-Clinician (motor and movement, communication, vision) and four domains for the CCSA-Caregiver (seizures, behavior, alertness, feeding), with good item loadings across both measures. Structural statistics, internal consistency, discriminant validity, and reliability were satisfactory for both measures, and scores were consistent between known groups. SIGNIFICANCE/CONCLUSIONS:This study provides strong evidence that the CCSA measures are suitable to assess the clinical severity of individuals with CDD, supporting their use in clinical trials. Further evaluation of responsiveness to change in a longitudinal assessment is planned. Use may also be appropriate in similar DEEs but would require validation in those populations.

BACKGROUND:Evidence suggests that adverse childhood experiences (ACEs) predict cognitive dysfunction, possibly through direct (e.g., brain structure/function changes) and indirect (e.g., increased psychopathology risk) pathways. However, extant studies have focused on young and older adults, with limited understanding of how ACEs affect cognitive health in midadulthood. OBJECTIVE:This study compared psychiatric and cognitive differences between adults at high- and low-risk of adverse health outcomes based on the ACE risk classification scheme. PARTICIPANTS AND SETTING/METHODS: METHOD/METHODS:Patients were divided into high and low ACE groups based on the number of ACEs endorsed. Subsequently, a series of one-way analyses of variances were conducted to compare high versus low ACE groups on the Test of Premorbid Functioning, Wechsler Adult Intelligence Scale-Fourth Edition Digit Span Test, Trail Making Test-Parts A and B, Rey Auditory Verbal Learning Test, Beck Depression Inventory-II, and Beck Anxiety Inventory scores. RESULTS:Significant group differences were detected for anxiety and depression with the high ACE group endorsing significantly greater depression and anxiety symptoms relative to the low ACE group. High and low ACE groups did not significantly differ on any cognitive measures. CONCLUSIONS:Results indicate that an individual's psychological health, but not cognitive functioning, is impacted by the level of ACE exposure. Study findings highlight the importance of including ACE measures in neuropsychological evaluations, as it will aid in case conceptualization and tailoring treatment recommendations. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

PURPOSE OF REVIEW/OBJECTIVE:Chronic headaches are a significant source of disability worldwide. Despite the development of conventional strategies, a subset of patients remain refractory and/or experience side effects following these treatments. Hence, occipital nerve stimulation (ONS) should be considered as an alternative strategy for intractable chronic headaches. This review aims to provide a comprehensive overview of the effectiveness, safety, mechanisms and practical application of ONS for the treatment of headache disorders. RECENT FINDINGS/RESULTS:Overall response rate of ONS is 35.7-100%, 17-100%, and 63-100% in patients with cluster headache, chronic migraine and occipital neuralgia respectively. Regarding the long-term effectivity in all groups, 41.6-88.0% of patients remain responders after ≥ 18.3 months. The most frequently reported adverse events include lead migration/fracture (13%) and local pain (7.3%). Based on our results, ONS can be considered a safe and effective treatment for chronic intractable headache disorders. To support more widespread application of ONS, additional research with larger sample sizes should be conducted.

OnabotulinumtoxinA (onabotA) is approved in the US for 12 therapeutic indications. Real-world data on onabotA multi-indication use are limited, often leading to delayed or reduced treatment. This study provides real-world evidence on the safety of onabotA when treating multiple indications concomitantly. SYNCHRONIZE was a multicenter, retrospective, chart-review study evaluating onabotA's safety for adults treated for ≥2 therapeutic indications within a 3-month period. The primary outcome was treatment-emergent adverse events (TEAEs) within 6 months post-treatment. A total of 279 patients were included. The most common concomitant indications treated were cervical dystonia and chronic migraine (43.4%). The average 3-month cumulative dose for multiple indications was 282.2 U. The treatment interval for multiple indications was ≤24 h for most patients (62.4%). Overall, 28.7% of patients reported ≥1 TEAE with no apparent trends in TEAEs and dose interval or cumulative dose. Reported TEAEs included UTI (5.7%), neck pain (5.0%), and headache (4.3%). No patient had a lack of effect according to clinical objective measurements. SYNCHRONIZE described the real-world safety of onabotA for patients treated concomitantly for ≥2 indications within a 3-month period. TEAEs were generally consistent with the known safety profiles of individual indications. No new safety signals were identified).

Nilotinib, a tyrosine kinase inhibitor that targets the Abelson tyrosine kinase (c-Abl) signaling pathway, is FDA-approved to treat chronic myeloid leukemia. Nilotinib has properties indicative of a possible utility in neuroprotection that have prompted exploration of repurposing the drug for the treatment of Alzheimer's disease (AD) and Parkinson's disease (PD). AD is a progressive age-related neurodegenerative disorder characterized by the deposition of extracellular amyloid-β plaques and intracellular neurofibrillary tangles. It is incurable and affects approximately 50 million patients worldwide. Nilotinib reduces c-Abl phosphorylation, amyloid-β levels, and dopaminergic neuron degeneration in preclinical AD models. This study explores the effects of nilotinib on amyloid processing and mitochondrial functioning in the SH-SY5Y human neuroblastoma cell line. SH-SY5Y cells were exposed to nilotinib (1, 5, and 10 µM). Real-time PCR and immunoblot analysis were performed to quantify the expression of genes pertaining to amyloid-β processing and neuronal health. Nilotinib did not significantly change APP, BACE1, or ADAM10 mRNA levels. However, BACE1 protein was significantly increased at 1 µM, and ADAM10 was increased at 10 µM nilotinib without affecting APP protein expression. Further, nilotinib treatment did not affect the expression of genes associated with neuronal health and mitochondrial functioning. Taken together, our findings do not support the efficacy of nilotinib treatment for neuroprotection.

DHPS deficiency syndrome is an ultra-rare neurodevelopmental disorder (NDD) which results from biallelic mutations in the gene encoding the enzyme deoxyhypusine synthase (DHPS). DHPS is essential to synthesize hypusine, a rare amino acid formed by post-translational modification of a conserved lysine in eukaryotic initiation factor 5 A (eIF5A). DHPS deficiency syndrome causes epilepsy, cognitive and motor impairments, and mild facial dysmorphology. In mice, a brain-specific genetic deletion of Dhps at birth impairs eIF5A^HYP-dependent mRNA translation. This alters expression of proteins required for neuronal development and function, and phenotypically models features of human DHPS deficiency. We studied the role of DHPS in early brain development using a zebrafish loss-of-function model generated by knockdown of dhps expression with an antisense morpholino oligomer (MO) targeting the exon 2/intron 2 (E2I2) splice site of the dhps pre-mRNA. dhps knockdown embryos exhibited dose-dependent developmental delay and dysmorphology, including microcephaly, axis truncation, and body curvature. In dhps knockdown larvae, electrophysiological analysis showed increased epileptiform activity, and confocal microscopy analysis revealed reduced arborisation of GABAergic neurons. Our findings confirm that hypusination of eIF5A by DHPS is needed for early brain development, and zebrafish with an antisense knockdown of dhps model features of DHPS deficiency syndrome.

BACKGROUND:Disorders of consciousness (DoC) are frequently encountered in both, acute and chronic brain injuries. In many countries, early withdrawal of life-sustaining treatments is common practice for these patients even though the accuracy of predicting recovery is debated and delayed recovery can be seen. In this review, we will discuss theoretical concepts of consciousness and pathophysiology, explore effective strategies for management, and discuss the accurate prediction of long-term clinical outcomes. We will also address research challenges. MAIN TEXT/METHODS:DoC are characterized by alterations in arousal and/or content, being classified as coma, unresponsive wakefulness syndrome/vegetative state, minimally conscious state, and confusional state. Patients with willful modulation of brain activity detectable by functional MRI or EEG but not by behavioral examination is a state also known as covert consciousness or cognitive motor dissociation. This state may be as common as every 4th or 5th patient without behavioral evidence of verbal command following and has been identified as an independent predictor of long-term functional recovery. Underlying mechanisms are uncertain but intact arousal and thalamocortical projections maybe be essential. Insights into the mechanisms underlying DoC will be of major importance as these will provide a framework to conceptualize treatment approaches, including medical, mechanical, or electoral brain stimulation. CONCLUSIONS:We are beginning to gain insights into the underlying mechanisms of DoC, identifying novel advanced prognostication tools to improve the accuracy of recovery predictions, and are starting to conceptualize targeted treatments to support the recovery of DoC patients. It is essential to determine how these advancements can be implemented and benefit DoC patients across a range of clinical settings and global societal systems. The Curing Coma Campaign has highlighted major gaps knowledge and provides a roadmap to advance the field of coma science with the goal to support the recovery of patients with DoC.

INTRODUCTION AND PROBLEM STATEMENT/UNASSIGNED:A chief resident's role incorporates administrative, academic, and interpersonal responsibilities essential to managing a successful residency program. However, rising chief residents receive little formal exposure to leadership training. OBJECTIVES/UNASSIGNED:To (1) define leadership styles; (2) understand the effect of cultural competence on leadership styles; (3) learn effective methods to advocate as the chief resident; (4) provide effective peer feedback; (5) provide effective supervisor feedback; (6) learn effective conflict management; (7) ensure psychological safety. METHODS AND CURRICULUM DESCRIPTION/UNASSIGNED:We developed a 1-day curriculum combining didactics and simulation activities for our program's rising chief residents. Implementation of our curricular design included a morning session focusing on small groups and didactic-based lectures on specific topics pertinent to leadership, along with a debriefing of a psychometric evaluation tool administered before the curriculum day. The simulation activity consisted of 3 group objective structured clinical examination (G-OSCE) scenarios: (1) providing a struggling junior trainee with feedback; (2) debriefing an adverse clinical outcome as the team leader; (3) navigating a challenging situation with a supervising physician. Standardized participants were surveyed for specific objectives. Learners completed precurricular and postcurricular surveys on their familiarity and preparedness for their chief year. RESULTS AND ASSESSMENT DATA/UNASSIGNED:= 0.421), learner-reported use of wellness resources was noted to be reduced after the curricular intervention and remains a result of further interest for exploration. DISCUSSION AND LESSONS LEARNED/UNASSIGNED:A 1-day leadership development curriculum combining didactics and simulation is an effective means of preparing rising chief residents to succeed in their transition to this leadership role.