Faculty Bibliography

OBJECTIVE:Carotid artery plaque burden, indirectly measured by the degree of stenosis, quantifies future embolic risk. In natural history studies, patients with moderate degrees of stenosis have a lower stroke risk than those with severe stenosis. However, patients with symptomatic carotid stenosis who have experienced TIA or stroke are found to have both moderate and severe degrees of stenosis. We sought to examine the association carotid artery stenosis severity with outcomes in symptomatic patients undergoing carotid interventions including carotid endarterectomy (CEA), transfemoral carotid artery stenting (CAS) and transcervical carotid artery revascularization (TCAR). METHODS:The Society for Vascular Surgery Quality Initiative database was queried for all patients undergoing CAS, CEA and TCAR between 2003 and 2020. Patients were stratified into two groups based on the severity of stenosis - non-severe (0 - 69%) and severe (≥ 70%). Primary endpoints were periprocedural neurologic events (strokes and transient ischemic attacks (TIAs)). Secondary endpoints were periprocedural death, myocardial infarction (MI) and composite outcomes of stroke/death and stroke/death/MI per reporting standards for carotid interventions. RESULTS:Of 29,614 symptomatic patients included in the analysis, 5,296 (17.9%) patients underwent TCAR, 7,844 (26.5%) underwent CAS, and 16,474 (55.6%) underwent CEA for symptomatic carotid artery stenosis. In the CEA cohort, the neurologic event rate was similarly significantly lower in patients with severe stenosis when compared to those with non-severe stenosis (2.6% vs. 3.2%, P=.024). In the TCAR cohort, the periprocedural neurologic even rate was lower in patients with severe stenosis when compared to those with non-severe stenosis (3% vs. 4.3%, P=.033). There was no similar difference noted in the CAS cohort, with periprocedural neurologic event rates of 3.8% in the severe group versus 3.5% in the non-severe group (P=.518). On multivariable analysis, severe stenosis was associated with significantly decreased odds of post procedural neurologic events in patients undergoing CEA (odds ratio [OR] 0.75, 95% confidence interval [CI], 0.6 - 0.92; P=.007) and TCAR (OR .83; CI, .69 - 0.99; P=.039), but not CAS. CONCLUSION/CONCLUSIONS:Severe carotid stenosis as opposed to more moderate degrees of stenosis was associated with decreased rates of periprocedural stroke and TIAs in symptomatic patients undergoing TCAR and CEA, but not CAS. The finding of increased rates of periprocedural neurologic events in symptomatic patients with lesser degrees of stenosis undergoing TCAR and CEA warrants further evaluation with a particular focus on plaque morphology and brain physiology, and their inherent risks with carotid revascularization procedures.

INTRODUCTION:This study investigated a combination of eight embedded performance validity tests (PVTs) derived from commonly administered neuropsychological tests to optimize sensitivity/specificity for detecting invalid neuropsychological test performance. The goal of this study was to evaluate what combination of these common embedded PVTs that have the most robust predictive power for detecting invalid neuropsychological test performance in a single diverse clinical sample. METHOD:Eight previously validated memory- and nonmemory-based embedded PVTs were examined among 231 patients undergoing neuropsychological evaluation. Patients were classified into valid/invalid groups based on four independent criterion PVTs. Embedded PVT accuracy was assessed using standard and stepwise multiple logistic regression models. RESULTS:Three PVTs, the Brief Visuospatial Memory Test-Revised Recognition Discrimination (BVMT-R-RD), Rey Auditory Verbal Learning Test Forced Choice, and WAIS-IV Digit Span Age Corrected Scaled Score, predicted 45.5% of the variance in validity group membership. BVMT-RD independently accounted for 32% of the variance in prediction of independent, criterion-defined validity group membership. CONCLUSIONS:This study demonstrated the incremental predictive power of multiple embedded PVTs derived from common neuropsychological measures in detecting invalid test performance and those measures accounting for the greatest portion of the variance. These results provide guidance for evaluating the most fruitful embedded PVTs and proof of concept to better guide selection of embedded validity indices. Further, this offers clinicians an efficient, empirically derived approach to assessing performance validity when time restraints potentially limit the use of freestanding PVTs.

Purpose: DS is a severe and progressive genetic epilepsy that is generally caused by spontaneous, heterozygous loss of function mutations in the SCN1A gene, which encodes the voltage-gated sodium channel subunit type 1 alpha (Nav1.1). STK-001 is an investigational ASO designed to upregulate Nav1.1 protein expression in brain by leveraging the wild-type (non-mutant) copy of SCN1A to restore physiological Nav1.1 levels, thereby potentially reducing seizure frequency (SF) and non-seizure comorbidities.
Method(s): Patients (N = 22) with DS were grouped by age (2-12 and 13-18 years) and SF was evaluated for 28 days before CSF collection (baseline). During the pre-treatment period, patients had a high rate of convulsive SF (median = 16). STK-001 was administered intrathecally on Day 1 as a single dose (SAD: 10, 20, or 30mg) or on Day 1, Week 4 and Week 8 as multiple ascending doses (MAD: 20mg).
Result(s): 20/22 patients were taking >=3 concomitant anti-seizure medicines as maintenance therapy, and 16/22 were taking >=4. Adverse events (AEs), SF, and plasma PK were monitored throughout. At datacut, 4 patients had study drug-related treatment-emergent (TE) AEs; none in 30mg SAD and 1 in the 20mg MAD cohorts. Five patients had serious TEAEs, none related to study drug. In addition, 12/17 SAD patients experienced a reduction in convulsive SF from Day 1 to Days 29-84, including 7/7 in the 2-12 years age group. Dose-dependent increases in plasma exposure were observed and STK-001 could be measured in the CSF up to 6 months post single intrathecal dose.
Conclusion(s): Single doses of STK-001 up to 30mg, and three 20mg doses of STK-001 given every four weeks, were well-tolerated with no study drug-related safety concerns observed. This MONARCH data analysis provides positive safety and PK data and evidence of seizure reduction, supporting continued development of STK-001 as the first disease-modifying precision medicine for DS

OBJECTIVES/OBJECTIVE:To assess differences in career longevity, as a potential marker of athlete well-being, before and after the 1995 implementation of the Women's Tennis Association (WTA) Age Eligibility Rule (AER) and Player Development Programmes (PDP), which focused on organisational, physical and psychosocial education, skill building and support for adolescent athletes (≤17 years). METHODS:Career longevity data were collected through 2019 on adolescent players who began professional tournament play between 1970 and 2014 and reached a WTA singles ranking of 1-150 for a minimum of 1 week during their careers. Players were separated into pre-AER/PDP and post-AER/PDP groups, consisting of those who played their first professional events (FPE) before or after 1 January 1995. Measures of career longevity included career duration and premature retirement. RESULTS:Eight-hundred and eleven players were included in this study (51% pre-AER/PDP). The median career duration was 14.2 years for the post-AER/PDP group compared with 12.1 years for the pre-AER/PDP group (p<0.001). Moreover, post-AER/PDP players had higher probabilities of 10-year and 15-year careers compared with pre-AER/PDP players. After adjusting for age at FPE, athletes in the pre-AER/PDP group had an increased risk of shorter career duration (HR 1.55; 95% CI 1.31 to 1.83) and increased odds of premature retirement (OR 5.39; 95% CI 2.28 to 12.75) than athletes in the post-AER/PDP group. CONCLUSIONS:Adolescent athletes participating on the WTA after the combined AER/PDP initiative had longer career durations, higher probabilities of 10-year and 15-year careers, and decreased risk of premature retirement compared with those participating prior to AER/PDP. Organisational practices that encompass both education and competition regulation can positively affect career longevity related to improving athlete well-being.

INTRODUCTION AND PROBLEM STATEMENT/UNASSIGNED:Neuroimmunology is a rapidly evolving subspecialty. At this time, fellowship training is not standardized. Discrepancies exist in fellowship programs across the United States, including in faculty expertise in rarer neuroimmunologic conditions. Many graduating fellows feel uncomfortable managing the full spectrum of diseases within neuroimmunology. OBJECTIVES/UNASSIGNED:To evaluate the feasibility and efficacy of a series of live, virtual, interinstitutional seminars educating neuroimmunology fellows on topics that may be infrequently encountered by trainees. METHODS AND CURRICULUM DESCRIPTION/UNASSIGNED:A steering committee of 6 neuroimmunology and multiple sclerosis fellowship program directors selected 18 topics felt to be high yield but representing unique areas of expertise. A live, interactive seminar series was organized. Recognized experts on each topic led seminars using a teleconferencing platform over the 2020-2021 academic year. Recordings were subsequently made available for asynchronous learning. Trainees were surveyed before and after the seminar series and comfort levels with each topic were recorded. RESULTS AND ASSESSMENT DATA/UNASSIGNED:< 0.0001). DISCUSSION AND LESSONS LEARNED/UNASSIGNED:A year-long series of live, interactive, interinstitutional seminars focusing on unique topics within a single subspecialty represents an effective way to increase trainee comfort levels with such topics.

Clinical studies of rescue medications for seizure clusters are limited and designed to satisfy regulatory requirements, which may not fully consider the needs of the diverse patient population that experiences seizure clusters or utilize rescue medication. The purpose of this narrative review is to examine factors that contribute to, or may influence the quality of, seizure cluster research with a goal of improving clinical practice. We address five areas of unmet needs and provide advice of how they could enhance future trials of seizure cluster treatments. The topics addressed in this manuscript are: 1) unaddressed endpoints to pursue in future studies, 2) roles for devices to enhance rescue medication clinical development programs, 3) tools to study seizure cluster prediction and prevention, 4) the value of other designs for seizure cluster studies, and 5) unique challenges of future trial paradigms for seizure clusters. By focusing on novel endpoints and technologies with value to patients, caregivers, and clinicians, data obtained from future studies can benefit the diverse patient population that experiences seizure clusters, providing more effective, appropriate care as well as alleviating demands on healthcare resources.