Faculty Bibliography

OBJECTIVE:The cause of perimesencephalic subarachnoid hemorrhage (pmSAH) is unclear but has historically been attributed to a venous source. The authors hypothesized that high-resolution cone-beam CT (CBCT) during angiography could better identify pmSAH etiology. METHODS:All patients with pmSAH treated at the authors' institution between January 2023 and December 2024 were retrospectively analyzed. Patients were excluded if CBCT was not performed as part of the digital subtraction angiography (DSA), if CBCT source data were not available for review, or if the images were deemed to be low quality. All images were reviewed by 2 neuroangiographers with extensive neurovascular imaging experience and discussed until consensus agreement. Data were recorded as counts and percentages. RESULTS:Among 152 patients who presented with spontaneous SAH in 2023-2024, 22 had a pmSAH defined according to the Rinkel criteria. These 22 patients had a catheter angiogram performed on 1 of 2 biplane machines. Thirteen of those patients had high-quality CBCT data available for review, 8 (61%) of whom were found to harbor a basilar perforator focal outpouching consistent with a site of rupture. All patients with pmSAH, including the 8 found to have a basilar perforator aneurysm, achieved an excellent neurological recovery with resolution of the basilar perforator finding on follow-up DSA with CBCT and without experiencing a re-rupture event or clinically significant vasospasm. CONCLUSIONS:In the setting of pmSAH, high-resolution CBCT acquired as part of catheter angiography frequently identifies a basilar perforator pseudoaneurysm. Conservative management was associated with excellent outcomes in this series. The authors propose that in the setting of pmSAH, a high suspicion of an arterial etiology should be considered until proven otherwise.

OBJECTIVES/OBJECTIVE:Cervical artery dissection (CeAD) is an important cause of ischemic stroke in young adults. Nearly 100 million annual chiropractic cervical manipulations are performed in the United States. The relationship between manipulation and CeAD remains controversial. METHODS:We analyzed patients in the multicenter STOP-CAD registry (n=4023) to identify CeAD cases diagnosed after chiropractic cervical manipulation. Demographics and clinical features were compared between manipulation-associated and nonmanipulation-associated cases using χ2 and t tests. Multivariable logistic regression identified key factors associated with manipulation-related CeAD. RESULTS:About 1 in 20 CeAD cases in this registry reported antecedent cervical manipulation. In multivariable binary logistic regression, compared with patients without prior manipulation, those with prior manipulation were younger (OR per year 0.98, 95% CI: 0.97-0.99, P=0.014), more often female (OR: 1.64, 95% CI: 1.21-2.23, P=0.001), less often diabetic (OR: 0.24, 95% CI: 0.08-0.78, P=0.018), presented with neck pain (OR: 2.80, 95% CI: 2.08-3.77, P<0.001), and had higher odds of isolated vertebral artery dissection (OR: 2.15, 95% CI: 1.57-2.94, P<0.001). Recurrent ischemic stroke rates were similar between groups. CONCLUSIONS:Given the very high number of manipulations performed annually, the absolute risk of secondary CeAD is extremely low. Manipulation-associated cases have distinct clinical features, occurring more often in younger women with vertebral dissections. Whether manipulation acts as a precipitating trigger or patients with early CeAD symptoms seek manipulation remains unresolved.

Mitotic surveillance pathways monitor the duration of mitosis (M phase) in the cell cycle. Prolonged M phase, caused by spindle attachment defects or microtubule-targeting drugs, triggers formation of the ternary 'mitotic stopwatch pathway' complex (MSP) consisting of 53BP1, USP28, and p53. This complex stabilizes p53, leading to cell cycle arrest or apoptosis in daughter cells. In cancers that are resistant to paclitaxel, a microtubule-targeting agent, cells bypass mitotic surveillance activation, allowing unchecked proliferation, although the underlying mechanisms remain poorly understood. Here, we identify GMCL1 as a key negative regulator of MSP signaling. We show that 53BP1 physically interacts with GMCL1, but not its paralog GMCL2, and we map their interaction domains. CRL3^GMCL1 functions as a ubiquitin ligase that targets 53BP1 for degradation during the M phase, thereby reducing p53 accumulation in daughter cells. Depletion of GMCL1 inhibits cell cycle progression upon release from prolonged mitotic arrest, a defect that is rescued by co-silencing 53BP1 or USP28. Moreover, GMCL1 depletion sensitizes cancer cells to paclitaxel in a p53-dependent manner. Together, our findings support a model in which dysregulated CRL3^GMCL1-mediated degradation of 53BP1 prevents proper MSP function, leading to p53 degradation and continued proliferation. Targeting GMCL1 may, therefore, represent one possible avenue for addressing paclitaxel resistance in cancer cells with functional p53.

BACKGROUND:Recent guidelines suggest that aspirin-ticagrelor may be considered for stroke prevention after mild acute ischemic stroke. However, it is unclear how commonly this dual antiplatelet therapy (DAPT) regimen is used in practice. METHODS:We performed a cross-sectional analysis of the Get With The Guidelines-Stroke registry 2017-2023. Patients with a non-cardioembolic mild ischemic stroke (defined as NIHSS <6) who presented within 24 hours of last known well without a contraindication to DAPT were included. The primary study outcome was the proportion of patients prescribed aspirin-ticagrelor at hospital discharge; temporal patterns of prescribing aspirin-ticagrelor and aspirin-clopidogrel over time are also described. In addition to standard tests of comparison, we used multiple logistic regression to evaluate associations between patient and facility factors and aspirin-ticagrelor use reported as odds ratios (OR) with 95% confidence intervals (CI). RESULTS:Among 1,018,736 patients meeting study criteria, 478,049 (46.9%) were female and median age was 68 (IQR: 59, 78) years. A total of 12,845 (1.3%) patients were discharged on aspirin-ticagrelor whereas 448,348 (44.0%) were discharged on aspirin-clopidogrel. Prescriptions for aspirin-ticagrelor and for aspirin-clopidogrel significantly increased over the study time-period. In regression analysis, coronary artery disease/prior myocardial infarction (OR: 2.6 [95% CI: 2.5-2.7]), Asian race (OR: 2.1 [95% CI: 1.9-2.2]), aspirin-clopidogrel prescription upon admission (OR: 2.0 [95% CI:1.9-2.1]), and history of stroke/TIA (OR: 1.98 [95% CI: (1.9-2.1)]), were substantially associated with aspirin-ticagrelor use whereas lacking insurance/self-pay (OR: 0.7 [95% CI: 0.6-0.8]), rural setting (OR: 0.8 [95% 0.7-0.9]), and primary stroke centers (OR: 0.3 [95% CI: 0.3-0.4]) were inversely associated with aspirin-ticagrelor. In the subgroup of 176,897 (17.4%) patients with NIHSS 4-5, 74,912 (50.8%) were discharged on aspirin-clopidogrel and 2,394 (1.4%) on aspirin-ticagrelor. CONCLUSION/CONCLUSIONS:Unlike aspirin-clopidogrel, aspirin-ticagrelor is infrequently administered after mild acute ischemic stroke (NIHSS <6) despite current guidelines, though the use of both DAPT regimens increased over time.

OBJECTIVE:To evaluate the risks of incident dyslipidemia and abnormal body mass index (BMI) during the 28-179-day post-acute phase after documented SARS-CoV-2 infection in a large pediatric sample. STUDY DESIGN/METHODS:A retrospective cohort study using the RECOVER pediatric electronic health record (EHR) datasets from 25 US children's hospitals and health institutions, from March 2020 to September 2023. This study included 384,289 COVID-19-positive patients aged 0-21 years for dyslipidemia analyses and 285,559 aged 2-21 years for BMI analyses, each with at least 6 months of follow-up. COVID-19-negative controls included 1,080,413 and 817,315 patients, respectively. SARS-CoV-2 infection was defined by a positive polymerase-chain-reaction (PCR), antigen, or serologic test; a clinical diagnosis of COVID-19; or a documented diagnosis of post-acute sequelae of SARS-CoV-2 (PASC). Incident dyslipidemia and abnormal BMI were identified using age-specific laboratory or anthropometric thresholds. Adjusted relative risks (aRRs) were estimated using propensity-score-stratified modified Poisson regression with multiple sensitivity analyses. RESULTS:During the post-acute phase, the COVID-19-positive cohort had higher rates of new-onset composite dyslipidemia (aRR 1.24; 95% CI 1.18-1.29) and abnormal BMI (aRR 1.15; 95% CI, 1.12-1.18). Results were robust to sensitivity and stratified analyses. CONCLUSION/CONCLUSIONS:Children and adolescents with documented COVID-19 infection were associated with an increased risk of new-onset dyslipidemia and abnormal BMI during the post-acute phase, highlighting the need for metabolic monitoring after infection.

Patients with Neuromyelitis Optica Spectrum Disorders (NMOSD) have a well-recognized predilection to autoimmune comorbidities, of which systemic lupus erythematosus (SLE), Sjögren's syndrome (SjS), and autoimmune thyroid diseases are the most common. The question of whether some autoimmune diseases, such as inflammatory bowel disease (IBD), may not be overrepresented (or may even be underrepresented) in NMOSD has not received much attention. Here, we retrospectively reviewed the electronic medical records of all patients diagnosed with NMOSD in our two large referral centers (NYU and MGB), as well as patients with two neuroinflammatory disorders as comparator groups (myelin oligodendrocyte glycoprotein antibody disease (MOGAD) and MS), and calculated the rates of IBD, SLE, SjS, autoimmune thyroid disorders, and myasthenia gravis (MG) in these groups. We found that 1 out of 347 NMOSD patients had a diagnosis of IBD (0.3%), and this patient was seronegative for anti-AQP4 autoantibodies, while 4/271 patients in the MS group (1.5%), 2 of whom were exposed to anti-CD20 therapy, had IBD, and 2/366 MOGAD patients (0.8%), neither of whom was exposed to anti-CD20 therapy, had IBD. In contrast, the rate of the other four autoimmune conditions was significantly higher in NMOSD (24%) than in MOGAD (8.5%, p < 0.0001) or MS (5.2%, p < 0.0001). Thus, IBD was not diagnosed in any of our 317 seropositive NMOSD patients, despite the fact that this group had a higher use of B-cell depletion than patients with MS and MOGAD. We discuss the various hypotheses that may explain this observation.

BACKGROUND:Depression, a debilitating mental disorder, has become the leading cause of disability worldwide. A growing body of evidence supports the feasibility and effectiveness of multicomponent lifestyle medicine programs for the treatment of depression, including the recent novel multicomponent Traditional Chinese Medicine Lifestyle Medicine (TCMLM) program (Registered at ClinicalTrials.Gov with registration number: NCT05799586). However, little is known about participants' experiences and perceptions of the program and the aspects that require improvement. This study aimed to explore the experiences and perceptions of participants attending the multicomponent TCMLM program and practicing the related lifestyle behaviors. METHODS:In this descriptive qualitative study, purposeful sampling was used to recruit Hong Kong Chinese adults who had participated in the multicomponent TCMLM program between August 2023 and January 2024. Face-to-face focus-group interviews and semi-structured interviews were conducted with audio recording, transcribed verbatim, and analyzed using conventional content analysis. All interviews were performed in classrooms in a university in Hong Kong. RESULTS:A total of 31 multicomponent TCMLM program attendees aged 20 to 65 years participated in the qualitative interviews. The content analysis identified three themes and 12 subthemes, namely, Theme 1: multicomponent TCMLM program originally being comprehensive and special (e.g., TCMLM program content originally being not unitary, increasing the number of methods for dealing with depressive symptoms); Theme 2: multicomponent TCMLM program being far more beneficial than expected (e.g., promoting diet, exercises, daily routine and sleep management based on TCMLM, improving physical functional status, improving one's personality); and Theme 3: practicing multicomponent TCMLM program having challenges (e.g., unsuitable conditions hindering some TCMLM practices in community). CONCLUSIONS:This study provides fresh in-depth insights into the perceptions and experiences of Hong Kong Chinese adults with depression who attended the multicomponent TCMLM program and engaged in the related lifestyle behaviors. Meanwhile, the challenges encountered while attending the program and practicing the related behaviors offer valuable information for further optimization of the program and expanding its application in Hong Kong or other regions.

OBJECTIVE:CDKL5 deficiency disorder (CDD) is a rare X-linked developmental and epileptic encephalopathy caused by loss-of-function variants in the CDKL5 gene. Preclinical experiments using enzyme replacement or gene therapies show promise and could be transformative therapies. This precompetitive consortium sought to harmonize nonseizure clinical endpoint selection for efficacy trials. Clinical Assessment of Neurodevelopmental Measures in CDD (CANDID) is an ongoing study evaluating the feasibility and suitability of neurocognitive tests and functioning scales in CDD patients. METHODS:CANDID is a 3-year, longitudinal, noninterventional global study involving children and adults with CDD. On-site and remote visits include clinical, behavioral, developmental, and quality of life assessments. RESULTS:We enrolled 112 patients (111 included in analyses); mean age = 8.3 years (range <1-28); 93% female; 10 participants were ≥18 years old. In the first 28 days, 82% had >16 seizures; six were seizure-free. Median seizure onset was at 1.5 months (range = 0-66). Patients used an average of 2.6 antiseizure medications at baseline. The most frequent comorbidities included gastrointestinal hypomotility, muscle tone abnormalities, and sleep disorders. Gross Motor Function Measure-88 (GMFM-88) scores indicated a floor effect in crawling, standing, and walking across all ages. Vineland-3 and Bayley-4 scores could be derived in most, with receptive language, interpersonal relationships, and fine and gross motor scores increasing with age. Bruni sleep questionnaire identified sleep initiation, sleep-awake transition, and excessive somnolence as the most disrupted components across all age groups. The mean Quality of Life Inventory-Disability total scores ranged from 53% to 64%, the independence domain being the most impacted. SIGNIFICANCE/CONCLUSIONS:The scales in the CANDID study capture disease-related deficits and phenotype variability in CDD. Floor effects in subdomains aligned with disease severity. The GMFM-88 lacks granularity, and its operational limitations make it unsuitable for CDD trials. Baseline analyses demonstrate the feasibility and potential value of most selected scales, supporting their use in optimizing trial design and endpoint selection for future CDD clinical trials.