Faculty Bibliography

STUDY OBJECTIVES/OBJECTIVE:Sleep difficulties are common in CDKL5 deficiency disorder (CDD), a developmental and epileptic encephalopathy (DEE). This study evaluated the factor structure of the Disorders of Initiating and Maintaining Sleep (DIMS), Disorders of Excessive Daytime Somnolence (DOES) and Sleep Breathing Disorders (SBD) domains of the Sleep Disturbance Scale for Children (SDSC) for CDD. METHODS:A cross-sectional psychometric study design was used. Data were collected for 125 individuals aged 3 years or older who attended a US Centers of Excellence clinic or registered with the International CDKL5 Disorder Database. RESULTS:The median age was 10.3 years (range 3.2 - 40.7 years) and 105 (84%) were female. Two of the three SBD items related were not observed by most respondents and analysis was restricted to the DIMS and DOES domains. Using all items in the initial confirmatory factor analysis, two items in the DIMS domain and one item in the DOES domain loaded poorly. After deleting these items and repeating the analysis, item loading (0.524-0.814) and internal consistency (DIMS: 0.78, DOES: 0.76) statistics were good. The square of the inter-domain correlation coefficient was 0.17, less than Average Variance Extracted values for both domains and indicating good discriminant validity. The Tucker-Lewis and Comparative Fit indices were slightly lower than the threshold of >0.9 for establishing goodness of fit. CONCLUSIONS:The modified DIMS and DOES domains from the SDSC could be suitable clinical outcome assessments of insomnia and related impairments in CDD and potentially other DEE conditions.

BACKGROUND AND OBJECTIVES/OBJECTIVE:Robotics are becoming increasingly widespread within various neurosurgical subspecialties, but data pertaining to their feasibility in vascular neurosurgery are limited. We present our novel attempt to evaluate the learning curve of a robotic platform for microvascular anastomoses. METHODS:One hundred and sixty one sutures were performed and assessed. Fourteen anastomoses (10 robotic [MUSA-2 Microsurgical system; Microsure] and 4 hand-sewn) were performed by the senior author on 1.5-mm caliber tubes and recorded with the Kinevo 900 (Zeiss) operative microscope. We separately compared interrupted sutures (from needle insertion until third knot) and running sutures (from needle insertion until loop pull-down). Average suture timing across all groups was compared using an unpaired Student's t test. Exponential smoothing (α = 0.2) was then applied to the robotic data sets for validation and a second set of t tests were performed. RESULTS:We compared 107 robotic sutures with 54 hand-sewn sutures. There was a significant difference between the average time/stitch for the robotic running sutures (n = 55) and the hand-sewn running sutures (n = 31) (31.2 seconds vs 48.3 seconds, respectively; P-value = .00052). Exponential smoothing (α = 0.2) reinforced these results (37.6 seconds vs 48.3 seconds; P-value = .014625). Average robotic running times surpassed hand-sewn by the second anastomosis (38.8 seconds vs 48.3 seconds) and continued to steadily decrease with subsequent stitches. The average of the robotic interrupted sutures (n = 52) was significantly longer than the hand-sewn (n = 23) (171.3 seconds vs 70 seconds; P = .000024). Exponential smoothing (α = 0.2) yielded similar results (196.7 seconds vs 70 seconds; P = .00001). However, average robotic interrupted times significantly decreased from the first to the final anastomosis (286 seconds vs 105.2 seconds; P = .003674). CONCLUSION/CONCLUSIONS:Our results indicate the learning curve for robotic microanastomoses is short and encouraging. The use of robotics warrants further study for potential use in cerebrovascular bypass procedures.

BACKGROUND:Hereditary optic neuropathies comprise a group of clinically and genetically heterogeneous disorders. Optic neuropathy has been previously reported in families with spastic paraplegia type 7 (SPG7) gene mutations. However, the typical time course and clinical presentation of SPG7-associated optic neuropathy is poorly understood. We report a series of 5 patients harboring pathogenic SPG7 mutations who originally presented to a neuro-ophthalmology clinic with symptoms of optic neuropathy. METHODS:Retrospective case series of 5 patients with pathogenic SPG7 mutations and optic atrophy from 3 neuro-ophthalmology clinics. Demographic, clinical, diagnostic, and treatment data were collected and reported by the clinician authors. RESULTS:Five patients ranging in age from 8 to 48 years were evaluated in the neuro-ophthalmology clinic. Although there were variable clinical presentations for each subject, all noted progressive vision loss, typically bilateral, and several also had previous diagnoses of peripheral neuropathy (e.g., Guillain-Barré Syndrome). Patients underwent neuro-ophthalmic examinations and testing with visual fields and optic coherence tomography of the retinal nerve fiber layer. Genetic testing revealed pathogenic variants in the SPG7 gene. CONCLUSIONS:Five patients presented to the neuro-ophthalmology clinic with progressive vision loss and were diagnosed with optic atrophy. Although each patient harbored an SPG7 mutation, this cohort was phenotypically and genotypically heterogeneous. Three patients carried the Ala510Val variant. The patients demonstrated varying degrees of visual acuity and visual field loss, although evaluations were completed during different stages of disease progression. Four patients had a previous diagnosis of peripheral neuropathy. This raises the prospect that a single pathogenic variant of SPG7 may be associated with peripheral neuropathy in addition to optic neuropathy. These results support the consideration of SPG7 testing in patients with high suspicion for genetic optic neuropathy, as manifested by symmetric papillomacular bundle damage without clear etiology on initial workup. Applied judiciously, genetic testing, including for SPG7, may help clarify the cause of unexplained progressive optic neuropathies.

Familial dysautonomia (FD) is a rare genetic neurodevelopmental and neurodegenerative disorder. In addition to the autonomic and peripheral sensory neuropathies that challenge patient survival, one of the most debilitating symptoms affecting patients' quality of life is progressive blindness resulting from the steady loss of retinal ganglion cells (RGCs). Within the FD community, there is a concerted effort to develop treatments to prevent the loss of RGCs. However, the mechanisms underlying the death of RGCs are not well understood. To study the mechanisms underlying RGC death, Pax6-cre;Elp1^loxp/loxp male and female mice and postmortem retinal tissue from an FD patient were used to explore the neuronal and non-neuronal cellular pathology associated with the FD optic neuropathy. Neurons, astrocytes, microglia, Müller glia, and endothelial cells were investigated using a combination of histological analyses. We identified a novel disruption of cellular homeostasis and gliosis in the FD retina. Beginning shortly after birth and progressing with age, the FD retina is marked by astrogliosis and perturbations in microglia, which coincide with vascular remodeling. These changes begin before the onset of RGC death, suggesting alterations in the retinal neurovascular unit may contribute to and exacerbate RGC death. We reveal for the first time that the FD retina pathology includes reactive gliosis, increased microglial recruitment to the ganglion cell layer (GCL), disruptions in the deep and superficial vascular plexuses, and alterations in signaling pathways. These studies implicate the neurovascular unit as a disease-modifying target for therapeutic interventions in FD.

OBJECTIVES/OBJECTIVE:To determine the proportion of individuals with detectable antigen in plasma or serum after SARS-CoV-2 infection and the association of antigen detection with postacute sequelae of COVID-19 (PASC) symptoms. METHODS:Plasma and serum samples were collected from adults participating in four independent studies at different time points, ranging from several days up to 14 months post-SARS-CoV-2 infection. The primary outcome measure was to quantify SARS-CoV-2 antigens, including the S1 subunit of spike, full-length spike, and nucleocapsid, in participant samples. The presence of 34 commonly reported PASC symptoms during the postacute period was determined from participant surveys or chart reviews of electronic health records. RESULTS:Of the 1569 samples analysed from 706 individuals infected with SARS-CoV-2, 21% (95% CI, 18-24%) were positive for either S1, spike, or nucleocapsid. Spike was predominantly detected, and the highest proportion of samples was spike positive (20%; 95% CI, 18-22%) between 4 and 7 months postinfection. In total, 578 participants (82%) reported at least one of the 34 PASC symptoms included in our analysis ≥1 month postinfection. Cardiopulmonary, musculoskeletal, and neurologic symptoms had the highest reported prevalence in over half of all participants, and among those participants, 43% (95% CI, 40-45%) on average were antigen-positive. Among the participants who reported no ongoing symptoms (128, 18%), antigen was detected in 28 participants (21%). The presence of antigen was associated with the presence of one or more PASC symptoms, adjusting for sex, age, time postinfection, and cohort (OR, 1.8; 95% CI, 1.4-2.2). DISCUSSION/CONCLUSIONS:The findings of this multicohort study indicate that SARS-CoV-2 antigens can be detected in the blood of a substantial proportion of individuals up to 14 months after infection. While approximately one in five asymptomatic individuals was antigen-positive, roughly half of all individuals reporting ongoing cardiopulmonary, musculoskeletal, and neurologic symptoms were antigen-positive.

Ensuring reliability of Large Language Models (LLMs) in clinical tasks is crucial. Our study assesses two state-of-the-art LLMs (ChatGPT and LlaMA-2) for extracting clinical information, focusing on cognitive tests like MMSE and CDR. Our data consisted of 135,307 clinical notes (Jan 12th, 2010 to May 24th, 2023) mentioning MMSE, CDR, or MoCA. After applying inclusion criteria 34,465 notes remained, of which 765 underwent ChatGPT (GPT-4) and LlaMA-2, and 22 experts reviewed the responses. ChatGPT successfully extracted MMSE and CDR instances with dates from 742 notes. We used 20 notes for fine-tuning and training the reviewers. The remaining 722 were assigned to reviewers, with 309 each assigned to two reviewers simultaneously. Inter-rater-agreement (Fleiss' Kappa), precision, recall, true/false negative rates, and accuracy were calculated. Our study follows TRIPOD reporting guidelines for model validation. For MMSE information extraction, ChatGPT (vs. LlaMA-2) achieved accuracy of 83% (vs. 66.4%), sensitivity of 89.7% (vs. 69.9%), true-negative rates of 96% (vs 60.0%), and precision of 82.7% (vs 62.2%). For CDR the results were lower overall, with accuracy of 87.1% (vs. 74.5%), sensitivity of 84.3% (vs. 39.7%), true-negative rates of 99.8% (98.4%), and precision of 48.3% (vs. 16.1%). We qualitatively evaluated the MMSE errors of ChatGPT and LlaMA-2 on double-reviewed notes. LlaMA-2 errors included 27 cases of total hallucination, 19 cases of reporting other scores instead of MMSE, 25 missed scores, and 23 cases of reporting only the wrong date. In comparison, ChatGPT's errors included only 3 cases of total hallucination, 17 cases of wrong test reported instead of MMSE, and 19 cases of reporting a wrong date. In this diagnostic/prognostic study of ChatGPT and LlaMA-2 for extracting cognitive exam dates and scores from clinical notes, ChatGPT exhibited high accuracy, with better performance compared to LlaMA-2. The use of LLMs could benefit dementia research and clinical care, by identifying eligible patients for treatments initialization or clinical trial enrollments. Rigorous evaluation of LLMs is crucial to understanding their capabilities and limitations.

BACKGROUND:Health insurance in the United States varies in coverage of essential diagnostic tests, therapies, and specialists. Health disparities between privately and publicly insured patients with MS have not been comprehensively assessed. The objective of this study is to evaluate the impact of public versus private insurance on longitudinal brain outcomes in MS. METHODS:Lesional, thalamic, and gray and white matter volumes were extracted from longitudinal MRI of 710 MS patients. Baseline volumes and atrophy rates of lesional, thalamic, and gray and white matter volumes were compared across insurance groups. RESULTS:After image quality assessment, 376 (284 private / 92 public), 638 (499 / 139), and 331 (250 / 81), patients were in MS lesion, thalamic, gray and white matter analyses respectively. Baseline lesion volume was higher for publicly insured patients but increased at a slightly higher rate in those privately insured (p = 0.01). Baseline gray matter measurements were lower for patients with public insurance, but thalamic (p < 0.01) and gray matter (p < 0.01) atrophy rates were slightly higher in the private insurance group. CONCLUSION/CONCLUSIONS:Insurance type was associated with lesion, thalamic, and gray matter volumes. The results suggest that patients with public insurance may present with more advanced disease.

BACKGROUND/UNASSIGNED:Bone regeneration following a fracture is dependent on multiple factors including skeletal stem cells (SSCs). Recruitment, proliferation, and differentiation of the SSCs is guided by the proteins and metabolites found within the fracture microenvironment. Understanding how intrinsic factors affect the fracture microenvironment has been a topic of ongoing investigation. This study sought to determine whether the levels of select proteins and metabolites within the fracture hematoma would be differentially expressed depending on the age of the patient. We hypothesized that a distinct set of proteins and metabolites found within the fracture hematoma microenvironment would be present at varying levels depending on patient age. METHODS/UNASSIGNED:The research study was reviewed and approved by an Institutional Review Board. Hematomas were collected from subjects aged 18 years old or older undergoing surgical intervention for a fracture. Hematoma samples were selected from the biorepository and assigned to one of two fracture groups including young ankle/hindfoot and aged ankle/hindfoot. Protein and metabolite levels within each hematoma were analyzed by liquid chromatography-mass spectrometry. RESULTS/UNASSIGNED:A total of seven hematomas were included in each the young ankle/hindfoot and aged ankle/hindfoot groups. From the global metabolomic analysis, creatine, 2-methylindoline, and acetyl-L-carnitine were identified as being differentially expressed between both groups. An untargeted metabolomic analysis of the two groups identified significant differences in the levels of an additional 66 metabolites. Proteomic analysis identified 34 proteins that were expressed at significantly different levels. CONCLUSIONS/UNASSIGNED:The level of metabolites and proteins found within the local fracture environment vary by patient age. Future investigations will focus on identifying a role for these proteins and metabolites in bone homeostasis and fracture healing. LEVEL OF EVIDENCE/UNASSIGNED:N/A, basic science investigation. SUPPLEMENTARY INFORMATION/UNASSIGNED:The online version contains supplementary material available at 10.1007/s43465-024-01284-3.