Region and layer-specific expression of GABAA receptor isoforms and KCC2 in developing cortex.

Introduction: γ-Aminobutyric acid (GABA) type A receptors (GABAARs) are ligand-gated Cl-channels that mediate the bulk of inhibitory neurotransmission in the mature CNS and are targets of many drugs. During cortical development, GABAAR-mediated signals are significantly modulated by changing subunit composition and expression of Cl-transporters as part of developmental processes and early network activity. To date, this developmental evolution has remained understudied, particularly at the level of cortical layer-specific changes. In this study, we characterized the expression of nine major GABAAR subunits and K-Cl transporter 2 (KCC2) in mouse somatosensory cortex from embryonic development to postweaning maturity. Methods: We evaluated expression of α1-5, ß2-3, γ2, and δ GABAAR subunits using immunohistochemistry and Western blot techniques, and expression of KCC2 using immunohistochemistry in cortices from E13.5 to P25 mice. Results: We found that embryonic cortex expresses mainly α3, α5, ß3, and γ2, while expression of α1, α2, α4, ß2, δ, and KCC2 begins at later points in development; however, many patterns of nuanced expression can be found in specific lamina, cortical regions, and cells and structures. Discussion: While the general pattern of expression of each subunit and KCC2 is similar to previous studies, we found a number of unique temporal, regional, and laminar patterns that were previously unknown. These findings provide much needed knowledge of the intricate developmental evolution in GABAAR composition and KCC2 expression to accommodate developmental signals that transition to mature neurotransmission.

Early inner plexiform layer thinning and retinal nerve fiber layer thickening in excitotoxic retinal injury using deep learning-assisted optical coherence tomography.

Excitotoxicity from the impairment of glutamate uptake constitutes an important mechanism in neurodegenerative diseases such as Alzheimer's, multiple sclerosis, and Parkinson's disease. Within the eye, excitotoxicity is thought to play a critical role in retinal ganglion cell death in glaucoma, diabetic retinopathy, retinal ischemia, and optic nerve injury, yet how excitotoxic injury impacts different retinal layers is not well understood. Here, we investigated the longitudinal effects of N-methyl-D-aspartate (NMDA)-induced excitotoxic retinal injury in a rat model using deep learning-assisted retinal layer thickness estimation. Before and after unilateral intravitreal NMDA injection in nine adult Long Evans rats, spectral-domain optical coherence tomography (OCT) was used to acquire volumetric retinal images in both eyes over 4 weeks. Ten retinal layers were automatically segmented from the OCT data using our deep learning-based algorithm. Retinal degeneration was evaluated using layer-specific retinal thickness changes at each time point (before, and at 3, 7, and 28 days after NMDA injection). Within the inner retina, our OCT results showed that retinal thinning occurred first in the inner plexiform layer at 3 days after NMDA injection, followed by the inner nuclear layer at 7 days post-injury. In contrast, the retinal nerve fiber layer exhibited an initial thickening 3 days after NMDA injection, followed by normalization and thinning up to 4 weeks post-injury. Our results demonstrated the pathological cascades of NMDA-induced neurotoxicity across different layers of the retina. The early inner plexiform layer thinning suggests early dendritic shrinkage, whereas the initial retinal nerve fiber layer thickening before subsequent normalization and thinning indicates early inflammation before axonal loss and cell death. These findings implicate the inner plexiform layer as an early imaging biomarker of excitotoxic retinal degeneration, whereas caution is warranted when interpreting the ganglion cell complex combining retinal nerve fiber layer, ganglion cell layer, and inner plexiform layer thicknesses in conventional OCT measures. Deep learning-assisted retinal layer segmentation and longitudinal OCT monitoring can help evaluate the different phases of retinal layer damage upon excitotoxicity.

Evaluating Large Language Models in Extracting Cognitive Exam Dates and Scores.

Importance: Large language models (LLMs) are crucial for medical tasks. Ensuring their reliability is vital to avoid false results. 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. Objective: Evaluate ChatGPT and LlaMA-2 performance in extracting MMSE and CDR scores, including their associated dates. Methods: 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. Results: 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. Conclusions: 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.

Interrater reproducibility of the Myoton and durometer devices to quantify sclerotic chronic graft-versus-host disease.

Chronic graft-versus-host disease (cGVHD) is a severe complication in long-term survivors of allogeneic hematopoietic stem cell transplantation. This disease is challenging to manage clinically due to a lack of validated tools to quantitatively measure skin sclerosis. The current gold standard for measuring skin sclerosis is the NIH Skin Score which has only moderate agreement among clinicians and experts. To more accurately assess skin sclerosis in cGVHD, the Myoton and durometer devices can be used to directly measure biomechanical parameters of the skin. However, the reproducibility of these devices is not known in patients with cGVHD. To determine this reproducibility, three observers independently measured 10 anatomic sites in each of seven patients with sclerotic cGVHD using the Myoton and durometer. Clinical reproducibility was measured by mean pairwise differences (U-statistic) and intraclass correlation coefficients (ICCs) with 95% confidence intervals (CIs). Mean pairwise differences, expressed in true physical units, were used to report typical errors for each anatomic site and device. Mean pairwise differences were less than 11% of the average overall values for all five Myoton parameters and durometer hardness. These were lower for Myoton creep (4.1%), relaxation time (4.7%), and frequency (5.1%) than decrement (9.0%), stiffness (10.4%), and durometer hardness (9.0%). Myoton parameters creep, relaxation time, and frequency showed promise for capturing skin biomechanics more accurately than Myoton stiffness, decrement, or durometer hardness. Mean pairwise differences trended highest in the shin and volar forearm and lowest in the dorsal forearm. The interobserver ICC for overall (averaged across all measured body sites of a patient) creep (0.94; 95% CI 0.87-1.00), relaxation time (0.96; 95% CI 0.90-1.00), and frequency (0.95; 95% CI 0.88-1.00), trended higher than that for decrement (0.43; 95% CI 0.00-0.88), stiffness (0.92; 95% CI 0.81-1.00), and durometer hardness (0.82; 95% CI 0.61-1.00). Similar trends were observed in healthy participants. These findings can help clinicians design better studies to assess therapeutic response to new cGVHD treatments and support the interpretation of future measurements.

Non-Expert Markings of Active Chronic Graft-Versus-Host Disease Photographs: Optimal Metrics of Training Effects.

Lack of reliable measures of cutaneous chronic graft-versus-host disease (cGVHD) remains a significant challenge. Non-expert assistance in marking photographs of active disease could aid the development of automated segmentation algorithms, but validated metrics to evaluate training effects are lacking. We studied absolute and relative error of marked body surface area (BSA), redness, and the Dice index as potential metrics of non-expert improvement. Three non-experts underwent an extensive training program led by a board-certified dermatologist to mark cGVHD in photographs. At the end of the 4-month training, the dermatologist confirmed that each trainee had learned to accurately mark cGVHD. The trainees' inter- and intra-rater intraclass correlation coefficient estimates were "substantial" to "almost perfect" for both BSA and total redness. For fifteen 3D photos of patients with cGVHD, the trainees' median absolute (relative) BSA error compared to expert marking dropped from 20 cm2 (29%) pre-training to 14 cm2 (24%) post-training. Total redness error decreased from 122 a*·cm2 (26%) to 95 a*·cm2 (21%). By contrast, median Dice index did not reflect improvement (0.76 to 0.75). Both absolute and relative BSA and redness errors similarly and stably reflected improvements from this training program, which the Dice index failed to capture.

The Natural History of Primary Inner Ear Schwannomas: Outcomes of Long-Term Follow-Up.

OBJECTIVE: To describe the natural history of primary inner ear schwannomas over a long follow-up period. STUDY DESIGN: Retrospective case series. SETTING: Tertiary referral center. PATIENTS: Patients with primary inner ear schwannomas with serial audiometric and radiologic follow-up. MAIN OUTCOME MEASURES: Patterns of hearing loss, rate of hearing decline, presence of vestibular symptoms, and rate of tumor growth. RESULTS: A total of 12 patients with 13 tumors were identified. The mean duration of follow-up was 7 years. Forty-six percent of tumors were intracochlear, 15% were intravestibular, 23% were transmodiolar, and 15% were intravestibular-cochlear. Hearing loss was the most common presenting symptom, occurring in all patients. Among patients with serviceable hearing (American Academy of Otolaryngology-Head and Neck Surgery Class A or B) at the time of presentation, the average time to decline to a nonserviceable hearing level was 57.3 months (range, 21-117 mo). Hearing loss was sudden in 31% of patients, progressive in 61% and fluctuating in 8%. No patients had intractable vertigo; however, two required vestibular physiotherapy. On initial magnetic resonance imaging, the mean largest tumor dimension was 3.1 mm (standard deviation, 1.2 mm), and the mean largest dimension on most recent magnetic resonance imaging was 4.4 mm (standard deviation, 1.1 mm). Two tumors exhibited no growth over a follow-up of 11.3 and 2.8 years, respectively. Overall, the mean growth was 0.25 mm per year followed. Two patients underwent cochlear implantation with simultaneous tumor resection and had favorable outcomes. CONCLUSION: Long-term follow-up suggests a conservative approach, with possible hearing rehabilitation at the time of deterioration, is a safe management strategy for primary inner ear schwannomas.