Faculty Bibliography

SIGNIFICANCE/CONCLUSIONS:Optimal meibography utilization and interpretation are hindered due to poor lid presentation, blurry images, or image artifacts and the challenges of applying clinical grading scales. These results, using the largest image dataset analyzed to date, demonstrate development of algorithms that provide standardized, real-time inference that addresses all of these limitations. PURPOSE/OBJECTIVE:This study aimed to develop and validate an algorithmic pipeline to automate and standardize meibomian gland absence assessment and interpretation. METHODS:A total of 143,476 images were collected from sites across North America. Ophthalmologist and optometrist experts established ground-truth image quality and quantification (i.e., degree of gland absence). Annotated images were allocated into training, validation, and test sets. Convolutional neural networks within Google Cloud VertexAI trained three locally deployable or edge-based predictive models: image quality detection, over-flip detection, and gland absence detection. The algorithms were combined into an algorithmic pipeline onboard a LipiScan Dynamic Meibomian Imager to provide real-time clinical inference for new images. Performance metrics were generated for each algorithm in the pipeline onboard the LipiScan from naive image test sets. RESULTS:Individual model performance metrics included the following: weighted average precision (image quality detection: 0.81, over-flip detection: 0.88, gland absence detection: 0.84), weighted average recall (image quality detection: 0.80, over-flip detection: 0.87, gland absence detection: 0.80), weighted average F1 score (image quality detection: 0.80, over-flip detection: 0.87, gland absence detection: 0.81), overall accuracy (image quality detection: 0.80, over-flip detection: 0.87, gland absence detection: 0.80), Cohen κ (image quality detection: 0.60, over-flip detection: 0.62, and gland absence detection: 0.71), Kendall τb (image quality detection: 0.61, p<0.001, over-flip detection: 0.63, p<0.001, and gland absence detection: 0.67, p<001), and Matthews coefficient (image quality detection: 0.61, over-flip detection: 0.63, and gland absence detection: 0.62). Area under the precision-recall curve (image quality detection: 0.87 over-flip detection: 0.92, gland absence detection: 0.89) and area under the receiver operating characteristic curve (image quality detection: 0.88, over-flip detection: 0.91 gland absence detection: 0.93) were calculated across a common set of thresholds, ranging from 0 to 1. CONCLUSIONS:Comparison of predictions from each model to expert panel ground-truth demonstrated strong association and moderate to substantial agreement. The findings and performance metrics show that the pipeline of algorithms provides standardized, real-time inference/prediction of meibomian gland absence.

PURPOSE/OBJECTIVE:We developed human cornea organoids (HCOs) from induced pluripotent stem cells (iPSCs) where single-cell RNA-sequence (scRNA-seq) analysis suggested similarity with developing rather than mature human corneas. We performed immunohistology to determine the presence of corneal glycosaminoglycans as an assessment of maturity. We undertook a detailed comparison of the HCO scRNA-seq data with a recent scRNA-seq study of human fetal corneas at different stages to gauge the HCO's maturity. METHODS:We generated HCOs from a second iPSC line, NCRM-1, to assess the reproducibility of HCO development. We stained sections from both HCO lines with Alcian blue and picrosirius red to determine deposition of sulfated glycosaminoglycans and fibrillar collagens. We immunolocalized glycosaminoglycan biosynthetic enzymes and proteoglycan core proteins. The scRNA-seq data from IMR90.4 HCOs were compared to that of fetal corneas using MetaNeighbor analysis to assess the similarity of HCOs to different stages of human corneal development. RESULTS:The MetaNeighbor analysis suggests closer alignment of the IMR90.4 HCOs with 17-18 post-conception week fetal human corneas. HCOs from both iPSC lines deposit sulfated glycosaminoglycans and fibrillar collagens. Immunohistology showed chondroitin/dermatan sulfate (CS/DS) and keratan sulfate in the presumptive stromal and some epithelial layers. The NCRM-1-derived HCOs show increased CS/DS staining compared to the IMR90.4 derived HCOs. CONCLUSIONS:Both HCO lines show similar developmental patterns and timeline. The NCRM-1 HCO line may have more glycosaminoglycan deposition. Overall, the glycosaminoglycan deposition pattern is consistent with an immature tissue. Optimizations based on our current findings may yield more mature stromal cells and cornea-typical proteoglycans.

The existence of a previously unrecognized subarachnoid lymphatic-like membrane (SLYM) was reported in a recent study. SLYM is described as an intermediate leptomeningeal layer between the arachnoid and pia mater in mouse and human brains, which divides the subarachnoid space (SAS) into two functional compartments. Being a macroscopic structure, having missed detection in previous studies is surprising. We systematically reviewed the published reports in animals and humans to explore whether prior descriptions of this meningeal layer were reported in some way. A comprehensive search was conducted in PubMed/Medline, EMBASE, Google Scholar, Science Direct, and Web of Science databases using combinations of MeSH terms and keywords with Boolean operators from inception until 31 December 2023. We found at least eight studies that provided structural evidence of an intermediate leptomeningeal layer in the brain or spinal cord. However, unequivocal descriptions for this layer all along the central nervous system were scarce. Obscure names like the epipial, intermediate meningeal, outer pial layers, or intermediate lamella were used to describe it. Its microscopic/ultrastructural details closely resemble the recently reported SLYM. We further examined the counterarguments in current literature that are skeptical of the existence of this layer. The potential physiological and clinical implications of this new meningeal layer are significant, underscoring the urgent need for further exploration of its structural and functional details.

PURPOSE/UNASSIGNED:We evaluated the efficacy of varenicline solution nasal spray (VNS) in treating dry eye disease (DED) associated with moderate to severe Sjogren's disease and analyzed tear film cytokine levels of patients with DED and Sjogren's disease before and after VNS use. METHODS/UNASSIGNED:This was a pilot study involving a single-center, single-arm investigator-initiated trial. Patients with moderate to severe Sjogren's disease were given VNS 0.03 mg twice daily for 28 days. Patients were assessed on day 0 before VNS use, day 14 and day 28. Clinical exam findings, symptomatology as measured by the eye dryness score, and tear cytokines were assessed at baseline and day 28. RESULTS/UNASSIGNED:Thirty-nine subjects were included. Between day 0 and day 28, there was a statistically significant improvement in the eye dryness score (p = 0.01), corneal staining (p < 0.001), and conjunctival staining (p = 0.04). There was a statistically significant increase in tear secretion by unanesthetized Schirmer's in subjects with a baseline Schirmer's ≤5 mm (n = 35 eyes, p = 0.02) and a non-statistically significant increase in tear secretion in subjects with a baseline Schirmer's of 6-10 mm (n = 16 eyes, p = 0.79). There was a statistically significant decrease in tear film cytokine concentration of IFNγ (p = 0.0003), IL-12p70 (p < 0.0001), IL-17a (p = 0.004), IL-1β (p = 0.007), IL-2 (p < 0.0001), IL-4 (p = 0.01), and TNF-α (p = 0.02), and no significant change in IL-6 (p = 0.56) and IL-10 (p = 0.18). CONCLUSION/UNASSIGNED:Our findings add to existing evidence that VNS improves subjective dry eye symptoms, corneal and conjunctival staining, and tear secretion in a subset of tear-deficient patients, while providing new evidence that VNS reduces concentration of pro-inflammatory cytokines in the tear film. CLINICAL TRIAL REGISTRATION NUMBER/UNASSIGNED:NCT05700422.

The XEN®45 Glaucoma Treatment System (gel stent; Allergan, an AbbVie company, Irvine, CA, USA) is a minimally invasive bleb-forming surgical device that was originally approved to lower intraocular pressure by diverting the aqueous humor from the anterior chamber to the subconjunctival space (like trabeculectomy) following ab-interno placement. Since approval of the gel stent in multiple countries, the implantation technique has evolved considerably, being performed ab interno or ab externo with open or closed conjunctiva, based on patients' needs and/or surgeons' preferences. Additional technical variations that can facilitate gel stent placement and/or improve outcomes have also emerged. This article aims to increase awareness of these developments to facilitate informed decision-making and improve surgical success and outcomes for patients.

PURPOSE/UNASSIGNED:To determine the characteristics of normal tension glaucoma referrals at a tertiary care center and risk factors associated with unilateral versus bilateral disease. PATIENTS AND METHODS/UNASSIGNED:Medical records were reviewed of patients who were referred to a single glaucoma provider at a tertiary care center and were given a presumptive diagnosis of normal tension glaucoma (NTG) between the years 2018 and 2021. Data collected included demographics, medical and family history, ophthalmic history, ophthalmic examination findings, neuro-ophthalmology referrals, and magnetic resonance imaging (MRI) results. RESULTS/UNASSIGNED:A total of 98 patients were included in this study. The majority of patients (82%) had bilateral disease at initial presentation. Most patients (65%) had a history of systemic disease, including hypertension (32%), cardiovascular disease (19%), diabetes (12%), obstructive sleep apnea (10%), or orthostatic hypotension (4%). Conditions associated with vascular dysregulation were identified in 24% of patients. Sixty six percent of patients had a family history of glaucoma, while nearly half (49%) were myopic. Of patients with unilateral disease, 39% had workup or consideration of other neuro-ophthalmic diagnoses compared to 13% of patients with bilateral disease (P = 0.01). CONCLUSION/UNASSIGNED:Patients referred for NTG commonly present with disc changes in both eyes. Clinicians should assess for the presence of systemic diseases associated with vascular dysregulation, myopia, and a family history of glaucoma. Patients with unilateral disease consistent with NTG may benefit from additional workup including neuroimaging or a neuro-ophthalmic evaluation.

We report the case of a 33-year-old woman with a history of hypothyroidism and ocular history of mild myopia who presented with a spontaneous filtering bleb. Extensive systemic rheumatologic evaluation was unrevealing. The bleb was observed for many months, until the patient's vision declined secondary to the development of hypotony maculopathy. The filtering bleb was closed using an allogenic scleral patch graft, resulting in normotensive intraocular pressure and improved best-corrected visual acuity. A unilateral, spontaneous filtering bleb is a rare occurrence and is typically associated with systemic or ocular conditions. Complications such as hypotony can lead to visual impairment, and intervention is required. Early diagnosis and repair with donor scleral patch graft can prevent complications and provide an excellent cosmetic outcome.

Currently there are no surgical solutions to restore vision in the irreversibly blind. Whole eye transplantation (WET), is an appealing surgical approach for restoration, replacement, and reconstruction of nonfunctioning eyes. Development of a reliable animal model to test the integrity and functionality of the transplanted eye is an essential step towards clinical whole eye transplantation. This study presents a feasible vascularized orthotopic eye transplantation preclinical rat model to study the structural and functional outcomes of whole eye transplantation. Syngeneic orthotopic transplants were performed in rats, involving anastomoses between carotid arteries, external jugular veins, and optic nerve coaptations of donors and recipients. The transplanted and recipient native eyes were assessed by ocular exam under anesthesia, optical coherence tomography (OCT), histology, magnetic resonance imaging and electroretinography. A 100% surgical survival rate of recipients with maintained long-term health demonstrated this to be a reliable and reproducible model. Assessment from clinical examination under anesthesia revealed that segments of native eyes appeared normal throughout the duration of the study, but transplanted eyes presented mild chemosis of the eye lids, mild ciliary flush of the conjunctiva, cornea neovascularization, mild engorgement of the vessels in the iris, and mild opacities in the lens in some animals. Most of these findings improved over time after transplantation. Doppler optical coherence tomography corroborated the presence of blood flow in transplanted retinas. There was no significant difference in measured IOP between native and transplanted eyes. Both histology and OCT scans demonstrated increased central corneal thickness and decreased total retinal thickness in transplanted eyes. Transplanted eyes exhibit minimal scotopic and photopic ERG responses. To date, no other vascularized orthotopic rodent WET transplantation models have been described in the literature. As functional visual return remains the ultimate goal, this model provides a foundation for future translational strategies and is ideal for testing immunomodulatory, neuroprotective, and neuroregenerative approaches either individually or in combination, as required for total human eye allotransplantation (THEA) to become a clinical reality.

BACKGROUND/UNASSIGNED:Attention Deficit Hyperactivity Disorder (ADHD) among children younger than 6 years is quite impairing, nearly half these youth with ADHD experience school exclusion from mainstream preschool classes due to related emotional and behavioral outbursts. While a range of behavior rating scales and subjective measures are used to assess these youth, objective methods of assessment and prediction derived from technology have potential to improve therapeutic and academic interventions outcomes for these youths. We hypothesized that biometric sensors would provide objective, highly sensitive and specific information regarding the physiological status of children prior to an impulsive outburst and could be feasibly implemented using a wearable device in the special education classroom. METHODS/UNASSIGNED: = 5 youth from the first grade) of a specialized therapeutic day-school for youth with ADHD and other psychiatric and developmental disorders to examine feasibility of obtaining continuous physiological data associated with behavioral and emotional outbursts through smartwatch use. Children wore a sensor watch during their daily classroom activities for two weeks and trained observers collected data using behavioral logs. Using Ecological Momentary Assessment methodology, to examine correlations between objective sensor data and observer observation. Data collected from parents regarding prior night's sleep was also examined. RESULTS/UNASSIGNED:All participants completed the study. With a few tolerability or palatability issues. Associations were found between physiological and behavioral/questionnaire data. The methodology holds promise for reliably measuring behavioral and emotional outbursts in young children. CONCLUSIONS/UNASSIGNED:among severely dysregulated pre-school aged youth throughout a full school day. This study established the feasibility of utilizing sensor derived physiological data as an objective biomarker of ADHD within the special education therapeutic classroom. Further research with larger samples is required to build a more robust and personalized AI predictive model.

PURPOSE/UNASSIGNED:To determine the efficacy and safety of repetitive transorbital alternating current stimulation (rtACS) treatment by assessing vision-related quality of life and visual function outcome in subjects treated with rtACS versus sham-control. STUDY DESIGN/UNASSIGNED:Double masked, randomized, sham-controlled clinical trial (NCT03188042). SUBJECTS/UNASSIGNED:Sixteen subjects with moderate-to-advanced glaucoma (visual field [VF] mean deviation [MD] ≤-6.00 decibels) randomized into sham (9 subjects) or rtACS intervention (7 subjects) groups. METHODS/UNASSIGNED:Subjects underwent 10 rtACS sessions over 2 weeks. All subjects had comprehensive ocular examination at baseline, 1-week, and 4-weeks posttreatment. MAIN OUTCOME MEASURES/UNASSIGNED:Visual acuity (VA), contrast sensitivity (CS), VF MD, number of threshold sensitivity points that changed or were unchanged, and vision-related quality of life (VR-QoL) questionnaire scores. RESULTS/UNASSIGNED: = 0.04). No significant changes were detected with VA, CS, and VF analyses for either group. No serious adverse events were noted in either study group. CONCLUSIONS/UNASSIGNED:Repetitive transorbital alternating current stimulation therapy showed a significant beneficial effect on several domains of VR-QoL. Further studies will determine its utility in glaucoma. FINANCIAL DISCLOSURES/UNASSIGNED:Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.