Faculty Bibliography

In the last decade, there has been tremendous growth in the number of accelerated three-year medical pathway programs. The needs of accelerated pathway students are different from traditional students, and a robust mentoring program should be developed to address specific issues and guarantee student success. We describe a unique approach to the development of a mentoring program for accelerated three-year MD students at New York University Grossman School of Medicine.

CYP1B1 is the most common gene implicated in primary congenital glaucoma (PCG) - the most common form of childhood glaucoma. How CYP1B1 mutations cause PCG is not known. Understanding the mechanism of PCG caused by CYP1B1 mutations is crucial for disease management, therapeutics development, and potential prevention. We performed a comprehensive metabolome/reactome analysis of CYP1B1 to enlist CYP1B1-mediated processes in eye development. The identified metabolic events were classified into major pathways. Functional analysis of these metabolic pathways was performed after cloning the CYP1B1 wild-type gene and expressing the wild-type and selected novel mutants (previously reported by our group L24R, F190L, H279D, and G329D) in heterologous hosts. Stability and enzymatic functions were investigated. Structural modeling of the wild-type and the variants was also performed. Reactome analysis revealed a total of 166 metabolic processes which could be classified into four major pathways including estradiol metabolism, retinoic acid metabolism, arachidonic acid metabolism, and melatonin metabolism. Stability assay revealed rapid denaturing of mutant proteins compared to wild-type. Enzymatic assays showed functional deficit in mutant proteins in metabolizing estradiol, retinoids, arachidonate, and melatonin. Modeling revealed that the examined mutations induced structural changes likely causative in functional loss in CYB1B1 as observed in enzymatic assays. Hence, mutations in the CYP1B1 gene are associated with a functional deficit in critical pathways of eye development. These findings implicate the potential contributions of altered metabolic regulations of estradiol, retinoids, arachidonate and melatonin to the pathogenesis of PCG during the processes of the formation of ocular structures and function.

Sjögren's disease (SjD) is an autoimmune disorder characterized by progressive salivary and lacrimal gland dysfunction, inflammation, and destruction, as well as extraglandular manifestations. SjD is associated with autoreactive B and T cells, but its pathophysiology remains incompletely understood. Abnormalities in regulatory T (T_reg) cells occur in several autoimmune diseases, but their role in SjD is ambiguous. We had previously shown that the function and development of T_reg cells depend on store-operated Ca²⁺ entry (SOCE), which is mediated by ORAI1 Ca²⁺ channels and stromal interaction protein 1 (STIM1) and STIM2. Here, we show that mice with a Foxp3⁺ T_reg cell-specific deletion of Stim1 and Stim2 develop a phenotype that fulfills all classification criteria of human SjD. Mutant mice have salivary and lacrimal gland inflammation characterized by strong lymphocyte infiltration and transcriptional signatures dominated by T helper 1 (T_H1) and interferon (IFN) signaling. CD4⁺ T cells from mutant mice are sufficient to induce SjD-like disease in an IFN-γ-dependent manner. Inhibition of IFN signaling with the JAK1/2 inhibitor baricitinib alleviated CD4⁺ T cell-induced SjD in mice. These findings are consistent with the transcriptional profiles of CD4⁺ T cells from patients with SjD, which indicate enhanced T_H1 but reduced memory T_reg cell function. Together, our study provides evidence for a critical role of dysfunctional T_reg cells and IFN-γ-producing T_H1 cells in the pathogenesis of SjD.

Corneal cross-linking (CXL) has profoundly changed the management of keratoconus and other ectatic corneal diseases. Introduced in the late 1990s, CXL marked the first effective intervention to halt disease progression. This chapter describes the history of CXL, beginning with its conceptual foundations and preclinical studies conducted at the University of Dresden. Early experiments established the efficacy of riboflavin and UV-A light to induce collagen cross-linking, which improved corneal stiffness. Clinical translation followed with the Dresden protocol, demonstrating safety and efficacy. Long-term studies confirm sustained benefits, with advances in accelerated protocols and modifications for thin corneas extending eligibility to more patients. Additionally, CXL has expanded into infectious keratitis treatment and refractive surgery. Emerging innovations, such as customized and two-photon CXL, promise further applications. By examining the milestones in its evolution, this paper highlights the transformative impact of CXL on corneal disease management.

PURPOSE/OBJECTIVE:We present a patient with a primary vasoproliferative tumor (VPT) accompanied by vitreous haze and an epiretinal membrane (ERM). We report for the first time the vitreous cytokine profile from an eye with a primary VPT to explore the relationship between intraocular inflammation and these tumors. METHODS:Retrospective chart review of a single patient case. RESULTS:25-gauge pars plana vitrectomy with membrane peel and vitreous biopsy was performed. Peripheral vitreous shave exposed an inferior grey-red mass located at the ora serrata, consistent with VPT. Treatment with confluent, long duration endolaser was performed. Vitreous cytology was negative for malignancy. A 13-cytokine panel (Associated Regional and University Pathologists, Inc. Laboratories, Salt Lake City, UT) revealed elevated interleukin 6 (13.3 pg/mL; normal <=2.0) and interleukin 8 (6.0 pg/mL; normal <=3.0). At one month post-operative, visual acuity improved from 20/40 to 20/25 OD, with mild anterior vitreous inflammation and regression of the VPT. CONCLUSION/CONCLUSIONS:Pro-inflammatory and pro-angiogenic cytokines were elevated in the vitreous of this patient's eye with a primary VPT. We suggest that the endothelial cells and macrophages which comprise VPTs could secrete these cytokines into the vitreous, resulting in vitreous haze and an overzealous fibrotic response manifested as ERM formation.

PURPOSE/OBJECTIVE:The purpose of this study was to characterize the morphological and immunological aspects of biointegration at the optic-cornea joint of a second-generation synthetic corneal device. METHODS:The initial prototype, single-piece optic-skirt configuration, is constructed from compact and flexible perfluoroalkoxy alkane with porous expanded polytetrafluoroethylene (ePTFE) overlying the skirt to allow skirt-cornea biointegration. The second-generation version was modified to add ePTFE around the optic wall to allow optic-cornea biointegration. Initial and amended second-generation devices were implanted into healthy rabbit eyes. Clinical examination, anterior segment optical coherence tomography, light microscopy, and immunofluorescence studies were performed to assess structural integrity and determine molecular signatures indicative of inflammation and tissue remodeling between the 2 prototypes. RESULTS:Recipient eyes with both device versions showed no epithelial defects or tissue retraction at 3 months postoperatively. Optical coherence tomography images demonstrated no appreciable perioptic space with either prototype. Histopathology of the initial device demonstrated lack of stromal adhesion at the optic-cornea joint with epithelium filling the perioptic space. Second-generation devices demonstrated full sealing of the recipient stroma along the optic stem. Although the routine histopathology did not demonstrate inflammatory cells in the recipient cornea with either device, immunohistochemistry stains demonstrated quiescent phenotype of stromal and epithelial cells only in the second-generation devices. CONCLUSIONS:Biointegration between the synthetic corneal device and recipient tissue at the optic-cornea joint seems to avert inflammation and may help prevent sterile tissue lysis and prolong retention.

PURPOSE/OBJECTIVE:The aim of this study was to identify successful recruitment strategies and obstacles reported by principal investigators (PIs) of the Zoster Eye Disease Study (ZEDS). METHODS:A web-based survey was created by a subset of ZEDS PIs and distributed to ZEDS PIs after study enrollment was closed. The survey queried investigators about recruitment strategies and obstacles, use of prophylactic oral antiviral medication, electronic medical records, telemedicine, COVID-19 effect, turnover of research staff, and recruitment outreach to minority and underserved populations. The survey allowed objective measures and free-text options. Analysis from centers with higher enrollment was compared with centers with lower enrollment to identify successful strategies and common obstacles. RESULTS:The most frequently cited helpful strategies were participation from ophthalmologists within the PI's institution (33/63, 52%), ophthalmology resident referrals (23/63, 37%), and chart review (23/63, 37%). Travel to participating clinical center (42/63, 67%) and ongoing prophylactic use of oral systemic antiviral medication (39/63, 62%) were common obstacles. Research coordinator turnover was identified as a contributor to reduced recruitment success by 49% (31/63) of PIs and made recruitment much harder for 22% (14/63). A small number of investigators used telemedicine (18/63, 29%) and few made efforts to recruit from minority and underserved populations (10/63, 16%). CONCLUSIONS:Our survey highlights the importance of internal ophthalmologist referral, chart review, and research coordinator commitment for successful clinical trial recruitment. We discuss the impact of prophylactic use of oral antiviral medication on recruitment. Future randomized clinical trials should mobilize the helpful recruitment strategies and improve outreach to underserved populations.

PURPOSE/OBJECTIVE:The Zoster Eye Disease Study (ZEDS) is the first randomized clinical trial to study the efficacy of long-term (1 year) suppressive valacyclovir treatment on herpes zoster ophthalmicus (HZO) outcomes. This article details the baseline characteristics of participants. SETTING/METHODS:The study was set at 95 participating clinical centers in 33 states, Canada, and New Zealand. STUDY POPULATION/METHODS:Immunocompetent adults with a history of a characteristic HZO unilateral rash and documentation of an episode of active dendriform epithelial keratitis, stromal keratitis, endothelial keratitis, or iritis within the preceding year, enrolled in ZEDS from November 2017 to January 2023. INTERVENTION/METHODS:Participants were randomized to double-masked oral valacyclovir 1 gm daily versus placebo for 1 year of treatment and followed for 18 months. RESULTS:Five hundred twenty-seven participants were enrolled across 4 strata according to age at HZO onset (younger or older than 60 years) and duration of HZO at enrollment (less or greater than 6 months), with an even distribution of men and women and a median age of 60 years. More participants with recent (57%, 300/527) than chronic HZO and younger than 60 years at HZO onset (54%, 286/527) were enrolled. Most participants were treated acutely with a recommended antiviral regimen (91%, 480/527) and had not been vaccinated against zoster (79%, 418/527). CONCLUSIONS:The broad ZEDS study population enhances the likelihood that ZEDS will provide generalizable high-quality evidence regarding the efficacy and safety of suppressive valacyclovir for HZO immunocompetent adults and whether it should become standard of care. TRIAL REGISTRATION/BACKGROUND:ClinicalTrials.gov Identifier: NCT03134196.