Faculty Bibliography

PURPOSE/OBJECTIVE:Herpes simplex virus (HSV) and varicella zoster virus (VZV) are known causes of chronic and recurrent interstitial keratitis. Determination of active corneal inflammation is important for appropriate management. This study aimed to investigate features of clinically active herpetic interstitial keratitis (HIK) by anterior segment optical coherence tomography (AS-OCT). METHODS:Twenty-seven patients with active HIK (17 with HSV, 10 with VZV) and AS-OCT imaging were retrospectively identified. Five patients also had stromal scarring (SS), presumably from prior HIK episodes. An additional 4 patients with SS, but without a history of HIK, were also identified. The AS-OCT images were analyzed qualitatively, followed by an automated segmentation analysis. Deidentified images were shown to 3 masked graders after a training module, and their diagnoses were compared with slit-lamp diagnoses. RESULTS:Qualitative analysis of AS-OCT images of active HIK revealed anterior stromal hyperreflectivity, often with a hazy border and convex posterior contour comparable with "posterior bowing" historically seen on slit lamp. Borders were sharper and typically more linear for SS. Automated segmentation analyses identified that epithelium overlying the stromal area of interest was thicker in SS than HIK. Survey results revealed a high degree of correlation with slit-lamp diagnoses. CONCLUSIONS:AS-OCT may be a useful adjunct to slit-lamp examination in the evaluation of active inflammation in patients with a history of HIK. Hyperreflectivity, hazy borders, convex contour, and epithelial thickness may be informative. Future studies could elucidate a role for deep learning algorithms in diagnosing active HIK.

Retinopathy of prematurity (ROP) is a leading cause of childhood blindness that arises from disrupted retinal vascular development in premature infants. Oxygen exposure remains a central driver of treatment-warranted ROP, as higher saturation levels suppress early retinal vascular growth and later promote pathological neovascularization. Large, randomized trials of oxygen targeting show that lower oxygen saturation ranges reduce the incidence of treatment-requiring ROP, though with trade-offs in mortality. Observational cohorts, including the CRYO-ROP, ETROP, and e-ROP trials, consistently report lower rates of treatment-warranted ROP and reduced treatment need among Black infants despite similar or greater prematurity risk. Multiple explanations have been proposed to account for the paradoxically lower rates of treatment-warranted ROP observed among Black infants. Although biologic variations in angiogenic pathways have been proposed, evidence suggests that structural and clinical factors may offer an alternative explanation for these patterns. Black race is strongly correlated with residence in neighborhoods with greater socioeconomic disadvantage, which is associated with increased risk of prematurity and missed ROP follow-up visits. In addition, pulse oximeters may overestimate oxygen saturation in individuals with darker skin pigmentation, potentially altering targeted oxygen exposure. Survival-related selection bias may further contribute to this paradox, as infants at the highest risk of both mortality and treatment-warranted ROP may not survive long enough to develop treatment-requiring disease. This review examines racial differences in ROP severity and examines how oxygen exposure and structural factors may contribute to these disparities, while acknowledging the limited evidence supporting biologic explanations.

The microbiome has been described as the last human "organ" and is currently the topic of great research interest worldwide. The application of culture-independent methods, like 16S ribosomal next-generation sequencing, has offered researchers the opportunity to identify bacterial populations that were impossible to detect previously using conventional culture methods. Further standardization of these new approaches to characterizing the microbiome is desirable. The present review discusses the mounting evidence suggesting that alterations in the microbiome and microbial metabolites, such as short-chain fatty acids in the gut, mouth, and ocular surface, may play a key role in the pathogenesis of ocular pathologies such as ocular surface disease, glaucoma, uveitis, age-related macular degeneration, and diabetic retinopathy. Clarifying the probable role of the microbiome in ocular diseases would not only offer valuable insights into pathogenesis but could also enable the development of novel therapeutic approaches. As yet, microbial-based therapeutic applications in ophthalmology are limited. Nevertheless, recently emerging strategies utilizing probiotics and prebiotics, or even fecal transplantation to regulate microbiome composition, offer promising research avenues for developing future innovative therapies for ocular diseases. Further studies employing standardized methodological protocols are needed to ensure the reproducibility of results and to eventually unlock the precise links between the microbiome and the eye.

Retinopathy of prematurity (ROP) is a leading cause of childhood blindness characterized by disrupted physiologic vascularization followed by pathologic neovascularization, classically organized around the insulin-like growth factor-1 (IGF-1)-vascular endothelial growth factor (VEGF) axis in the retina. Increasing evidence suggests that early-life gut dysbiosis may act as an upstream modifier of this biphasic process. In this review, we synthesize human cohort studies, multi-omics analyses, and experimental animal models examining associations between the neonatal gut microbiome and ROP. Preterm infants who develop severe ROP demonstrate enrichment of facultative anaerobes and reduced acquisition of obligate anaerobes, alongside altered predicted metabolic capacity. Microbiome-derived metabolites, including short-chain fatty acids, bile acid derivatives, and lipid mediators, have been shown in experimental systems to influence systemic IGF-1 production, hypoxia-inducible factor-1α stabilization, and VEGF signaling. Rodent oxygen-induced retinopathy models offer a translation framework to assess the functional link between microbial perturbation and retinal angiogenic responses. Collectively, these findings support a conceptual microbiome-IGF-1-VEGF-retina axis in which early intestinal dysbiosis may modulate inflammatory tone, metabolic signaling, and retinal vascular development. Although current evidence remains largely associative, integrating microbiome profiling with mechanistic and longitudinal studies may clarify potential causal pathways and identify novel biomarkers or preventive strategies for severe ROP.

INTRODUCTION/UNASSIGNED:Vision loss in older adults is largely driven by age-related macular degeneration (AMD), characterized by progressive central visual field damage and functional decline. While current options for wet and dry AMD are limited and expensive, drug repurposing represents a promising strategy to accelerate the discovery of effective, accessible treatment by leveraging medications with established safety profiles. Notably, anti-diabetic agents including metformin, sulfonylureas, glucagon-like peptide-1 receptor agonists (GLP-1RAs), and insulin have emerged as modulators of the retinal pigment epithelium (RPE) function, photoreceptors, and retinal vascular integrity. AREAS COVERED/UNASSIGNED:This review highlights the roles of oxidative stress, inflammation, and complement-mediated immune dysregulation in AMD pathogenesis, alongside preclinical data demonstrating metformin's protective effects via AMP-activated protein kinase (AMPK) activation. Population-based studies and meta-analyses further suggest a modest reduction in AMD risk associated with metformin use in both diabetic and non-diabetic cohorts. Additional pharmacological agents include statins, glyburide, L-DOPA, fluoxetine, dimethyl fumarate, and nutraceuticals such as curcumin, melatonin, and N-acetylcysteine. EXPERT OPINION/UNASSIGNED:Early AMD prevention through repurposed therapeutics, guided by AI-driven design and systems biology, may enable personalized care via multimodal risk stratification incorporating genetic, metabolomic, and microbiome data. Rigorous, stratified clinical trials integrating bioinformatics and precision medicine are essential to validate the most effective candidates.

Current therapies slow down advanced features but do not halt or reverse degeneration and neovascularization in dry and wet age-related macular degeneration (AMD). Recent research implicates the gastrointestinal microbiome as a potential critical modulator in AMD pathogenesis through the gut-retina axis. Dysbiosis, characterized by imbalanced microbial diversity, composition and function, can exacerbate systemic and retinal inflammation through microglial priming, inflammasome activation, and secretion of pro-angiogenic cytokines (IL-6, IL-1β, TNF-α, VEGF). Additionally, microbiome-derived metabolites such as short-chain fatty acids and bile acids may exert modulatory roles in host immunity and homeostasis. Their depletion in conjunction with enrichment of specific microbial taxa have been linked to progression of advanced AMD. Together, these complex systems of immune crosstalk in relation to dysbiosis highlight the gut-retina axis as a promising therapeutic target. Dietary modifications, particularly Mediterranean and high-fiber diets, enhance production of protective metabolites and are associated with decreased AMD progression risk compared to Western dietary patterns. Experimental strategies such as fecal microbiota transplantation in animal models and drug repurposing strategies show promise in modulating disease severity. This review synthesizes current mechanistic insights into microbial-immune crosstalk in AMD, emphasizing the interplay of dysbiosis, immune activation, and metabolite signaling.

OBJECTIVE/UNASSIGNED:Retinopathy of prematurity (ROP) has been linked to neonatal sepsis, with antibiotic use suggested as a connection. Given the role of antibiotics in gut dysbiosis and the gut-retina axis, we assessed whether exposure to different antibiotic classes is associated with the incidence of treatment-necessary ROP. DESIGN/UNASSIGNED:Retrospective cohort study. SUBJECTS/UNASSIGNED:Preterm infants born at the University of Chicago Medicine and screened for ROP between January 2012 and December 2023. METHODS/UNASSIGNED:Retrospective analysis was performed to compare systemic antibiotic exposure within the first 2 months of life between infants with type 1 ROP (ie, required treatment) and those that did not require treatment. Multivariable adjustment included birth weight (BW), gestational age (GA), bronchopulmonary dysplasia (BPD), intraventricular hemorrhage, necrotizing enterocolitis (NEC), and neonatal sepsis. To reduce potential confounding by indication, propensity score matching was performed. MAIN OUTCOME MEASURES/UNASSIGNED:Type 1 ROP by systemic exposure to antibiotic classes. RESULTS/UNASSIGNED:= 0.014). CONCLUSIONS/UNASSIGNED:Early exposure to broad-spectrum antibiotic classes, particularly cephalosporins, carbapenems, and monobactams, may be associated with type 1 ROP. FINANCIAL DISCLOSURES/UNASSIGNED:The authors has no/the authors have no proprietary or commercial interest in any materials discussed in this article.

PURPOSE/OBJECTIVE:To investigate whether metformin use is associated with decreased odds of new-onset International Classification of Disease (ICD) coding of neovascular age-related macular degeneration (nAMD). DESIGN/METHODS:Case-control study. PARTICIPANTS/METHODS:22,205 cases with new-onset ICD coding of nAMD and 22,126 matched controls without AMD were identified in the Merative™ MarketScan® Research Databases between 2008 and 2017. A subgroup of patients diagnosed with diabetes included 6,664 cases and 5,513 controls. METHODS:Cases with new-onset ICD coding of nAMD were propensity score matched to controls without AMD. Multivariable conditional logistic regression analyzed the association between new-onset ICD coding of nAMD and metformin use controlling for (1) AMD risk factors, including diabetes, diabetic retinopathy, hyperlipidemia, obesity, and smoking, (2) exposures to other antidiabetic medications, including insulin, sulfonylureas, glitazones, meglitinides, other diabetic medications, and statins, and (3) the number of antidiabetic medications. MAIN OUTCOME MEASURES/METHODS:Adjusted odds ratios of new-onset ICD coding of nAMD for any metformin use and cumulative two-year metformin dose in grams (g). RESULTS:Any metformin use was associated with decreased adjusted odds of new-onset nAMD (aOR 0.84, 95% CI 0.74-0.95). In an exploratory dosing analysis, associations across cumulative-dose categories were heterogeneous, with the largest magnitude in the mid-dose range (between 271 and 600 g; aOR 0.73, 95% CI 0.63-0.85); because adherence cannot be verified from claims, dose-response findings are interpreted as hypothesis-generating. These associations persisted among diabetic patients (Any metformin use: aOR 0.83, 95% CI 0.72-0.94; 271 to 600 g: aOR 0.72, 95% CI 0.61-0.85; >1080 g: aOR 0.85, 95% CI 0.72-0.999). Any metformin use in diabetic patients without retinopathy was associated with decreased odds of new-onset ICD nAMD (aOR 0.85, 95% CI 0.78-0.93); however, this association was absent in diabetic patients with retinopathy. CONCLUSIONS:In this claims-based analysis, metformin use was associated with lower odds of incident ICD-coded nAMD, and an exploratory dosing analysis suggests a low to moderate cumulative dose may be associated with the greatest decrease. These associations persisted among diabetic patients without retinopathy. Causal inference is limited by the observational design, potential diagnostic misclassification, imperfect exposure measurement, and residual confounding. Replication with validated case definitions, active-comparator new-user designs, and adjudicated outcomes is warranted.