Faculty Bibliography

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.

PURPOSE/OBJECTIVE:To characterize the clinical and ultra-widefield (UWF) imaging of the chrysanthemum phenotype of multifocal choroiditis with panuveitis (MFCPU) and to describe a related variant, termed the miliary phenotype. DESIGN/METHODS:Multicenter, retrospective, observational case series. SUBJECTS/METHODS:Fifteen patients (20 eyes) with MFCPU exhibiting chrysanthemum lesions. METHODS:Comprehensive ophthalmic examination and multimodal imaging, including UWF color fundus photography, fundus autofluorescence, fluorescein angiography, indocyanine green angiography (ICGA), and optical coherence tomography (OCT), at baseline-first visit with both UWF-ICGA and OCT through active MFCPU lesions) and follow-up-were reviewed. Lesion morphology, topography, quadrant distribution, and choroidal vascular features such as vortex vein (VV) dilation, intervortex vein anastomoses (IVA) and choroidal vascular hyperpermeability (CVH) were analyzed. OCT was evaluated for subretinal hyperreflective material (SHRM), subfoveal choroidal thickness (SFCT), and secondary choroidal neovascularization (CNV). MAIN OUTCOME MEASURES/METHODS:Morphologic and topographic characterization of chrysanthemum and miliary lesions, prevalence of VV dilation, IVA, and CVH, complications, and visual outcomes. RESULTS:Baseline, mean age was 37.1±17.3 years; 80% were female and 73% myopic. Mean follow-up duration was 23.2±20.5 months. Disease was unilateral 67% and bilateral in 33% of patients. Lesions were predominantly peripheral, involving the mid- and far periphery in 60% of eyes and multiple quadrants in 65%. ICGA revealed VV dilation and CVH in 17/20 (85%) eyes and IVA in 15/20 (75%) eyes, colocalizing with chrysanthemum lesions. OCT showed focal (lesion-level) choroidal thickening, SHRM, and outer retinal atrophy; CNV developed in 10/20 (50%) eyes and persisted in 56% at follow-up, while subretinal fibrosis occurred in 25%. Mean SFCT decreased from 318.8±73.2 µm to 285.8±69.6 µm. Visual acuity remained stable with long-term follow-up (0.24 logMAR, 20/35). The miliary variant, identified in 4/20 (20%) eyes, presented as clusters of confluent white-yellow lesions spanning all quadrants. CONCLUSIONS:Chrysanthemum MFCPU predominantly affects the peripheral choroid and is associated with venocentric features including CVH, IVA, and VV dilation on UWF-ICGA, suggesting a potential pathogenetic role for focal choroidal congestion. The identification of a miliary variant broadens the morphologic spectrum of MFCPU. Recognition of these patterns is critical for accurate diagnosis, differentiation from other inflammatory chorioretinopathies, and prevention of CNV and fibrosis.

What makes human brains distinctive? The answer is hidden at least partially in the myriad synaptic connections made between neurons - the connectome. The foveal retina is a primate specialization which presents a feasible site for deriving a complete connectome of a human CNS structure. In the fovea, cells and circuits are miniaturized and compressed to densely sample the visual image at highest resolution and initiate form, color and motion perception. Here we provide a draft connectome of all neurons in a human fovea. We found synaptic connections, distinct to humans, linking short-wavelength sensitive cones to color vision pathways. Moreover, by reconstructing excitatory synaptic pathways arising from cone photoreceptors we found that over 95% of foveal ganglion cells contribute to only three major pathways to the brain. Our study reveals unique features of a human neural system and opens a door to a complete foveal connectome.

INTRODUCTION/BACKGROUND:A retrospective analysis was performed to determine if a glueless, sutureless surgical technique utilizing a triple-layer dehydrated, decellularized amniotic basement membrane tissue, combined with short exposure to mitomycin‑C (MMC), can reduce recurrence and complications after pterygium surgery. Surgical excision remains the mainstay of treatment when symptoms such as vision impairment, foreign body sensation, or cosmetic concerns arise. Wide variation in recurrence rates reflects differences in patient populations, follow-up duration, surgical technique nuances, and definition of recurrence. A dehydrated triple-layer decellularized amniotic basement membrane tissue has unique attributes compared to other amniotic membrane tissue (AMT). Decellularization removes the pro-inflammatory chorion and residual donor cellular debris, thereby reducing immunogenicity while preserving extracellular matrix proteins such as collagen, fibronectin, and laminin, which produce anti-inflammatory cytokines and growth factors, promoting epithelial adhesion and migration. In pterygium excision, decellularized basement membrane may contribute to faster, more comfortable recovery, improved cosmesis, and a reduced risk of recurrence. METHODS:A total of 34 eyes from 33 patients underwent pterygium excision using dehydrated, three-layer decellularized basement membrane. RESULTS:All patients reported minimal postoperative discomfort, and the operative eyes were relatively quiet with minimal subconjunctival injection. Recurrence was 0% (0/34 eyes) at a mean follow-up of 394 days (range, 174-668). In addition, no pyogenic granuloma, infections, dellen, or melts occurred. CONCLUSIONS:Compared with traditional AMT and conjunctival autograft (CAG) methods using glue or sutures, this approach not only reduces operative time, postoperative discomfort, postoperative visits, and topical steroids but also saves costs without compromising outcomes.

BACKGROUND/UNASSIGNED:Outdoor navigation poses significant challenges for people with blindness or low vision, yet the role of gaze behaviour in supporting mobility remains underexplored. Fully sighted individuals typically adopt consistent scanning strategies, whereas those with visual impairments rely on heterogeneous adaptations shaped by residual vision and experience. METHODS/UNASSIGNED:We conducted a comparative eye-tracking study of fully sighted, low vision, blind, and fully blind participants navigating outdoor routes. Using a wearable eye tracker, we quantified fixation counts, fixation rate, fixation area, direction, peak fixation location, and walking speed. RESULTS/UNASSIGNED:Walking speed declined systematically with worsening vision. Fixation count increased with greater impairment, reflecting slower travel times and more frequent sampling. Fixation rate differed across groups, though between-group differences were generally not significant between most groups. Fixation spatial coverage decreased along the continuum of vision loss. Fixation patterns were most consistent in the fully sighted group. Peak fixation locations were centred in fully sighted participants but shifted outward and became more variable with impairment. CONCLUSION/UNASSIGNED:Gaze strategies during navigation form a graded continuum across vision groups, with fully sighted and fully blind participants at opposite poles and low vision and blind groups spanning the middle. Visual acuity alone does not predict functional gaze use, as rehabilitation experience and adaptive strategies strongly shape behaviour. These findings highlight the need for personalised rehabilitation and assistive technologies, with residual gaze patterns offering insight into mobility capacity and training opportunities for safer navigation.IMPLICATIONS FOR REHABILITATIONDistinct Residual Vision Patterns: This research reveals that residual vision patterns differ significantly, with fully sighted individuals exhibiting a consistent fixation pattern while low vision participants show more varied strategies during navigation.Highly Individualised Gaze Behaviours: Low vision participants demonstrate highly individualised gaze behaviours, indicating that a one-size-fits-all approach is inadequate for effective rehabilitation.Tailored Assistive Solutions: Assistive technologies and rehabilitation programs should be designed to address these unique, individualised needs, providing personalised feedback and training to enhance mobility and safety.

Cerebrospinal fluid (CSF), partly driven by sensory stimulation, is crucial for maintaining homeostasis and clearing metabolic waste. Whether such stimulus-driven CSF flow is disrupted in age-related neurodegenerative diseases of the visual system remains unclear. This study examined the CSF flow during visual stimulation in glaucoma patients and healthy older adults using functional magnetic resonance imaging. In glaucoma, CSF inflow becomes progressively decoupled from the visually evoked blood-oxygenation-level-dependent (BOLD) response. Specifically, the characteristic stimulus-locked CSF patterns, which decrease after stimulus onset and increase after offset, diminish with disease severity. Mediation analysis suggests this flattened CSF pattern is driven by a flatter ascending BOLD slope, leading to a shallower CSF trough and a reduced post-stimulus surge. These results indicate that glaucoma-related functional impairments contribute to downstream alterations in CSF dynamics. Overall, this study provides insight into how glaucoma disrupts visually driven CSF inflow and highlights in vivo biomarkers for monitoring CSF dynamics.

Black women with estrogen receptor-positive, HER2-negative (ER + /HER2-) breast cancer experience higher rates of distant recurrence and worse survival outcomes compared to White women. This may be due not only to disparities in social determinants of health, but also differences in the tumor microenvironment (TME), including TMEM (Tumor Microenvironment of Metastasis) doorway score. TMEM doorways serve as portals for cancer cell hematogenous dissemination to distant sites. While higher TMEM doorway scores have been observed in Black (compared to White) patients with residual ER + /HER2- breast cancer after neoadjuvant chemotherapy, this has not been evaluated in treatment-naïve primary breast cancers. Here, we report on a multi-institutional study to evaluate TMEM doorway score in 418 treatment-naïve archived human breast cancer samples, including 265 patients with ER + /HER2-, 102 with triple negative (TNBC), and 51 with HER2-positive breast cancer. In addition to analyzing TMEM doorway scores by race across breast cancer subtypes, we examined their association with distant recurrence and assessed whether the effect of TMEM doorway scores on recurrence differed by race. Black patients had significantly higher TMEM doorway score than White patients in the overall study population (median 29.9 vs 17.9, p < 0.001), in the ER + /HER2- (median 25.0 vs 16.8, p < 0.001) and the HER2-positive subset (median 37.2 vs 12.9, p = 0.003), but not in TNBC (median 36.2 vs 36.3, p = 0.86). Racial differences in macrophage density mirrored racial differences in the TMEM doorway score. In multivariate models including age, body mass index, tumor size, grade, lymph node status, and chemotherapy treatment, neither Black race nor TMEM doorway density was associated with a higher distant recurrence risk alone. However, there was a statistically significant interaction between race and high TMEM doorway score with respect to distant recurrence risk in ER + /HER2- patients; Black patients with high TMEM doorway score were 4.6-fold (95% CI 1.28-22.82, p = 0.03) and 4.2-fold (95% CI 1.17 - 18.23, p = 0.04) more likely to have a distant recurrence at 5-years and 10-years, respectively, while White patients with high TMEM doorway scores did not (p = 0.21, p = 0.11). Our study reveals racial disparities in the TME of women with ER + /HER2- breast cancer, which may play a critical role in driving disparities in breast cancer outcomes.

PURPOSE/OBJECTIVE:To describe the multimodal imaging findings of the angular sign of Henle fiber layer (HFL) hyperreflectivity (ASHH) at baseline and follow-up in patients with contusion maculopathy. METHODS:Eleven eyes of ten patients were captured with multimodal imaging after non-penetrating ocular blunt trauma from a soccer ball, fist, or airsoft pellet. Baseline clinical and imaging characteristics and follow-up outcomes are presented. RESULTS:Hyper-reflective lesions extending along the HFL from the ellipsoid zone (EZ) to the outer plexiform layer consistent with ASHH were identified with optical coherence tomography (OCT). Mean presenting visual acuity (VA) was logMAR 0.59 ± 0.64 (Snellen VA 20/77, range 20/25 to counting fingers) and follow-up visual acuity was logMAR 0.43 ± 0.35 (Snellen VA 20/53, range 20/20 to 20/200). Additional OCT findings included external limiting membrane attenuation and retinal pigment epithelium (RPE) disruption. On follow-up, resolution of ASHH was accompanied by outer nuclear layer thinning with varying degrees of EZ attenuation and RPE loss. A macular hole was detected in one patient on follow-up. CONCLUSION/CONCLUSIONS:ASHH is a distinctive acute OCT feature of contusion maculopathy secondary to blunt injury, causing disruption of the photoreceptors and presumably anterograde alterations in the HFL. Associated RPE alterations may ensue, either acutely or delayed, and are a biomarker of persistent structural abnormalities and variable visual outcomes.

IMPORTANCE/UNASSIGNED:The current ocular Common Terminology Criteria for Adverse Events (CTCAE) mix eye signs with symptoms and lack standardized clinical photographs and experimental oncology drug dose modification recommendations. Robust reporting of ocular adverse events (AEs) is important to maintain patient safety and to guide the development of novel efficacious drugs. OBJECTIVE/UNASSIGNED:To develop improved ocular AE grading scales to reliably evaluate and grade ocular AEs in patients on experimental oncology drug therapy and to provide clear drug dose modification recommendations. DESIGN, SETTING, AND PARTICIPANTS/UNASSIGNED:A collaborative multicenter interspecialty working group consisting of oncologists and academic ophthalmologists from 11 academic centers in the US and ophthalmologists from the US Food and Drug Administration was assembled in February 2023 to form a consensus on new experimental oncology drug-related ocular AE grading scales. The grading scales were released in June 2023. MAIN OUTCOMES AND MEASURES/UNASSIGNED:Expert consensus on novel experimental oncology drug-related ocular AE grading scales. RESULTS/UNASSIGNED:Six experimental oncology drug-related ocular AE grading scales were developed with agreement from ophthalmologists and oncologists for use in antibody-drug conjugate clinical trials: visual acuity, eye symptoms, cornea, conjunctiva/sclera, anterior chamber, and retina/posterior segment. CONCLUSIONS AND RELEVANCE/UNASSIGNED:The new experimental oncology drug-related ocular AE grading scales developed by the consensus panel were developed to be more concise, containing photographs where applicable, and to provide clear drug dose modification recommendations compared with the previous CTCAE. Use of these ocular AE grading scales may allow for more objective and consistent incidence measurements of ocular AEs throughout clinical trials and postmarketing, potentially facilitating safe testing of novel agents that may cause eye toxicity.