Faculty Bibliography

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.

PURPOSE/UNASSIGNED:In geographic atrophy (GA) of AMD, comparing photoreceptor disintegrity and RPE loss in optical coherence tomography (OCT) and microscopy may elucidate atrophy expansion and suggest imaging biomarkers. METHODS/UNASSIGNED:One eye of a 93-year-old woman with bilateral drusen-driven GA of AMD was analyzed. RPE loss and reduced photoreceptor segment integrity (rPSi) was quantified automatically in clinical OCT volumes over a five-year period ending six years pre-mortem. In transmission electron micrographs of the outer junctional zone (OJZ) and a comparison area, tissue component volumes were measured. RESULTS/UNASSIGNED:By OCT, rPSi area exceeded RPE loss at baseline. Yearly RPE loss (2.432 mm2) exceeded rPSi (1.770 mm2) as these areas converged. By microscopy, the mean distance between the external limiting membrane (ELM) and RPE basal lamina in the OJZ was 50% of the comparison. Volumes of interphotoreceptor space, outer segments, inner segment myoids, inner segment ellipsoids, and in-layer RPE were 16%, 17%, 25%, 50%, and 104%, respectively, of the comparison. Cone inner segments exhibited fragmented and translocating mitochondria over drusen and at the ELM descent. In some OCT scans, the descent appeared especially hyperreflective. CONCLUSIONS/UNASSIGNED:In this first clinicopathologic correlation of an AMD eye with a known GA growth rate, the area of rPSi (a composite representing photoreceptor shortening, disorganization, altered waveguiding, and true cell death) exceeds the area of RPE loss. The OJZ exhibits dysmorphic but continuous RPE. Photoreceptors degenerate from the outer segments inward. Mitochondrial fission and translocation at the ELM descent may be visible clinically.

PURPOSE/UNASSIGNED:Müller cell morphology and markers were investigated using histology and immunohistochemistry in an eye with clinically documented multifocal geographic atrophy (GA) and correlated with clinical images. METHODS/UNASSIGNED:The donor was followed clinically for 5 years, 6 years before death. The superior posterior pole retina of the right eye was dissected and immunolabeled with antibodies against glial fibrillary acidic protein (GFAP; activated Müller cells and astrocytes) and glutamine synthetase (GS; Müller cells) and Ulex europaeus Agglutinin-1 lectin (blood vessels) before embedding for JB-4 cross section analysis. The inferior macula was cryopreserved. Cryosections were immunolabeled with Müller cell homeostatic and activation markers. Transmission electron microscopy (TEM) of the left eye was used to study ultrastructure changes. RESULTS/UNASSIGNED:Gross examination demonstrated mottled retinal pigment epithelium (RPE) over presumably calcified drusen. In the macular area, Müller cell processes surrounding both drusen and outer retinal pigmented lesions created a large subretinal membrane. Cryosection analysis demonstrated persistence of aquaporin 4 and GS in Müller cells with both proteins prominently expressed in the subretinal membrane. Increased MC S100B and GFAP expression were also observed in the atrophic area as well as the outer junctional zone. Cryosection labeling and TEM confirmed Müller cell encasing calcified drusen and RPE debris as well as invading basal laminar deposits. CONCLUSIONS/UNASSIGNED:This multifocal GA case demonstrates how MC activation and structural changes surrounding individual drusen could coalesce, contributing to photoreceptor loss. Müller cells penetrating basal laminar deposits and encasing calcified drusen suggests attempting clearing and/or protecting the retina from harmful contents.

PURPOSE/OBJECTIVE:To describe the first successful whole eye transplantation (WET) in a human, performed with concurrent partial face transplantation, and to characterize postoperative outcomes. DESIGN/METHODS:Case report. PARTICIPANT/METHODS:A 46-year-old male with severe facial and ocular deficits following high-voltage electrical injury, including left eye enucleation and extensive soft tissue and aesthetic deformities. METHODS:Comprehensive preoperative evaluation, precise microsurgical techniques including vascular anastomosis and optic nerve coaptation, and serial postoperative assessments with optical coherence tomography (OCT), fluorescein angiography (FA), electroretinography (ERG), and visual evoked potentials (VEP). MAIN OUTCOME MEASURES/METHODS:Sustained globe viability, vascular perfusion, retinal structural integrity, and electrophysiological function. RESULTS:The transplanted globe demonstrated robust vascular perfusion and structural preservation over 12 months. Outer retinal function was maintained, as indicated by ERG, despite retinal nerve fiber layer loss and optic nerve transection. VEP confirmed absence of visual perception. The procedure achieved substantial aesthetic restoration. CONCLUSIONS:This study establishes the feasibility of WET in humans, with sustained globe viability and preserved outer retinal function. These findings serve as a critical step toward future exploration of ocular transplantation.

PURPOSE/UNASSIGNED:We aim to study a case of pathologic myopia with visible light OCT. DESIGN/UNASSIGNED:Case report. SUBJECTS/UNASSIGNED:We recruit 1 patient with pathologic myopia presenting with an acute lacquer crack with submacular hemorrhage (SMH) in the right eye and a chronic lacquer crack in the left eye. METHODS/UNASSIGNED:We acquire visible light OCT images with 1 μm axial resolution. Images are processed to depict spectral centroid shift, and spectral fitting is performed to determine oxygen saturation. Results are compared to clinical imaging. MAIN OUTCOME MEASURES/UNASSIGNED:Visible light OCT images, spectral centroid shift (redshift), oximetry, and spectral fitting. RESULTS/UNASSIGNED:with spectral evidence of an overlying RPE deficit (deficient red shift) and photoreceptor abnormalities. CONCLUSIONS/UNASSIGNED:As visible light OCT technology advances, its application toward well-characterized human retinal pathology can clarify its utility. We describe the first case of visible light OCT applied to pathologic myopia, a primary RPE-BM-choriocapillaris interface disease. We confirm that extravascular hemoglobin can be subject to spectral fitting, and we quantify the oxygen saturation of acute SMH. We further show that structural changes in chronic lacquer cracks can be characterized with this new technology. FINANCIAL DISCLOSURES/UNASSIGNED:Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

PURPOSE/OBJECTIVE:This study aimed to assess the efficacy and safety of intensity-modulated radiotherapy (IMRT) combined with regorafenib with or without immune checkpoint inhibitors (ICIs) as a second- or later-line treatment for advanced hepatocellular carcinoma (HCC). MATERIALS AND METHODS/METHODS:Patients diagnosed with advanced HCC who had received RT combined with concurrent or sequential regorafenib treatment or regorafenib plus ICIs after failures of at least one line of systemic treatment in a single center from April 2018 to August 2022 were retrospectively reviewed. Progression-free survival (PFS) was the primary endpoint, while overall survival (OS), objective response rate (ORR), disease control rate (DCR), and toxicity were the secondary endpoints. RESULTS:Fifty patients were included, with 44 (88.0%) in BCLC stage C, 37 (74.0%) having portal vein tumor thrombosis (PVTT), and 12 (24.0%) with extrahepatic metastasis. Thirty-eight patients received conventional fractionated RT (56.4Gy/22-28f), while 12 received hyperfractionated RT (50Gy/5-10f). Twenty-six were treated concurrently with regorafenib and 24 sequentially. ICIs were applied in 34 patients. For the entire cohort, when measured from the start of RT initiation, the median PFS and OS were 10.9 months and not reached. The corresponding 2-year PFS and OS rates were 25.3% and 53.5%, respectively. When assessed from regorafenib initiation, the median PFS and OS were 5.9 months and not reached, with 2-year PFS and OS rates of 22.8% and 54.9%, respectively. For tumors in the RT field, the ORR was 74.0% (RECIST) and 92.0% (mRECIST). The most common grade 3 toxicities were hand-foot syndrome (16.0%), thrombocytopenia (8.0%), dermatitis (8.0%), and transaminase elevation (6.0%). CONCLUSION/CONCLUSIONS:IMRT concurrently or sequentially combined with regorafenib with or without ICIs is an effective, well-tolerated, and promising regimen as second-line or further-line treatment in patients with advanced HCC.

BACKGROUND:Delayed diagnosis of venous thromboembolism (VTE) is prevalent among hospitalized patients, yet case identification is challenging and feedback limited. OBJECTIVE:To develop a large language model (LLM)-based electronic-trigger to identify VTE diagnostic delays. METHODS:All admissions to internal medicine (IM) residents at NYU Langone Health between January 2022 and December 2023 (n = 20,843) were included. Using an open-source LLM, prompts were validated to detect (1) residents considering VTE in admission notes and (2) VTE confirmation in five types of imaging reports (n = 100 for each prompt validation set). The validated prompts were applied to determine discordance between admission note differential omitting VTE and imaging report confirming VTE. Two hospitalists reviewed discordant cases using a validated tool to identify diagnostic delays. Hospitalizations were labeled as diagnostic delays, in-hospital complication, or false-positive. Based on in-hospital complication and false-positive patterns, exclusion criteria were implemented. Positive predictive value (PPV) and negative predictive value (NPV) were calculated. RESULTS:The LLM prompts correctly classified admission notes and VTE imaging studies with high accuracy (range 98%-100%, n = 699 VTE cases identified). Of the 137 diagnostic delays the LLM-based electronic-trigger identified, 31 were true-positives, 60 in-hospital complications, and 46 false-positives. 4.4% of all VTE hospitalizations had a diagnostic delay. With the exclusion criteria, the PPV was 48% (95% confidence interval [CI], 35%-62%) and NPV was 95% (95% CI, 87%-98%). CONCLUSIONS:We developed the first LLM-based electronic-trigger to identify VTE diagnostic delays, with higher performance than existing non-LLM electronic-triggers. LLM-based approaches can facilitate diagnostic performance feedback and are scalable to other conditions and institutions.