Objective To assess ophthalmology program directors' (PDs) knowledge, attitude, and perceptions regarding the adoption of Competency-Based Medical Education (CBME) and Entrustable Professional Activities (EPAs) in residency training. Design Cross-sectional study. Setting An anonymous online survey was distributed across the Association of University Professors of Ophthalmology (AUPO) PDs directory over a two-month period. The survey assessed familiarity with CBME and EPAs, perceived barriers to implementation, and opinions on essential competencies for ophthalmology training. Participants Ophthalmology Residency PDs across the U.S. Results 55 complete responses were received. While 65.5% of PDs reported being familiar with CBME, only 43.6% felt confident explaining EPAs. Currently, only 22% of residency programs utilize EPA-based assessment. 60% of PDs agreed that better assessment tools are needed. 43.6% reported having extended training for at least one resident, and 60% indicated that some residents were competent to graduate early. Cataract surgery and Nd:YAG capsulotomy were ranked as the most essential surgical competencies, while strabismus surgery was ranked the lowest. Conclusion PDs demonstrated overall support for integrating CBME and adopting EPA-based guidelines in ophthalmology residency training. These findings highlight the need for structured assessment frameworks and suggest that further research is needed to assess the impact of these initiatives on patient outcomes and resident performance.

Thyroid eye disease (TED) is characterized by fibroblast-driven inflammation and extracellular matrix expansion, which contribute to orbital congestion and proptosis. Platelet-derived growth factor-β (PDGFβ) promotes hyaluronan (HA) synthesis and cytokine production in orbital fibroblasts (OFs); however, whether metabolic modulation can counteract this pathway is unknown. We tested whether metformin, an indirect activator of AMP-activated protein kinase (AMPK), attenuates PDGFβ signaling in TED OFs. Primary OFs from 14 TED and 4 non-TED donors were treated with PDGFβ with or without metformin or the direct AMPK activator 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR). PDGFβ elicited markedly greater HA and cytokine responses in TED OFs than in non-TED OFs and suppressed AMPK phosphorylation. Metformin treatment restored AMPK phosphorylation, reduced HA accumulation (∼2.3-3.1-fold), and decreased IL-6 and IL-8 production. AICAR produced similar AMPK-dependent effects. Mechanistically, metformin attenuated PDGFβ-driven activation of the phosphoinositide 3-kinase (PI3K)-AKT-forkhead box O1 (FoxO1)-nuclear factor kappa B (NF-κB) axis, a pro-inflammatory and pro-survival cascade. These data identify PDGFβ-mediated AMPK suppression as a pathogenic mechanism in TED fibroblasts and demonstrate that AMPK reactivation reduces pro-fibrotic and inflammatory signals. Together, these findings support the therapeutic repurposing of metformin in TED.

IntroductionThyroid eye disease (TED) is a debilitating condition characterized by orbital fibroblast (OF) activation and excessive hyaluronan (HA) accumulation within the retroocular space. While IGF-1R blockade has significantly advanced TED management, incomplete clinical responses and disease relapse underscore the need to identify alternative targets.MethodsWe performed high-throughput RNA sequencing on primary human TED OFs compared with non-TED controls, followed by pathway enrichment analysis and confirmation of select targets by RT-qPCR. We also performed computational drug repositioning using the TED OF gene signature. Candidate therapeutic activity was validated using functional assays measuring AKT phosphorylation, gene expression, and HA synthesis in primary TED OFs.ResultsOur analysis identified enrichment of pathways critical to the TED phenotype, including PI3K-AKT signaling, the platelet-derived growth factor (PDGF) pathway, and extracellular matrix remodeling. We validated several key upregulated mediators that may contribute to orbital remodeling, including FOXC2, HGF, MET, HMGA2, and PLEKHG5, alongside the downregulation of the Wnt antagonist SFRP2. We identified sorafenib, which targets VEGFR, PDGFR, and RAF, as a leading candidate to counteract the TED-specific gene signature. Functional assays demonstrated that sorafenib dose-dependently inhibited PDGFβ-induced AKT phosphorylation, gene expression, and significantly attenuated PDGFβ-induced HA synthesis in primary TED OFs.ConclusionsThese results define a persistent, receptor tyrosine kinase-driven program in orbital fibroblasts obtained from TED and provide a molecular rationale for repurposing sorafenib as a therapeutic strategy for patients with refractory or relapsing TED.

CONTEXT:In thyroid eye disease (TED), the connective tissue behind the eye becomes inflamed and expands, partly due to excessive deposition of hyaluronan (HA), which absorbs water, leading to osmotic swelling. Orbital fibroblasts (OFs) from patients with TED overexpress insulin-like growth factor 1 receptor (IGF-1R), a receptor that promotes cell survival, proliferation, and HA production. These processes contribute to orbital tissue remodeling and expansion, as well as to the inflammation and fibrosis characteristic of TED. Therapeutic options remain limited, highlighting the need for additional targeted therapies. Lonigutamab is a next-generation anti-IGF-1R monoclonal antibody that binds to a distinct epitope on IGF-1R with high affinity, eliciting a novel mechanism of action. OBJECTIVE:To evaluate whether lonigutamab inhibits HA production and characterize its mechanism of action using TED OFs. METHODS:TED OFs were treated with lonigutamab in the presence or absence of IGF-1. HA was measured by ELISA and agarose gel electrophoresis. IGF-1R levels were assessed by flow cytometry and Western blot. The proteasome inhibitor MG132 and the lysosome/autophagy inhibitor bafilomycin were used to probe lonigutamab-mediated degradation pathways. RESULTS:Lonigutamab significantly reduced basal and IGF-1-induced HA production across all evaluated TED OF strains. Lonigutamab also decreased mature IGF-1R protein levels in a time- and dose-dependent manner by promoting IGF-1R internalization and subsequent degradation through proteasomal and lysosomal pathways. CONCLUSIONS:These findings suggest that lonigutamab suppresses HA production in TED OFs via efficient IGF-1R internalization and degradation, supporting its unique mechanism of action and potential as a therapeutic option for TED.

Background: Thyroid eye disease (TED) is an autoimmune disorder characterized by proptosis, inflammation, and fibrosis. Elevated insulin-like growth factor 1 receptor (IGF1R) signaling in TED orbital fibroblasts (OFs) drives the proliferation and biosynthesis of hyaluronan, which causes enlargement of orbital tissue volume. The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that regulates cellular stress responses, metabolism, and inflammation. Given its important role in regulating cellular responses, we hypothesized that activation of the AHR could limit excessive IGF1R signaling in TED OFs, offering therapeutic potential. Methods: We measured IGF1R and AHR expression levels in TED, non-TED, and non-OF controls. OF activation was analyzed using proliferation, hyaluronan accumulation, and migration assays. RNA sequencing was used to detect transcriptome-wide changes in IGF1-treated TED OFs. After gene set enrichment analysis, select gene expression changes were validated by quantitative polymerase chain reaction. OFs were treated with the AHR ligands 6-formylindolo[3,2-b]carbazole (FICZ) or tapinarof with or without IGF1. Western blotting evaluated signaling pathways impacted by AHR and IGF1R signaling. Results: TED OFs showed elevated IGF1R and AHR expression levels compared to controls. IGF1 significantly increased hyaluronan accumulation, proliferation, and migration in TED OFs compared to non-TED OFs. IGF1R signaling altered the expression of hundreds of genes controlling cell migration, proliferation, and metabolism in TED OFs. These genes included TUBA1B, TUBA1C, CRABP2 (upregulated), and IRS2 and SOD3 (downregulated). AHR activation blocked proliferation, migration, hyaluronan production, and gene expression mediated through IGF1R signaling. The AHR inhibited these pathways by reducing phosphorylation of GSK3β, an important mediator of IGF1R/β-catenin mediated signaling. Conclusions: AHR activation represents a promising therapeutic strategy for mitigating TED progression by inhibiting IGF1R signaling. Through modulation of GSK3β-mediated pathways, AHR activation may target additional pathologically relevant pathways beyond those affected by direct IGF1R inhibitors. This research provides novel insights into TED pathophysiology and offers a potential avenue for developing therapies to improve patient outcomes.

Background Thyroid eye disease (TED) is a debilitating autoimmune disorder affecting 25-50% of patients with Graves’ disease. TED is characterized by inflammation and tissue remodeling of orbital tissues. Orbital fibroblasts (OFs) and platelet-derived growth factor (PDGF) signaling promote tissue remodeling in TED. While metformin’s therapeutic potential has been proposed in various inflammatory conditions, its role in modulating PDGF signaling in TED remains unexplored. Methods OFs were isolated from TED (n= 14) and non-TED subjects (n=4). OFs were treated with PDGFβ (25 ng/mL) and/or AMPK activators metformin (1-5 mM) and AICAR (0.4-1 mM). Hyaluronan (HA) production was assessed via agarose gel electrophoresis and ELISA. Inflammatory mediators (IL6 and IL8) were measured by ELISA. Protein expression and signaling pathways were analyzed by Western blot. Results TED OFs showed enhanced HA synthesis (∼3-fold increase) and IL6 and IL8 responses to PDGFβ. PDGFβ treatment suppressed AMPK phosphorylation in a dose-dependent manner. Metformin increased AMPK phosphorylation (3.2-fold) and decreased IL6 and IL8 production. Both metformin and AICAR attenuated PDGFβ-induced HA production (56-68% reduction), IL6 (∼50% reduction), and IL8 (∼65% reduction) production in TED OFs. Conclusions This study demonstrates that PDGFβ suppresses AMPK signaling while AMPK activation by metformin counters PDGFβ-induced responses. These findings suggest that metformin is a potential therapeutic option for TED through modulation of HA and inflammatory cytokine production. ### Competing Interest Statement The authors have declared no competing interest. National Eye Institute, https://ror.org/03wkg3b53, EY031398 Research to Prevent Blindness, unrestricted grant

Background/objectivesStroke damage to the primary visual cortex induces large, homonymous visual field defects that impair daily living. Here, we asked if vision‐related quality of life (VR‐QoL) is impacted by time since stroke.Subjects/methodsWe conducted a retrospective meta‐analysis of 95 occipital stroke patients (female/male = 26/69, 27–78 years old, 0.5–373.5 months poststroke) in whom VR‐QoL was estimated using the National Eye Institute Visual Functioning Questionnaire (NEI‐VFQ) and its 10‐item neuro‐ophthalmic supplement (Neuro10). Visual deficit severity was represented by the perimetric mean deviation (PMD) calculated from 24‐2 Humphrey visual fields. Data were compared with published cohorts of visually intact controls. The relationship between VR‐QoL and time poststroke was assessed across participants, adjusting for deficit severity and age with a multiple linear regression analysis.ResultsOccipital stroke patients had significantly lower NEI‐VFQ and Neuro10 composite scores than controls. All subscale scores describing specific aspects of visual ability and functioning were impaired except for ocular pain and general health, which did not differ significantly from controls. Surprisingly, visual deficit severity was not correlated with either composite score, both of which increased with time poststroke, even when adjusting for PMD and age.ConclusionsVR‐QoL appears to improve with time postoccipital stroke, irrespective of visual deficit size or patient age at insult. This may reflect the natural development of compensatory strategies and lifestyle adjustments. Thus, future studies examining the impact of rehabilitation on daily living in this patient population should consider the possibility that their VR‐QoL may change gradually over time, even without therapeutic intervention.

Purpose:Damage to the adult primary visual cortex (V1) causes vision loss in the contralateral hemifield, initiating a process of transsynaptic retrograde degeneration (TRD). Here, we examined retinal correlates of TRD using a new metric to account for global changes in inner retinal thickness and asked if perceptual training in the intact or blind field impacts its progression. Methods:We performed a meta-analysis of optical coherence tomography data in 48 participants with unilateral V1 stroke and homonymous visual defects who completed clinical trial NCT03350919. After measuring the thickness of the macular ganglion cell and inner plexiform layer (GCL-IPL) and the peripapillary retinal nerve fiber layer (RNFL), we computed individual laterality indices (LI) at baseline and after ∼6 months of daily motion discrimination training in the intact or blind field. Increasingly positive LI denoted greater layer thinning in retinal regions affected versus unaffected by the cortical damage. Results:Pretraining, the affected GCL-IPL and RNFL were thinner than their unaffected counterparts, generating LI values positively correlated with time since stroke. Participants trained in their intact field exhibited increased LIGCL-IPL. Those trained in their blind field had no significant change in LIGCL-IPL. LIRNFL did not change in either group. Conclusions:Relative shrinkage of the affected versus unaffected macular GCL-IPL can be reliably measured at an individual level and increases with time post-V1 stroke. Relative thinning progressed during intact-field training but appeared to be halted by training within the blind field, suggesting a potentially neuroprotective effect of this simple behavioral intervention.

Purpose:In thyroid eye disease (TED), activation and proliferation of orbital fibroblasts (OFs) promotes remodeling and causes an increase in the volume of orbital tissue. Platelet-derived growth factors (PDGFs) are elevated in TED and promote OF activation. The aryl hydrocarbon receptor (AHR), a ligand activated nuclear receptor, is important in regulating OF activation. AHR ligands have been evaluated as therapeutic agents for inflammatory diseases. Here, we hypothesize that AHR ligands will block PDGF-induced signaling in TED OFs. Methods:OFs from both non-TED and TED patients were treated with PDGFβ, with or without the AHR ligands 6-Formylindolo[3,2-b]carbazole (FICZ) or tapinarof. Cell viability was measured by the Alamar Blue assay. Cell proliferation was quantified using the BrdU assay. Cell lysates were collected and analyzed by Western blotting and real-time quantitative PCR (RT-qPCR) to measure PDGF and AHR signaling. Scratch assays were used to measure OF migration. Results:PDGFβ induced proliferation in TED OFs significantly more than in non-TED OFs. Additionally, PDGFβ increased phosphorylation of AKT and expression of thymidylate synthase (TYMS). PDGFβ dependent proliferation and downstream signaling were attenuated by FICZ or tapinarof. TYMS and other PDGF target genes were upregulated by PDGFβ and reduced by AHR activation. PDGFβ induced TED OF migration while both FICZ and tapinarof diminished this effect. Conclusions:PDGF signaling led to increased proliferation and activation of TED OFs. Treatment of TED OFs with the AHR ligands, FICZ and tapinarof, mitigated PDGF induced effects. These studies support the concept that AHR and PDGF signaling could form the basis for new TED therapeutics.

Background/Objectives Stroke damage to the primary visual cortex induces large, homonymous visual field defects that impair daily living. Here, we asked if vision-related quality of life (V-QoL) is impacted by time since stroke. Subjects/Methods We conducted a retrospective meta-analysis of 95 occipital stroke patients (F/M=26/69, 27-78 years old, 0.5 to 373.5 months post-stroke) in whom V-QoL was estimated using the National Eye Institute Visual Functioning Questionnaire (NEI-VFQ) and its 10-item neuro-ophthalmic supplement (Neuro10). Visual deficit severity was represented by the Perimetric Mean Deviation (PMD) calculated from 24-2 Humphrey visual fields. Data were compared with published cohorts of visually-intact controls. The relationship between V-QoL and time post-stroke was assessed across participants, adjusting for deficit severity and age with a multiple linear regression analysis. Results Occipital stroke patients had significantly lower NEI-VFQ and Neuro10 composite scores than controls. All subscale scores describing specific aspects of visual ability and functioning were impaired except for ocular pain and general health, which did not differ significantly from controls. Surprisingly, visual deficit severity was not correlated with either composite score, both of which increased with time post-stroke, even when adjusting for PMD and age. Conclusions V-QoL appears to improve with time post-occipital stroke, irrespective of visual deficit size or patient age at insult. This may reflect the natural development of compensatory strategies and lifestyle adjustments. Thus, future studies examining the impact of rehabilitation on daily living in this patient population should consider the possibility that their V-QoL may change gradually over time, even without therapeutic intervention. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was funded by the National Eye Institute and Office of Behavioral and Social Sciences Research (R01 EY027314, R01 EY027314-05S1 Research Supplement to Promote Diversity in Health-Related Research Program, R01 EY027314-05S2 Administrative Supplement, P30 EY001319 and T32 EY007125 to the Center for Visual Science); Research to Prevent Blindness (Unrestricted Grant to the Department of Ophthalmology); Center of Emerging and Innovative Science for Empire State Development (project no.: 1730C004); the Center of Excellence (project no: 1689bC2). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Research Subject Review Board of the University of Rochester gave ethical approval for this work. Western Institutional Review Board gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes

CONTEXT:Inhibition of the neonatal fragment crystallizable receptor (FcRn) reduces pathogenic thyrotropin receptor antibodies (TSH-R-Ab) that drive pathology in thyroid eye disease (TED). OBJECTIVE:We report the first clinical studies of an FcRn inhibitor, batoclimab, in TED. DESIGN:Proof-of-concept (POC) and randomized, double-blind placebo-controlled trials. SETTING:Multicenter. PARTICIPANTS:Patients with moderate-to-severe, active TED. INTERVENTION:In the POC trial, patients received weekly subcutaneous injections of batoclimab 680 mg for 2 weeks, followed by 340 mg for 4 weeks. In the double-blind trial, patients were randomized 2:2:1:2 to weekly batoclimab (680 mg, 340 mg, 255 mg) or placebo for 12 weeks. MAIN OUTCOME:Change from baseline in serum anti-TSH-R-Ab and total IgG (POC); 12-week proptosis response (randomized trial). RESULTS:The randomized trial was terminated because of an unanticipated increase in serum cholesterol; therefore, data from 65 of the planned 77 patients were analyzed. Both trials showed marked decreases in pathogenic anti-TSH-R-Ab and total IgG serum levels (P < .001) with batoclimab. In the randomized trial, there was no statistically significant difference with batoclimab vs placebo in proptosis response at 12 weeks, although significant differences were observed at several earlier timepoints. In addition, orbital muscle volume decreased (P < .03) at 12 weeks, whereas quality of life (appearance subscale) improved (P < .03) at 19 weeks in the 680-mg group. Batoclimab was generally well tolerated, with albumin reductions and increases in lipids that reversed upon discontinuation. CONCLUSIONS:These results provide insight into the efficacy and safety of batoclimab and support its further investigation as a potential therapy for TED.

Background: Long-duration spaceflight crewmembers are at risk for spaceflight-associated neuro-ocular syndrome (SANS). One of the earliest manifestations of SANS is optic disc edema (ODE), which could be missed using the subjective Frisén scale. The primary objective of this study is to determine the inter-rater and intrarater reliability of Frisén grade for SANS-induced ODE among a trained observer cohort. The secondary objective is to propose a standardized evaluation process for SANS-induced ODE across International Space Station Partner Agencies. Methods: Retrospective, double-blinded diagnostic study. Preflight and postflight fundus photographs were presented to subject matter experts who identified and graded ODE. Pairs of images were also compared side-by-side for disc ranking. Grader concordance was assessed for Frisén grading and disc ranking. Results: Expert graders identified Grade 1 ODE in 17.35% of images from 62 crewmembers (9 female, mean [SD] age, 47.81 [5.19] years). Grades 2 and 3 were identified less than 2% of the time. Concordance in Frisén grades among pairs of graders was 70.99%. Graders identified a difference in preflight and postflight fundus photographs 17.21% of the time when using disc ranking. Pairs of graders had complete concordance in disc ranking 79.79% of the time. Perfect intrarater agreement between Frisén grade and disc ranking occurred 77.7% of the time. Conclusions: These findings demonstrate intergrader and intragrader variability when using the Frisén scale to identify SANS-induced ODE, which is typically milder in presentation than terrestrial cases of idiopathic intracranial hypertension. It is possible to miss early ODE on fundoscopy alone, making it insufficient as a sole criterion for the diagnosis of SANS. A more sensitive and objective method of surveillance is necessary to monitor international crewmembers for ODE, perhaps using a multimodal approach that includes technology such as optical coherence tomography.

The aryl hydrocarbon receptor (AHR) is a ligand activated transcription factor originally identified as an environmental sensor of xenobiotic chemicals. However, studies have revealed that the AHR regulates crucial aspects of cell growth and metabolism, development and the immune system. The importance of the AHR and AHR signaling in eye development, toxicology and disease is now being uncovered. The AHR is expressed in many ocular tissues including the retina, choroid, cornea and the orbit. A significant role for the AHR in age-related macular degeneration (AMD), autoimmune uveitis, and other ocular diseases has been identified. Ligands for the AHR are structurally diverse organic molecules from exogenous and endogenous sources. Natural AHR ligands include metabolites of tryptophan and byproducts of the microbiome. Xenobiotic AHR ligands include persistent environmental pollutants such as dioxins, benzo (a) pyrene [B (a) P] and polychlorinated biphenyls (PCBs). Pharmaceutical agents including the proton pump inhibitors, esomeprazole and lansoprazole, and the immunosuppressive drug, leflunomide, activate the AHR. In this review, we highlight the role of the AHR in the eye and discuss how AHR signaling is involved in responding to endogenous and environmental stimuli. We also present the emerging concept that the AHR is a promising therapeutic target for eye disease.

Thyroid eye disease (TED) is an autoimmune disorder that manifests in the orbit. In TED, the connective tissue behind the eye becomes inflamed and remodels with increased fat accumulation and/or increased muscle and scar tissue. As orbital tissue expands, patients develop edema, exophthalmos, diplopia, and optic neuropathy. In severe cases vision loss may occur secondary to corneal scarring from exposure or optic nerve compression. Currently there is no cure for TED, and treatments are limited. A major breakthrough in TED therapy occurred with the FDA approval of teprotumumab, a monoclonal insulin-like growth factor 1 receptor (IGF1R) blocking antibody. Yet, teprotumumab therapy has limitations, including cost, infusion method of drug delivery, variable response, and relapse. We describe approaches to target orbital fibroblasts and the complex pathophysiology that underlies tissue remodeling and inflammation driving TED. Further advances in the elucidation of the mechanisms of TED may lead to prophylaxis based upon early biomarkers as well as lead to more convenient, less expensive therapies.