Midwest Eye Institute

Background/Objectives: The objective of this study was to determine the treatment effect of foselutoclax in neovascular age-related macular degeneration (AMD) by multifocal electroretinography (mfERG) and evaluate mfERG as a potential clinical endpoint in AMD studies. Methods: A total of five subjects were included in the study who had active choroidal neovascularization and a history of at least two anti-vascular endothelial growth factor (VEGF) injections in the last 6 months. Subjects received a 50 µL intravitreal injection of foselutoclax at the baseline visit and Weeks 4, 24, and 28 of the study period. Results: After foselutoclax treatment, the largest improvement in the mfERG N1-P1 response density occurred at Week 8 as three of five subjects achieved a ≥20% gain. In addition, three of five subjects demonstrated a BCVA improvement of ≥5 ETDRS letters over baseline at Weeks 4, 8, and 24. The mean change in BCVA demonstrated statistical significance in Weeks 4 and 8, showing increases of 5 (p = 0.02) and 6.2 (p = 0.02) letters, respectively. Conclusions: Foselutoclax treatment was shown to have the potential to recover outer retinal function as determined by mfERG and BCVA at approximately Week 8 of treatment.

The trabecular meshwork (TM) tissue plays a crucial role in maintaining intraocular pressure (IOP) homeostasis. Increased TM contractility and stiffness are directly correlated with elevated IOP. Although cholesterol is known to be a determinant of glaucoma occurrence and elevated IOP, the underlying mechanisms remain elusive. In this study, we used human TM (HTM) cells to unravel the effects of cholesterol on TM stiffness. We achieved this by performing acute cholesterol depletion with Methyl-β-cyclodextrin (MβCD) and cholesterol enrichment/replenishment with MβCD cholesterol complex (CHOL). Interestingly, cholesterol depletion triggered notable actin depolymerization and decreased focal adhesion formation, while enrichment/replenishment promoted actin polymerization, requiring the presence of actin monomers. Using a specific reporter of phosphatidylinositol 4,5-bisphosphate (PIP2), we demonstrated that cholesterol depletion decreases PIP2 levels on the cell membrane, whereas enrichment increases them. Given the critical role of PIP2 in actin remodeling and focal adhesion formation, we postulate that cholesterol regulates actin dynamics by modulating PIP2 levels on the membrane. Furthermore, we showed that cholesterol levels regulate integrin α5β1 and αVβ3 distribution and activation, subsequently altering cell-extracellular matrix (ECM) interactions. Notably, the depletion of cholesterol, as a major lipid constituent of the cell membrane, led to a decrease in HTM cell membrane tension, which was reversed upon cholesterol replenishment. Overall, our systematic exploration of cholesterol modulation on TM stiffness highlights the critical importance of maintaining appropriate membrane and cellular cholesterol levels for achieving IOP homeostasis.

Purpose: To examine disparities in visual acuity (VA) outcomes 1 year and 2 years after initiation of diabetic retinopathy (DR) or diabetic macular edema (DME) treatment in patients based on race/ethnicity and insurance status, accounting for disease severity. Methods: This retrospective analysis used the IRIS Registry and included DR patients older than 18 years with documented antivascular endothelial growth factor (anti-VEGF) treatment and VA data for at least 2 years. International Classification of Diseases, Tenth Revision, Clinical Modification codes were used to determine the severity of DR and DME presence. VA outcomes were assessed using multivariable linear regressions and anti-VEGF drug use by multivariable logistic regressions, with race and insurance status as independent variables. Main outcome measures comprised the mean VA change at 1 year and 2 years and percentage of patients treated with bevacizumab. Results: The study included 43 274 eyes. White patients presented with a higher mean VA and lower mean DR severity than Black patients and Hispanic patients. Multivariable logistic regression showed Hispanic patients were significantly more likely to be treated with bevacizumab than White patients across all insurance types, controlling for disease severity and VA. After 1 year, the letter improvement was 1.73, 1.33, and 1.13 in White patients, Black patients, and Hispanic patients, respectively. Multivariable linear regression suggested that across races, Medicaid-insured patients had significantly smaller gains in VA than privately insured patients. Conclusions: Race-based and insurance-based differences in 1-year and 2-year outcomes after anti-VEGF treatment for DR and anti-VEGF treatment patterns suggest a need to ensure earlier and more effective treatment of minority and underserved patients in the United States.

Clusterin, also known as apolipoprotein J, is an ATP-independent holdase chaperone protein. Clusterin is involved in various functions including protein quality controland lipid transport. Though clusterin is secreted upon stress, the intracellular fate of clusterin after a stress response is not well understood. The protocol described here utilizes clusterin tagged to fluorescent proteins like green fluorescent protein and red fluorescent protein to understand the intracellular fate of clusterin.

Diabetic retinopathy (DR) is a late microvascular complication of Diabetes Mellitus (DM) that could lead to permanent blindness in patients, without early detection. Although adequate management of DM via regular eye examination can preserve vision in in 98% of the DR cases, DR screening and diagnoses based on clinical lesion features devised by expert clinicians; are costly, time-consuming and not sufficiently accurate. This raises the requirements for Artificial Intelligent (AI) systems which can accurately detect DR automatically and thus preventing DR before affecting vision. Hence, such systems can help clinician experts in certain cases and aid ophthalmologists in rapid diagnoses. To address such requirements, several approaches have been proposed in the literature that use Machine Learning (ML) and Deep Learning (DL) techniques to develop such systems. However, these approaches ignore the highly valuable clinical lesion features that could contribute significantly to the accurate detection of DR. Therefore, in this study we introduce a framework called DR-detector that employs the Extreme Gradient Boosting (XGBoost) ML model trained via the combination of the features extracted by the pretrained convolutional neural networks commonly known as transfer learning (TL) models and the clinical retinal lesion features for accurate detection of DR. The retinal lesion features are extracted via image segmentation technique using the UNET DL model and captures exudates (EXs), microaneurysms (MAs), and hemorrhages (HEMs) that are relevant lesions for DR detection. The feature combination approach implemented in DR-detector has been applied to two common TL models in the literature namely VGG-16 and ResNet-50. We trained the DR-detector model using a training dataset comprising of 1,840 color fundus images collected from e-ophtha, retinal lesions and APTOS 2019 Kaggle datasets of which 920 images are healthy. To validate the DR-detector model, we test the model on external dataset that consists of 81 healthy images collected from High-Resolution Fundus (HRF) dataset and MESSIDOR-2 datasets and 81 images with DR signs collected from Indian Diabetic Retinopathy Image Dataset (IDRID) dataset annotated for DR by expert. The experimental results show that the DR-detector model achieves a testing accuracy of 100% in detecting DR after training it with the combination of ResNet-50 and lesion features and 99.38% accuracy after training it with the combination of VGG-16 and lesion features. More importantly, the results also show a higher contribution of specific lesion features toward the performance of the DR-detector model. For instance, using only the hemorrhages feature to train the model, our model achieves an accuracy of 99.38 in detecting DR, which is higher than the accuracy when training the model with the combination of all lesion features (89%) and equal to the accuracy when training the model with the combination of all lesions and VGG-16 features together. This highlights the possibility of using only the clinical features, such as lesions that are clinically interpretable, to build the next generation of robust artificial intelligence (AI) systems with great clinical interpretability for DR detection. The code of the DR-detector framework is available on GitHub at https://github.com/Janga-Lab/DR-detector and can be readily employed for detecting DR from retinal image datasets.

Background and ObjectiveRetinal vein occlusion (RVO) is a major cause of vision loss and elevated intraocular pressure (IOP), high ocular perfusion pressure, and glaucoma are known ophthalmic risk factors for RVO. The aim of this paper is to provide the update on the association and management of high IOP/glaucoma and RVO.MethodsA literature review was performed in PubMed and Medline until May 2022 utilizing specific keywords and cross-matched reference lists.Key Content and FindingsThe association of RVO with high IOP/glaucoma may be attributed to retinal ganglion cell loss due to retinal ischemia in high IOP and glaucoma. As new modalities showed, decreased optic disc perfusion, reduced density of blood vessels in the optic nerve head of glaucoma patients, changes in the peripapillary microvascular parameters, and decreased retinal nerve fiber layer (RNFL) thickness of the optic nerve head of eyes with RVO suggest a common pathway between RVO and glaucoma. Literature suggests the close follow up for glaucoma development among patients with non-arteriovenous (AV) crossing (optic cup or optic nerve sited) RVO in fellow eye and management of elevated IOP among RVO cases treated with anti-vascular endothelial growth factor (VEGF) antibodies/corticosteroids and those with preexisting primary open angle glaucoma (POAG).ConclusionsDetermining potential patient responses to treatment and considering therapeutic options are challenging among patients with RVO and glaucoma. However, IOP lowering managements in preventing IOP spikes in patients with preexisting glaucoma and early treatment of macular edema in eyes with RVO is recommended.

ABSTRACT Introduction Age-related macular degeneration (AMD) is the leading cause of irreversible blindness among people age 60 years or older in developed countries. Current standard-of-care anti-vascular endothelial growth factor (VEGF) therapy, which inhibits angiogenesis and vascular permeability, has been shown to stabilize choroidal neovascularization and increase visual acuity in neovascular AMD. However, therapeutic limitations of anti-VEGF therapy include limited durability with consequent need for frequent intravitreal injections, and a ceiling of efficacy. Current strategies under investigation include targeting VEGF-C and VEGF-D, integrins, tyrosine kinase receptors, and the Tie2/angiopoietin-2 pathway. A literature search was conducted through November 30, 2021 on PubMed, Medline, Google Scholar, and associated digital platforms with the following keywords: wet macular degeneration, age-related macular degeneration, therapy, VEGF-A, VEGF-C, VEGF-D, integrins, Tie2/Ang2, and tyrosine kinase inhibitors. Areas covered The authors provide a comprehensive review of AMD disease pathways and mechanisms involved in wet AMD as well as novel targets for future therapies. Expert opinion With novel targets and advancements in drug delivery, there is potential to address treatment burden and to improve outcomes for patients afflicted with neovascular AMD.