Safety and Tolerability of Suprachoroidal Axitinib Injectable Suspension, for Neovascular Age-related Macular Degeneration; Phase I/IIa Open-Label, Dose-Escalation Trial.

Purpose: To evaluate the safety and tolerability of a single dose of axitinib injectable suspension (CLS-AX), a pan-anti-VEGF tyrosine kinase inhibitor (TKI), administered via suprachoroidal injection in patients with neovascular age-related macular degeneration (nAMD). Design: Phase I/IIa, open-label, sequential dose escalation. Participants: Anti-VEGF treatment-experienced patients with active subfoveal choroidal neovascularization secondary to nAMD. Methods: The study included 4 cohorts (0.03, 0.10, 0.50, and 1.0 mg) of approximately 5 patients each enrolled in a dose-escalating fashion. Enrolled patients received intravitreal aflibercept (2 mg) followed by a single unilateral dose of CLS-AX 1 month later. All patients were followed monthly for 3 months with the option of an additional 3 months of extended follow-up for cohorts 2 to 4. End points included systemic and ocular safety and tolerability, visual acuity, retinal thickness, and need for aflibercept therapy. Main Outcome Measures: The number of patients reporting treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs), changes in ophthalmic examinations, and the number of patients qualifying for additional therapy for nAMD based on protocol-defined criteria. Results: OASIS enrolled 27 patients with nAMD with mean age of 81 years, mean duration of nAMD diagnosis of 54 months, and between 5 and 90 prior anti-VEGF treatments. Twenty-six patients completed through 3 months, with 14 entering and completing the 3-month extension. No SAEs, drug-related TEAEs, or TEAEs leading to discontinuation were observed after CLS-AX administration; there were no adverse events related to ocular inflammation, vasculitis, intraocular pressure, or dispersion of drug into the vitreous or anterior chamber. Through 6 months, stable mean best-corrected visual acuity and stable mean central subfield thickness (CST) were observed, suggestive of TKI biologic effect. No aflibercept therapy was administered up to 3 months in 58% (15/26) of patients who completed 3 months of follow-up in OASIS. In the Extension, 57% (8/14) of patients went up to 6 months without receiving aflibercept therapy. Conclusions: Up to 1.0 mg CLS-AX, a highly potent TKI targeted to the suprachoroidal space (SCS) via the SCS Microinjector, was well tolerated, with stable mean visual acuity and mean CST. A majority of patients followed for 6 months did not require aflibercept therapy. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Estimating Uncertainty of Geographic Atrophy Segmentations with Bayesian Deep Learning.

Purpose: To apply methods for quantifying uncertainty of deep learning segmentation of geographic atrophy (GA). Design: Retrospective analysis of OCT images and model comparison. Participants: One hundred twenty-six eyes from 87 participants with GA in the SWAGGER cohort of the Nonexudative Age-Related Macular Degeneration Imaged with Swept-Source OCT (SS-OCT) study. Methods: The manual segmentations of GA lesions were conducted on structural subretinal pigment epithelium en face images from the SS-OCT images. Models were developed for 2 approximate Bayesian deep learning techniques, Monte Carlo dropout and ensemble, to assess the uncertainty of GA semantic segmentation and compared to a traditional deep learning model. Main Outcome Measures: Model performance (Dice score) was compared. Uncertainty was calculated using the formula for Shannon Entropy. Results: The output of both Bayesian technique models showed a greater number of pixels with high entropy than the standard model. Dice scores for the Monte Carlo dropout method (0.90, 95% confidence interval 0.87-0.93) and the ensemble method (0.88, 95% confidence interval 0.85-0.91) were significantly higher (P < 0.001) than for the traditional model (0.82, 95% confidence interval 0.78-0.86). Conclusions: Quantifying the uncertainty in a prediction of GA may improve trustworthiness of the models and aid clinicians in decision-making. The Bayesian deep learning techniques generated pixel-wise estimates of model uncertainty for segmentation, while also improving model performance compared with traditionally trained deep learning models. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Comparison between Spectral-Domain and Swept-Source OCT Angiography for the Measurement of Persistent Hypertransmission Defects in Age-Related Macular Degeneration.

Purpose: Spectral-domain OCT angiography (SD-OCTA) scans were tested in an algorithm developed for use with swept-source OCT angiography (SS-OCTA) scans to determine if SD-OCTA scans yielded similar results for the detection and measurement of persistent choroidal hypertransmission defects (hyperTDs). Design: Retrospective study. Participants: Forty pairs of scans from 32 patients with late-stage nonexudative age-related macular degeneration (AMD). Methods: Patients underwent both SD-OCTA and SS-OCTA imaging at the same visit using the 6 × 6 mm OCTA scan patterns. Using a semiautomatic algorithm that helped with outlining the hyperTDs, 2 graders independently validated persistent hyperTDs, which are defined as having a greatest linear dimension ≥250 µm on the en face images generated using a slab extending from 64 to 400 µm beneath Bruch's membrane. The number of lesions and square root (sqrt) total area of the hyperTDs were obtained from the algorithm using each imaging method. Main Outcome Measures: The mean sqrt area measurements and the number of hyperTDs were compared. Results: The number of lesions and sqrt total area of the hyperTDs were highly concordant between the 2 instruments (rc = 0.969 and rc = 0.999, respectively). The mean number of hyperTDs was 4.3 ± 3.1 for SD-OCTA scans and 4.5 ± 3.3 for SS-OCTA scans (P = 0.06). The mean sqrt total area measurements were 1.16 ± 0.64 mm for the SD-OCTA scans and 1.17 ± 0.65 mm for the SS-OCTA scans (P < 0.001). Because of the small standard error of the differences, the mean difference between the scans was statistically significant but not clinically significant. Conclusions: Spectral-domain OCTA scans provide similar results to SS-OCTA scans when used to obtain the number and area measurements of persistent hyperTDs through a semiautomated algorithm previously developed for SS-OCTA. This facilitates the detection of atrophy with a more widely available scan pattern and the longitudinal study of early to late-stage AMD. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Evaluating the Persistence of Large Choroidal Hypertransmission Defects using SS-OCT Imaging.

In age-related macular degeneration (AMD), large choroidal hypertransmission defects (hyperTDs) are identified on en face optical coherence tomography (OCT) images as bright lesions measuring at least 250 µm in greatest linear dimension (GLD). These choroidal hyperTDs arise from focal attenuation or loss of the retinal pigment epithelium (RPE). We previously reported that once large hyperTDs formed, they were likely to persist compared with smaller lesions that were more likely to be transient. Due to their relative persistence, these large persistent choroidal hyperTDs are a point-of-no-return in the progression of intermediate AMD to the late stage of atrophic AMD. Moreover, the onset of these large choroidal hyperTDs can serve as a clinical trial endpoint when studying therapies that might slow disease progression from intermediate AMD to late atrophic AMD. To confirm the persistence of these large choroidal hyperTDs, we studied an independent dataset of AMD eyes enrolled in an ongoing prospective swept-source OCT (SS-OCT) natural history study to determine their overall persistence. We identified a total of 202 eyes with large choroidal hyperTDs containing 1725 hyperTDs followed for an average of 46.6 months. Of the 1725 large hyperTDs, we found that 1718 (99.6%) persisted while only 7 hyperTDs (0.4%) were non-persistent. Of the 7 non-persistent large hyperTDs in 6 eyes, their average GLD at baseline was 385 µm. Of the large hyperTDs ranging in size between 250-300 µm when first detected, only one was not persistent with a baseline GLD of 283 µm. In 6 of the non-persistent hyperTDs, the loss of a detectable large hyperTD was due to the accumulation of hyperreflective material along the retinal pigment epithelium (RPE) and in the retina over the area where the hyperTD was located. This hyperreflective material is thought to represent the migration and aggregation of RPE cells into this focal region where the choroidal hyperTD arose due to attenuated or lost RPE.

Genome-wide association study of subfoveal choroidal thickness in a longitudinal cohort of older adults.

To identify genetic influences on subfoveal choroidal thickness of older adults using a genome-wide association study (GWAS). We recruited 300 participants from the population-based Korean Longitudinal Study on Health and Aging (KLoSHA) and Korean Longitudinal Study on Cognitive Aging and Dementia (KLOSCAD) cohort studies and 500 participants from the Bundang age-related macular degeneration (AMD) cohort study dataset. We conducted a GWAS on older adult populations in the KLoSHA and KLOSCAD cohorts. Single nucleotide polymorphisms (SNPs) associated with choroidal thickness were identified with P values < 1.0 × 10-4 in both the right and left eyes, followed by validation using the Bundang AMD cohort dataset. This association was further confirmed by a functional in vitro study using human umbilical vein endothelial cells (HUVECs). The ages of the cohort participants in the discovery and validation datasets were 73.5 ± 3.3 and 71.3 ± 7.9 years, respectively. In the discovery dataset, three SNPs (rs1916762, rs7587019, and rs13320098) were significantly associated with choroidal thickness in both eyes. This association was confirmed for rs1916762 (genotypes GG, GA, and AA) and rs7587019 (genotypes GG, GA, and AA), but not for rs13320098. The mean choroidal thickness decreased by 56.7 µm (AA, 73.8%) and 31.1 µm (GA, 85.6%) compared with that of the GG genotype of rs1916762, and by 55.4 µm (AA, 74.2%) and 28.2 µm (GA, 86.7%) compared with that of the GG genotype of rs7587019. The SNPs rs1916762 and rs7587019 were located close to the FAM124B gene near its cis-regulatory region. Moreover, FAM124B was highly expressed in vascular endothelial cells. In vitro HUVEC experiments showed that the inhibition of FAM124B was associated with decreased vascular endothelial proliferation, suggesting a potential mechanism of choroidal thinning. FAM124B was identified as a susceptibility gene affecting subfoveal choroidal thickness in older adults. This gene may be involved in mechanisms underlying retinal diseases associated with altered choroidal thickness, such as age-related macular degeneration.

Long Term Visual Outcomes of an Extended Macular Vision IOL in Eyes with Macular Disease and Visually Insignificant Cataract.

Purpose: To determine long-term efficacy and safety of an extended macular vision intraocular lens (IOL) implanted in patients with dry age-related macular degeneration (AMD) and visually insignificant cataracts. Design: Retrospective observational case series. Setting: MicroChirurgia Oculare, Italy. Methods: A retrospective case series of patients with dry AMD and visually insignificant cataracts undergoing phacoemulsification and implantation of an extended macular vision IOL designed to optimize image quality up to 10° from the foveal center (EyeMax Mono, Sharpview Ophthalmology, London, UK). Criteria for implantation were visually insignificant cataract (NC1 according to LOCS III classification) with dry age-related macular degeneration. Hypermetropia was targeted in most eyes to provide magnification when corrected with spectacles. Primary outcome measures were changes in corrected distant and secondary outcome measures included near visual acuity (CDVA and CNVA, respectively) between baseline and latest follow-up and safety outcomes. Results: 113 eyes of 86 patients (mean age 70.3±7.9 years) were included (mean follow-up: 48.3±25.1 months). Mean CDVA improved by 0.22 logMAR (11 ETDRS letters), from 0.53±0.4 to 0.31±0.3 (n=113, p<0.001). Similarly, mean CNVA improved by 0.08 logMAR (4 ETDRS letters), from 0.45±0.2 to 0.37±0.2 (n=77, p<0.001). Eleven eyes had AMD with extensive atrophy, and their mean CDVA improved by 0.32 logMAR (16 ETDRS letters). Three eyes (2.7%) experienced loss of more than one line in logMAR CDVA and four eyes (5.2%) experienced loss of more than one line in logMAR CNVA. No complications or instances of IOL exchange were reported. Conclusion: Visual improvement in eyes with visually insignificant cataract and AMD who underwent phacoemulsification and were implanted with EyeMax Mono IOL appears to be influenced by the IOL optical design. Vision enhancement in eyes with visually insignificant cataracts underscores the IOL's ability to optimize use of healthy retinal areas. Prospective studies with control groups are needed to confirm these findings.

Dysfunction of Endothelial Cell-Mediated Intercellular Communication and Metabolic Pathways in Age-Related Macular Degeneration.

PURPOSE: Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly, but the therapies are not satisfactory. This study aimed to find AMD specific features through the analysis of high-throughput sequencing. METHODS: In this study, we integrated six projects containing single-cell RNA sequencing (scRNA-seq) data to perform a comprehensive analysis for AMD samples in the tissues of retina and retinal pigment epithelium/choroid, and in the positions of macula and periphery. Differentially expressed genes (DEGs) were analyzed and crucial signaling pathways were identified across cell types and between the macula and periphery. The intercellular signaling transduction among cell types were inferred by "CellChat" to build cell-cell communication network under normal and AMD conditions, and verified at the transcriptional level. The CD31+ endothelial cells were obtained to evaluate the enrichment of KEGG pathways in atrophic and neovascular AMD, and GSVA was adopted to discover differential metabolic signals in each AMD type. RESULTS: Thirteen major cell types were identified in the integrated scRNA-seq data. Although no disease-specific cell type or differential cell proportion was found, DEGs and enriched pathways were shown in cell-type- and position-dependent manners. Severe impairment of endothelial cell-mediated cell interactions was found in the signaling transduction network of the macula, and compromised cell interactions were observed in the periphery. Furthermore, distinct signaling pathways and metabolic states were uncovered in atrophic and neovascular AMD. Striking reduction in energy metabolism, lipid metabolism, and oxidative stress was indicated in the atrophic AMD. CONCLUSION: Conclusively, we discover aberrant signals and metabolic pathways in AMD samples, providing insight into mechanisms and potential therapeutic targets for the AMD treatment.

Assessment of Relation between Periodontal Disease and Macular Degeneration.

Background and Aim: Periodontal disease may result in chronic inflammation and bacteremia in some people. The study aimed to evaluate the connection between periodontal disease and macular degeneration. Materials and Methods: The specialist dental surgeon conducted the dental examination using a community periodontal index probe. An ophthalmologist performed the eye examination. Age-related macular degeneration (AMD) was identified through specific criteria such as the existence of particular types of drusen and pigmentary abnormalities. Results: Two hundred participants were part of the study. According to the data, factors such as advanced age, limited education, low income, hypertension, cardiovascular disease (CVD), and hepatitis B surface antigen (HBsAg) presence were strongly linked to AMD in all participants. Conclusion: Multiple studies have indicated a connection between periodontitis in the mouth and macular degeneration in individuals under 60 years of age.

Treatment and Characteristics of Pachychoroid Neovasculopathy Accompanying Recalcitrant Intraretinal Cysts.

PURPOSE: To evaluate the clinical characteristics associated with chronic pachychoroid neovasculopathy (PNV) accompanying recalcitrant intraretinal cysts. METHODS: This is a retrospective, single-center, case-series study involving 20 eyes of 18 patients with PNV who did not respond to bevacizumab or ranibizumab and had to switch to aflibercept. Optical coherence tomography images were assessed before and after switching of intravitreal injection drug. RESULTS: The intraretinal cysts involved the outer nuclear layer and inner nuclear layer in 15 patients (75.0%), and involved only the inner nuclear layer in five patients (25.0%). All participants showed retinal pigment epithelium atrophy and outer retinal layer defect including external limiting membrane defect co-localized to the intraretinal cystic lesion. With the initial injection, bevacizumab and ranibizumab injections did not show a significant decrease in choroidal thickness (CT). Twenty (100.0%) patients showed poor response of intraretinal cyst response (IRCR). After a switch to aflibercept, IRCR was good in 17 (85.0%) patients and poor in three (15.0%) patients. Reduction of CT was great in aflibercept injections (from 229.0 µm to 204.0 µm, median, p < 0.001). Best-corrected visual acuity did not show significant improvement before or after switching drugs. CONCLUSION: Intravitreal aflibercept injections were more effective in the reduction of CT and IRCR than bevacizumab and ranibizumab injections. The primary source of the intraretinal cyst fluid could be from the choroid.

From Gut to Eye: Exploring the Role of Microbiome Imbalance in Ocular Diseases.

Background: The gut microbiome plays a crucial role in human health, and recent research has highlighted its potential impact on ocular health through the gut-eye axis. Dysbiosis, or an imbalance in the gut microbiota, has been implicated in various ocular diseases. Methods: A comprehensive literature search was conducted using relevant keywords in major electronic databases, prioritizing recent peer-reviewed articles published in English. Results: The gut microbiota influences ocular health through immune modulation, maintenance of the blood-retinal barrier, and production of beneficial metabolites. Dysbiosis can disrupt these mechanisms, contributing to ocular inflammation, tissue damage, and disease progression in conditions such as uveitis, age-related macular degeneration, diabetic retinopathy, dry eye disease, and glaucoma. Therapeutic modulation of the gut microbiome through probiotics, prebiotics, synbiotics, and fecal microbiota transplantation shows promise in preclinical and preliminary human studies. Conclusions: The gut-eye axis represents a dynamic and complex interplay between the gut microbiome and ocular health. Targeting the gut microbiome through innovative therapeutic strategies holds potential for improving the prevention and management of various ocular diseases.

Color Doppler Imaging, Endothelin-1, Corneal Biomechanics and Scleral Rigidity in Asymmetric Age-Related Macular Degeneration.

Purpose: Age-related macular degeneration (AMD) presents a multifaceted etiopathogenesis involving ischemic, inflammatory, and genetic components. This study investigates the correlation between ocular hemodynamics, scleral rigidity (SR), and plasma endothelin-1 (ET1) levels in treatment-naive patients with asymmetrical AMD. Patients and Methods: This study included 20 treatment-naive patients (12 females and 8 males) with an average age of 76.4 ± 3.7 years, who presented with AMD with neovascular membrane formation (nAMD) in one eye, and intermediate grade 2 AMD (iAMD) in the other eye. The control group consisted of 20 healthy subjects (13 females and 7 males) with a mean age of 74.7 ± 3.9 years. All patients and healthy controls underwent color Doppler imaging (i) of the ophthalmic artery (OA), short posterior ciliary arteries (SPCAs), and central retinal artery (CRA); Plasma ET-1 levels were measured for all patients and healthy subjects. Corneal biomechanics were assessed using an Ocular Response Analyzer and two indices were obtained: corneal hysteresis (CH) and corneal resistance factor (CRF). Results: Results showed reduced blood flow velocities and increased resistance indices in AMD eyes, particularly affecting the short posterior ciliary arteries. According to mechanical theory, ARMD eyes exhibited elevated scleral rigidity and corneal resistance factor compared to controls, with a notable rise in SR in neovascular AMD (nAMD) eyes. As per the chronic subacute inflammation theory, plasma ET-1 levels were significantly higher in AMD patients, correlating with abnormal SPCAs blood flow and increased resistance indices. Conclusion: Findings suggest a multifactorial etiology of AMD involving an increase of ET-1 plasma levels with biomechanic damages of corneal and scleral tissue in nAMD.

Sex-dependent regulation of retinal pigment epithelium and retinal function by Pgc-1α.

Age-related macular degeneration (AMD) is a major cause of blindness that affects people over 60. While aging is the prominent factor in AMD, studies have reported a higher prevalence of AMD in women compared to age-matched men. Higher levels of the innate immune response's effector proteins complement factor B and factor I were also found in females compared to males in intermediate AMD. However, the mechanisms underlying these differences remain elusive. Peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) is a key regulator of mitochondrial biogenesis and metabolic pathways. Previously, we showed that Pgc-1α repression and high-fat diet induce drastic AMD-like phenotypes in mice. Our recent data revealed that Pgc-1α repression alone can also induce retinal pigment epithelium (RPE) and retinal dysfunction in mice, and its inhibition in vitro results in lipid droplet accumulation in human RPE. Whether sex is a contributing factor in these phenotypes remains to be elucidated. Using electroretinography, we demonstrate that sex could influence RPE function during aging independent of Pgc-1α in wild-type (WT) mice. We further show that Pgc-1α repression exacerbates RPE and retinal dysfunction in females compared to aged-match male mice. Gene expression analyses revealed that Pgc-1α differentially regulates genes related to antioxidant enzymes and mitochondrial dynamics in males and females. RPE flat mounts immunolabeled with TOMM20 and DRP1 indicated a sex-dependent role for Pgc-1α in regulating mitochondrial fission. Analyses of mitochondrial network morphology suggested sex-dependent effects of Pgc-1α repression on mitochondrial dynamics. Together, our study demonstrates that inhibition of Pgc-1α induces a sex-dependent decline in RPE and retinal function in mice. These observations on the sex-dependent regulation of RPE and retinal function could offer novel insights into targeted therapeutic approaches for age-related RPE and retinal degeneration.

Improving the re-use potential of reactive waste rock using sieving: a laboratory geochemical study.

Stockpiles containing sulfide minerals are subject to oxidation reactions when exposed to atmospheric conditions, which can result in the formation of acid mine drainage (AMD). Reactive waste rock has limited re-use potential due to the contamination risk associated with the generated drainage water. The re-use of reactive waste rock could lead to a significant reduction in the volume of waste rock as it mitigates the environmental impact of mine waste deposition. Acid mine drainage generation rate depends on sulfide weathering kinetics which are controlled by many parameters such as the mineralogy and the particle size. Fine fractions of waste rock have higher specific surface areas and degree of liberation of sulfides, resulting in greater reactivity than the coarse fractions. The objective of this research was therefore to evaluate the potential of re-use by controlling particle size using the sieving method. Two different potentially acid-generating waste rocks were divided into six fractions and subjected to both static and kinetic tests. Prediction of the geochemical behavior using static test did not consider the liberation of the minerals, and the long-term prediction was therefore overestimated. Results of the kinetic columns showed there was less oxidation of the sulfide minerals in the coarse fractions than in the fine fractions. Additionally, the distribution of sulfidic minerals and neutralizing minerals with particle size is influencing the potential of the re-use of the reactive waste rock.

Atrophic Macular Degeneration and Stem Cell Therapy: A Clinical Review.

Age-related macular degeneration (AMD) is one of the leading causes of visual loss in older patients. No effective drug is available for this pathology, but studies about therapy with stem cells replacing the damaged retinal cells with retinal pigment epithelium (RPE) were described. The documentation of AMD progression and the response to stem cell therapy have been performed by optical coherence tomography, microperimetry, and other diagnostic technologies.This chapter reports a clinical review of the most important clinical trials and protocols regarding the use of stem cells in AMD.

Safety, Tolerability, and Short-Term Efficacy of Low-Level Light Therapy for Dry Age-Related Macular Degeneration.

INTRODUCTION: Photobiomodulation (PBM) has become a promising approach for slowing the progression of early and intermediate dry age-related macular degeneration (dAMD) to advanced AMD. This technique uses light to penetrate tissues and activate molecules that influence biochemical reactions and cellular metabolism. This preliminary analysis is aimed at assessing the safety, tolerability, and short-term effectiveness of the EYE-LIGHT®PBM treatment device in patients with dAMD. METHODS: The EYE-LIGHT® device employs two wavelengths, 590 nm (yellow) and 630 nm (red), in both continuous and pulsed modes. Patients over 50 years of age with a diagnosis of dAMD in any AREDS (Age-Related Eye Disease Study) category were randomly assigned to either the treatment group or the sham group. The treatment plan consisted of an initial cycle of two sessions per week for 4 weeks. Safety, tolerability, and compliance outcomes, along with functional and anatomical outcomes, were assessed at the end of the fourth month. RESULTS: This preliminary analysis included data from 76 patients (152 eyes). All patients were fully compliant with treatment sessions, and only one fifth of patients treated with PBM reported mild ocular adverse events, highlighting exceptional results in terms of tolerability and adherence. Changes in best-corrected visual acuity (BCVA) from baseline to month 4 differed significantly between the sham and PBM-treated groups, favoring the latter, with a higher proportion achieving a gain of five or more letters post-treatment (8.9% vs. 20.3%, respectively; p = 0.043). No significant differences in central subfield thickness (CST) were observed between the two groups over the 4-month period. The study also found a statistically significant disparity in mean drusen volume changes from baseline to month 4 between the groups in favor of patients treated with PBM (p = 0.013). CONCLUSION: These preliminary results indicate that PBM treatment using the EYE-LIGHT® system is safe and well tolerated among patients with dAMD. Furthermore, both functional and anatomical data support the treatment's short-term efficacy. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT06046118.

Metformin Alleviates Inflammation and Induces Mitophagy in Human Retinal Pigment Epithelium Cells Suffering from Mitochondrial Damage.

Mitochondrial malfunction, excessive production of reactive oxygen species (ROS), deficient autophagy/mitophagy, and chronic inflammation are hallmarks of age-related macular degeneration (AMD). Metformin has been shown to activate mitophagy, alleviate inflammation, and lower the odds of developing AMD. Here, we explored the ability of metformin to activate mitophagy and alleviate inflammation in retinal pigment epithelium (RPE) cells. Human ARPE-19 cells were pre-treated with metformin for 1 h prior to exposure to antimycin A (10 µM), which induced mitochondrial damage. Cell viability, ROS production, and inflammatory cytokine production were measured, while autophagy/mitophagy proteins were studied using Western blotting and immunocytochemistry. Metformin pre-treatment reduced the levels of proinflammatory cytokines IL-6 and IL-8 to 42% and 65% compared to ARPE-19 cells exposed to antimycin A alone. Metformin reduced the accumulation of the autophagy substrate SQSTM1/p62 (43.9%) and the levels of LC3 I and II (51.6% and 48.6%, respectively) after antimycin A exposure. Metformin also increased the colocalization of LC3 with TOM20 1.5-fold, suggesting active mitophagy. Antimycin A exposure increased the production of mitochondrial ROS (226%), which was reduced by the metformin pre-treatment (84.5%). Collectively, metformin showed anti-inflammatory and antioxidative potential with mitophagy induction in human RPE cells suffering from mitochondrial damage.

Choroidal Control Technology: New Horizons in Maculopathy and Presbyopia.

OBJECTIVE: To evaluate changes in choroidal thickness in presbyopes, when reading with regular glasses versus choroidal control glasses, in patients with or without Age-Related Macular Degeneration (AMD). METHODS: This was a pilot study on short-term axial length (AL) in 33 eyes of 24 presbyopic patients aged 60 to 80 years, assigned to two age-matched groups, with or without AMD. About them, changes in choroidal thickness were evaluated with ocular biometry through indirect measurements of axial length at baseline, after 20' of reading with conventional lenses, and after another 20' of reading with peripheral hyperopic defocus glasses. The differences in axial length between the three different times were analyzed. RESULTS: In presbyopes without AMD there was a significant axial length shortening of -13.44 microns in the first conventional reading period, which was reversed by 90% with hyperopic defocus lenses, recovering + 12.11 microns by axial lengthening (choroidal thinning, p = 0.03). In patients with AMD, axial shortening was significantly greater than controls, -23.86 microns with conventional lenses (p < 0.001) and they, also increased their axial length with defocus, although this response was smaller in proportion (+ 15.52 microns). CONCLUSION: Reading with positive lenses produces myopic defocus and choroidal thickening in presbyopes with and without AMD but was significantly greater in the latter. Glasses with Choroidal Control Technology reduced thickening during reading. KEY MESSAGES: What is known • Presbyopia spectacles for near produce myopic defocus and choroidal thickening. What is new • There are differences in choroidal thickening during reading between normal subjects and those with age related macular degeneration. • Spectacles with Defocus Choroidal Control Technology reduce choroidal thickening during reading in presbyopes.

Overview of the Use of Optical Coherence Tomography Angiography in Neovascular Age-Related Macular Degeneration.

The aim of this review is to present and discuss the use of optical coherence tomography angiography (OCTA) in age-related macular degeneration (AMD). OCTA is a non-invasive imaging procedure that gives a detailed indirect view of physiological and pathological vessels in the retina and choroid membrane. Compared with dye-based imaging, OCTA provides a segmented presentation of the individual vascular layers and plexuses, thus enabling previously unattainable differentiation and classification of pathological vascular changes within or underneath the retina. In particular, OCTA facilitates early detection of exudative macular neovascularizations (MNV) so that treatment with anti-VEGF medication can be initiated. Moreover, in the context of both screening and therapy monitoring, it is hoped that OCTA can provide more detailed data to enable greater personalization of treatment and follow-up. The image quality of OCTA is, however, susceptible to artifacts, and validation of the results by studies is required. Recent developments have shown constant improvement both in the algorithms for image calculation and avoidance of artifacts and in image quality, so the scope of OCTA will certainly expand with time.

Thyroid Function, Diabetes, and Common Age-Related Eye Diseases: A Mendelian Randomization Study.

Background: Previous Mendelian randomization (MR) studies showed an association between hypothyroidism and cataract and between high-normal free thyroxine (FT4) and late age-related macular degeneration (AMD), but not between FT4, thyroid stimulating hormone (TSH), or hyperthyroidism and diabetic retinopathy or cataract. These studies included a limited number of genetic variants for thyroid function and did not investigate autoimmune thyroid disease (AITD) or glaucoma, include bidirectional and multivariable MR (MVMR), and examine sex differences or potential mediation effects of diabetes. We aimed to address this knowledge gap. Methods: We examined the causality and directionality of the associations of AITD, and FT4 and TSH within the reference range with common age-related eye diseases (diabetic retinopathy, cataract, early and late AMD, and primary open-angle glaucoma). We conducted a bidirectional two-sample MR study utilizing publicly available genome-wide association study (GWAS) summary statistics from international consortia (ThyroidOmics, International AMD Genetics Consortium, deCODE, UK Biobank, FinnGen, and DIAGRAM). Bidirectional MR tested directionality, whereas MVMR estimated independent causal effects. Furthermore, we investigated type 1 diabetes (T1D) and type 2 diabetes (T2D) as potential mediators. Results: Genetic predisposition to AITD was associated with increased risk of diabetic retinopathy (p = 3 × 10-4), cataract (p = 3 × 10-3), and T1D (p = 1 × 10-3), but less likely T2D (p = 0.01). MVMR showed attenuated estimates for diabetic retinopathy and cataract when adjusting for T1D, but not T2D. We found pairwise bidirectional associations between AITD, T1D, and diabetic retinopathy. Genetic predisposition to both T1D and T2D increased the risk of diabetic retinopathy and cataract (p < 4 × 10-4). Moreover, genetically predicted higher FT4 within the reference range was associated with an increased risk of late AMD (p = 0.01), particularly in women (p = 7 × 10-3). However, we neither found any association between FT4 and early AMD nor between TSH and early and late AMD. No other associations were observed. Conclusions: Genetic predisposition to AITD is associated with risk of diabetic retinopathy and cataract, mostly mediated through increased T1D risk. Reciprocal associations between AITD, diabetic retinopathy, and T1D imply a shared autoimmune origin. The role of FT4 in AMD and potential sex discrepancies needs further investigation.