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We reevaluate acute retinal pigment epitheliitis (ARPE) first described by Krill and Deutman in 1972, integrating a meticulous literature review with advanced multimodal imaging analyses. Our review included 98 eyes from 86 published cases diagnosed with ARPE. We scrutinized ARPE's clinical presentations, variability, and imaging characteristics, revealing that a large majority (90 %) of cases previously diagnosed as ARPE align more closely with other retinal disorders based on modern diagnostic criteria and imaging techniques. Only a small fraction (5 eyes) did not fit into any known categories, casting doubt on ARPE's distinct existence. This underscores the critical role of multimodal imaging in redefining our understanding of macular diseases and challenges the historical classification of ARPE as a unique clinical entity. [ABSTRACT FROM AUTHOR]

Ophthalmic treatment demands precision and consistency in delivering therapeutic agents over extended periods to address many conditions, from common eye disorders to complex diseases. This diversity necessitates a range of delivery strategies, each tailored to specific needs. We delve into various delivery cargos that are pivotal in ophthalmic care. These cargos encompass biodegradable implants that gradually release medication, nonbiodegradable implants for sustained drug delivery, refillable tools allowing flexibility in treatment, hydrogels capable of retaining substances while maintaining ocular comfort, and advanced nanotechnology devices that precisely target eye tissues. Within each cargo category, we explore cutting-edge research-level approaches and FDA-approved methods, providing a thorough overview of the current state of ophthalmic drug delivery. In particular, our focus on nanotechnology reveals the promising potential for gene delivery, cell therapy administration, and the implantation of active devices directly into the retina. These advancements hold the key to more effective, personalized, and minimally- invasive ophthalmic treatments, revolutionizing the field of eye care. [ABSTRACT FROM AUTHOR]

Intravitreal injection of biodegradable implant drug carriers shows promise in reducing the injection frequency for neovascular retinal diseases. However, current intravitreal ocular devices have limitations in adjusting drug release rates for individual patients, thereby affecting treatment effectiveness. Accordingly, we developed mesoporous silica nanoparticles (MSNs) featuring a surface that reverse its charge in response to reactive oxygen species (ROS) for efficient delivery of humanin peptide (HN) to retinal epithelial cells (ARPE-19). The MSN core, designed with a pore size of 2.8 nm, ensures a high HN loading capacity 64.4% (w /w). We fine-tuned the external surface of the MSNs by incorporating 20% Acetyl-L-arginine (Ar) to create a partial positive charge, while 80% conjugated thioketal (TK) methoxy polyethylene glycol (mPEG) act as ROS gatekeeper. Ex vivo experiments using bovine eyes revealed the immobilization of Ar-MSNs-TK-PEG (mean zeta potential: 2 mV) in the negatively charged vitreous. However, oxidative stress reversed the surface charge to −25 mV by mPEG loss, facilitating the diffusion of the nanoparticles impeded with HN. In vitro studies showed that ARPE-19 cells effectively internalize HN-loaded Ar-MSNs-TK, subsequently releasing the peptide, which offered protection against oxidative stress-induced apoptosis, as evidenced by reduced TUNEL and caspase3 activation. The inhibition of retinal neovascularization was further validated in an in vivo oxygen-induced retinopathy (OIR) mouse model. The study discusses the development of a novel drug delivery system utilizing charge reversal mesoporous silica nanoparticles (MSNs) for the treatment of neovascular retinal diseases. [Display omitted] • Mesoporous Silica Nanoparticles' surface charge was delicately adjusted for reversal under ROS-response. • Intravitreal injection of Ar-MSNs-TK-PEG was immobilized in the mouse vitreous; however, under oxidative stress, the surface charge reversed, facilitating nanoparticle diffusion. • HN loaded Ar-MSNs-TK-PEG provides protection against oxidative stress-induced apoptosis, evidenced by reduced TUNEL and caspase3 activation. • Intravitreal injection of HN-loaded Ar-MSNs-TK-PEG inhibit retinal neovascularization in a mice model of oxygen-induced retinopathy without inducing toxicity in retinal tissues. [ABSTRACT FROM AUTHOR]

Epigenomic and metabolic changes impact retinal health and disease. Metabolite levels influence key epigenomic changes that regulate the retinal transcriptome. Epigenome-metabolism crosstalk underlies retinal adaptation to aging and the environment. The epigenome–metabolism nexus suggests interventions for retinal diseases. Intimate links between epigenome modifications and metabolites allude to a crucial role of cellular metabolism in transcriptional regulation. Retina, being a highly metabolic tissue, adapts by integrating inputs from genetic, epigenetic, and extracellular signals. Precise global epigenomic signatures guide development and homeostasis of the intricate retinal structure and function. Epigenomic and metabolic realignment are hallmarks of aging and highlight a link of the epigenome–metabolism nexus with aging-associated multifactorial traits affecting the retina, including age-related macular degeneration and glaucoma. Here, we focus on emerging principles of epigenomic and metabolic control of retinal gene regulation, with emphasis on their contribution to human disease. In addition, we discuss potential mitigation strategies involving lifestyle changes that target the epigenome-metabolome relationship for maintaining retinal function. [ABSTRACT FROM AUTHOR]

To investigate the distribution of genotypes and natural history of ABCA4 -associated retinal disease in a large cohort of patients seen at a single institution. Retrospective, single-institution cohort review. Patients seen at the University of Iowa between November 1986 and August 2022 clinically suspected to have disease caused by sequence variations in ABCA4. DNA samples from participants were subjected to a tiered testing strategy progressing from allele-specific screening to whole genome sequencing. Charts were reviewed, and clinical data were tabulated. The pathogenic severity of the most common alleles was estimated by studying groups of patients who shared 1 allele. Groups of patients with shared genotypes were reviewed for evidence of modifying factor effects. Age at first uncorrectable vision loss, best-corrected visual acuity, and the area of the I2e isopter of the Goldmann visual field. A total of 460 patients from 390 families demonstrated convincing clinical features of ABCA4 -associated retinal disease. Complete genotypes were identified in 399 patients, and partial genotypes were identified in 61. The median age at first vision loss was 16 years (range, 4–76 years). Two hundred sixty-five families (68%) harbored a unique genotype, and no more than 10 patients shared any single genotype. Review of the patients with shared genotypes revealed evidence of modifying factors that in several cases resulted in a > 15-year difference in age at first vision loss. Two hundred forty-one different alleles were identified among the members of this cohort, and 161 of these (67%) were found in only a single individual. ABCA4 -associated retinal disease ranges from a very severe photoreceptor disease with an onset before 5 years of age to a late-onset retinal pigment epithelium–based condition resembling pattern dystrophy. Modifying factors frequently impact the ABCA4 disease phenotype to a degree that is similar in magnitude to the detectable ABCA4 alleles themselves. It is likely that most patients in any cohort will harbor a unique genotype. The latter observations taken together suggest that patients' clinical findings in most cases will be more useful for predicting their clinical course than their genotype. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article. [ABSTRACT FROM AUTHOR]

Patients with incurable corneal diseases experience visual impairment (VI) despite having a healthy retina and optic pathway. Low-vision aids (LVAs) can optimize the use of remaining vision through magnification and contrast enhancement, but do not harness the full visual capacity because they rely on the optic media. Therefore, we investigated a novel laser eyewear (LEW) technology that bypasses the anterior segment of the eye. Images captured by an integrated camera are projected directly onto the retina using a low-energy laser. The patient is able to view a full-color video, realized as augmented reality. We aimed to evaluate the efficacy of the LEW to enhance the vision of individuals with corneal diseases. Prospective, randomized, crossover clinical trial. We examined the retinal projection glasses in 21 patients (25–69 years) with VI (0.7 logarithm of the minimum angle of resolution [logMAR] or worse) resulting from corneal diseases. Patients with comorbidities that impact vision, such as retinal disorders, were excluded. Standardized measurements of visual acuity (VA) for near vision (NV) and distance vision (DV) were conducted using ETDRS charts with the respective best correction (BC) and then with LEW. In addition reading speed, vision-related quality of life (QoL) and capacity to carry out daily tasks were assessed at an initial visit and at 2 subsequent visits after a home phase with and without the device. Six weeks after last use of the LEW, an ophthalmologic examination including spectral-domain-OCT or full-field-electroretinography was conducted and compared with baseline findings to evaluate the safety of the device. Four patients participated and completed a subsequent 12-month follow-up phase. Improvement of VA using the LEW. Secondary objectives included safety, reading speed, QoL, and usability in daily activities. The mean VA in patients with VI was improved by 0.43 logMAR in DV using the LEW compared with BC (P < 0.0001). Using the ×2 magnification mode of the LEW resulted in an average improvement of 0.66 logMAR compared with BC (P < 0.0001). In NV, an increase of 0.47 logMAR was achieved compared with BC (P < 0.0001). Although only 4 of 21 participants were able to read with BC, 17 of 21 participants were able to read with the LEW. Quality of life significantly improved in the 17 participants who completed all visits. We demonstrated that the retinal projection glasses resulted in enhanced VA for all participants by directly projecting images onto the intact retina. In future, the LEW could represent a new option as an LVA for patients with corneal diseases. No pathological alterations were observed in the safety assessments. The author(s) have no proprietary or commercial interest in any materials discussed in this article. [ABSTRACT FROM AUTHOR]

Subretinal hyperreflective material (SHRM) is a common and remarkable optical coherence tomography (OCT) biomarker whose importance is emerging in several retinal and chorioretinal diseases, including age-related macular degeneration, central serous chorioretinopathy, polypoidal choroidal vasculopathy, pathologic myopia, posterior uveitis, vitelliform lesions and macular dystrophies, and rarer disorders. Multimodal imaging, also thanks to the introduction of OCT angiography, allowed a deeper characterisation of SHRM components and its morphological changes after treatment, suggesting its usefulness in clinical practice. We discuss and summarize the nature, multimodal imaging characteristics, and prognostic and predictive significance of SHRM in the different retinal and choroidal disorders in which it has been described. [ABSTRACT FROM AUTHOR]

Multicolor (MC) imaging is an innovative pseudocolor fundus imaging modality based on confocal scanning laser ophthalmoscopy. It effectively scans the retina at different depths to create a composite image. The green reflectance image depicts the middle retinal while blue reflectance image provides images of the retinal surface. The infrared reflectance image depicts retinal structures at the level of outer retina and choroid. We systematically analyze published case reports, case series, and original articles on MC imaging where it has helped in discovering additional clinical features of retinal diseases not readily apparent on conventional color fundus photography and played a role in monitoring the response to treatment. [ABSTRACT FROM AUTHOR]

Hypomorphic variants decrease, but do not eliminate, gene function via a reduction in the amount of mRNA or protein product produced by a gene or by production of a gene product with reduced function. Many hypomorphic variants have been implicated in inherited retinal diseases (IRDs) and other genetic ocular conditions; however, there is heterogeneity in the use of the term "hypomorphic" in the scientific literature. We searched for all hypomorphic variants reported to cause IRDs and ocular disorders. We also discuss the presence of hypomorphic variants in the patient population of our ocular genetics department over the past decade. We propose that standardized criteria should be adopted for use of the term "hypomorphic" to describe gene variants to improve genetic counseling and patient care outcomes. [ABSTRACT FROM AUTHOR]

The degeneration of retinal pigment epithelium (RPE) plays an important role in the development of age-related macular degeneration (AMD). However, the underlying mechanism remains elusive. In this study, we identified that ZIP8, a metal-ion transporter, plays a crucial role in the degeneration of RPE cells mediated by ferroptosis. ZIP8 was found to be upregulated in patients with AMD through transcriptome analysis. Upregulated ZIP8 was also observed in both oxidative-stressed RPE cells and AMD mouse model. Importantly, knockdown of ZIP8 significantly inhibited ferroptosis in RPE cells induced by sodium iodate-induced oxidative stress. Blocking ZIP8 with specific antibodies reversed RPE degeneration and restored retinal function, improving visual loss in a mouse model of NaIO 3 -induced. Interestingly, the modification of the N-glycosylation sites N40, N72 and N88, but not N273, was essential for the intracellular iron accumulation mediated by ZIP8, which further led to increased lipid peroxidation and RPE death. These findings highlight the critical role of ZIP8 in RPE ferroptosis and provide a potential target for the treatment of diseases associated with retinal degeneration, including AMD. [Display omitted] • ZIP8 is upregulated in oxidative-stressed RPE cells in vitro and in vivo. • ZIP8 promotes RPE ferroptosis via increasing iron import, oxidative stress and lipid peroxidation. • N-Glycosylation is necessary for ZIP8 mediated RPE ferroptosis. • Blockage of ZIP8 reverses RPE degeneration and restores retinal function in NaIO 3 induced AMD animal model. [ABSTRACT FROM AUTHOR]

Retinal diseases affect the eye's retina and are the leading cause of vision loss. Timely detection and diagnosis can provide more treatment options and preserve vision. Retinal imaging, such as Optical Coherence Tomography (OCT), is used for screening patients and enables clinicians to visualize the retinal layers in detail, helping in early diagnosis and tailoring appropriate treatment plans. This study uses OCT images to detect diseases related to macular disorders common in old age. A custom convolution Neural Network (CNN) model is proposed in this study to classify OCT images of normal, choroidal neovascularization (CNV), diabetic macular edema (DME), and Drusen from a public dataset. Experiments were conducted using conventional machine learning (ML) and transfer learning-based models other than the proposed one. The proposed model performed favorably, attaining the training and validation accuracy of 97% and 93%, respectively. The proposed model achieves a testing accuracy of 98% with a loss of 0.051 and outperforms the existing models compared to this study. [ABSTRACT FROM AUTHOR]

Neurodegenerative diseases affecting the visual system encompass glaucoma, macular degeneration, retinopathies, and inherited genetic disorders such as retinitis pigmentosa. These ocular pathologies pose a serious burden of visual impairment and blindness worldwide. Current treatment modalities include small molecule drugs, biologics, or gene therapies, most of which are administered topically as eye drops or as injectables. However, the topical route of administration faces challenges in effectively reaching the posterior segment and achieving desired concentrations at the target site, while injections and implants risk severe complications, such as retinal detachment and endophthalmitis. This necessitates the development of innovative therapeutic strategies that can prolong drug release, deliver effective concentrations to the back of the eye with minimal systemic exposure, and improve patient compliance and safety. In this review, we introduce retinal degenerative diseases, followed by a discussion of the existing clinical standard of care. We then delve into detail about drug and gene delivery systems currently in preclinical and clinical development, including formulation and delivery advantages/drawbacks, with a special emphasis on potential for clinical translation. [Display omitted] • Retinal degeneration arises from various conditions ranging from inherited disorders to complications of preexisting disease • Drug delivery to the eye is faced by many barriers including the tear film, cornea, and blood retina barrier • Direct injections to specific eye compartments such as the subretinal or vitreous space facilitates drug delivery • Drug delivery systems can sustain release, enhance uptake and diffusion, and improve efficacy of ocular therapeutics • Studying ocular therapeutics in higher order animals is imperative in demonstrating clinical translatability [ABSTRACT FROM AUTHOR]

Diseases leading to retinal cell loss can cause severe visual impairment and blindness. The lack of effective therapies to address retinal cell loss and the absence of intrinsic regeneration in the human retina leads to an irreversible pathological condition. Progress in recent years in the generation of human three-dimensional retinal organoids from pluripotent stem cells makes it possible to recreate the cytoarchitecture and associated cell-cell interactions of the human retina in remarkable detail. These human three-dimensional retinal organoid systems made of distinct retinal cell types and possessing contextual physiological responses allow the study of human retina development and retinal disease pathology in a way animal model and two-dimensional cell cultures were unable to achieve. We describe the derivation of retinal organoids from human pluripotent stem cells and their application for modeling retinal disease pathologies, while outlining the opportunities and challenges for its application in academia and industry. [ABSTRACT FROM AUTHOR]

• Quercetin has therapeutic effects on retinopathy induced by hyperglycemia. • Quercetin protects against retinopathy by regulating gut-retina axis. • Quercetin can enhance the antioxidant capacity in the retina. Hyperglycemia-related retinopathy is a disease with a high blindness rate. Recent reports indicate that many flavonol compounds have the potential to prevent the occurrence of disease in the retina by regulating the gut–retina axis. Here, we hypothesized that quercetin could alleviate the symptoms of retinopathy. To clarify the mechanism, Sprague Dawley rats were fed a high-fat diet containing quercetin for 12 weeks and injected with streptozotocin in the ninth week. Additionally, neomycin and ampicillin were used to establish a pseudo-sterile rat model. Afterward, changes in the retina were investigated by using electroretinogram and optical coherence tomography. Blood and tissue samples were collected and biochemical components were analyzed. The extent of intestinal injury was determined via hematoxylin-eosin staining. Microbial community structure was analyzed by using 16S ribosomal RNA sequencing. Finally, the expression of genes was analyzed using real-time polymerase chain reaction. The results showed that quercetin reduced the decline in electroretinography amplitude and outer nuclear layer thickness, increased the activities of antioxidant enzymes, decreased the contents of proinflammatory factors and blood glucose, enhanced the concentration of insulin, and inhibited intestinal dysbiosis and improved gut morphology. Importantly, the underexpression of nuclear factor erythroid-2 related factor 2 in the retina was reversed by quercetin. However, trend changes were no longer significant in most of the indicators after antibiotic treatment. In summary, quercetin has therapeutic effects on retinopathy by regulating the gut–retina axis and nuclear factor erythroid-2 related factor 2 pathway, and the presence of gut microbiota helps quercetin exert its effects on the retina. Quercetin has therapeutic effects on hyperglycemia-induced retinopathy. It increases antioxidant capacity of the retina, decreases the contents of pro-inflammatory factors and the concentration of blood sugar, and restores the gut microbial composition. After the use of broad-spectrum antibiotics, the protective effects of quercetin on retinopathy are no longer significant. Red arrows indicate decreased trend, green arrows indicate increased trend, and purple circles indicate no changes. [Display omitted] [ABSTRACT FROM AUTHOR]

Numerous clinical trials have explored adeno-associated virus (AAV)-mediated gene therapy for inherited retinal diseases (IRDs). Yet, recent findings indicate serious adverse effects, and some trials have failed to meet endpoints. The advent of in vitro -transcribed (IVT) mRNA has broadened the possibility of new ocular gene therapies. Synthetic mRNA achieves higher translation efficiency without nuclear translocation, poses no genomic integration risks, is transiently expressed, and its production is cost-effective, making therapies more accessible globally. Ocular gene therapy relies heavily on viral vectors, such as AAVs; however, AAVs face challenges, including limited gene-carrying capacity, restricting treatment for certain IRDs, while the use of large transgenes, such as CRISPR tools, requires further refinement to enable their packaging into AAVs. Recently, nonviral nanoparticles emerged as promising alternatives, offering increased packaging, stability, and cost-effectiveness. Inherited retinal diseases (IRDs) stem from genetic mutations that result in vision impairment. Gene therapy shows promising therapeutic potential, exemplified by the encouraging initial results with voretigene neparvovec. Nevertheless, the associated costs impede widespread access, particularly in low-to-middle income countries. The primary challenge remains: how can we make these therapies globally affordable? Leveraging advancements in mRNA therapies might offer a more economically viable alternative. Furthermore, transitioning to nonviral delivery systems could provide a dual benefit of reduced costs and increased scalability. Relevant stakeholders must collaboratively devise and implement a research agenda to realize the potential of mRNA strategies in equitable access to treatments to prevent vision loss. [ABSTRACT FROM AUTHOR]

Nanoscale extracellular vesicles (EVs), consisting of exomers, exosomes and microvesicles/ectosomes, have been extensively investigated in the last 20 years, although their biological role is still something of a mystery. EVs are involved in the transfer of lipids, nucleic acids and proteins from donor to recipient cells or distant organs as well as regulating cell-cell communication and signaling. Thus, EVs are important in intercellular communication and this is not limited to sister cells, but may also mediate the crosstalk between different cell types even over long distances. EVs play crucial functions in both cellular homeostasis and the pathogenesis of diseases, and since their contents reflect the status of the donor cell, they represent an additional valuable source of information for characterizing complex biological processes. Recent advances in isolation and analytical methods have led to substantial improvements in both characterizing and engineering EVs, leading to their use either as novel biomarkers for disease diagnosis/prognosis or even as novel therapies. Due to their capacity to carry biomolecules, various EV-based therapeutic applications have been devised for several pathological conditions, including eye diseases. In the eye, EVs have been detected in the retina, aqueous humor, vitreous body and also in tears. Experiences with other forms of intraocular drug applications have opened new ways to use EVs in the treatment of retinal diseases. We here provide a comprehensive summary of the main in vitro , in vivo , and ex vivo literature-based studies on EVs' role in ocular physiological and pathological conditions. We have focused on age-related macular degeneration, diabetic retinopathy, glaucoma, which are common eye diseases leading to permanent blindness, if not treated properly. In addition, the putative use of EVs in retinitis pigmentosa and other retinopathies is discussed. Finally, we have reviewed the potential of EVs as therapeutic tools and/or biomarkers in the above-mentioned retinal disorders. Evidence emerging from experimental disease models and human material strongly suggests future diagnostic and/or therapeutic exploitation of these biological agents in various ocular disorders with a good possibility to improve the patient's quality of life. [Display omitted] [ABSTRACT FROM AUTHOR]

Adaptive optics (AO) imaging enables direct, objective assessments of retinal cells. Applications of AO show great promise in advancing our understanding of the etiology of inherited retinal disease (IRDs) and discovering new imaging biomarkers. This scoping review systematically identifies and summarizes clinical studies evaluating AO imaging in IRDs. Ovid MEDLINE and EMBASE were searched on February 6, 2023. Studies describing AO imaging in monogenic IRDs were included. Study screening and data extraction were performed by 2 reviewers independently. This review presents (1) a broad overview of the dominant areas of research; (2) a summary of IRD characteristics revealed by AO imaging; and (3) a discussion of methodological considerations relating to AO imaging in IRDs. From 140 studies with AO outcomes, including 2 following subretinal gene therapy treatments, 75% included fewer than 10 participants with AO imaging data. Of 100 studies that included participants' genetic diagnoses, the most common IRD genes with AO outcomes are CNGA3 , CNGB3 , CHM , USH2A , and ABCA4. Confocal reflectance AO scanning laser ophthalmoscopy was the most reported imaging modality, followed by flood-illuminated AO and split-detector AO. The most common outcome was cone density, reported quantitatively in 56% of studies. Future research areas include guidelines to reduce variability in the reporting of AO methodology and a focus on functional AO techniques to guide the development of therapeutic interventions. [ABSTRACT FROM AUTHOR]

Inherited retinal diseases (IRDs) are the most common cause of blindness in working-age adults. Macular neovascularization (MNV) may be a presenting feature or occurs as a late-stage complication in several IRDs. We performed an extensive literature review on MNV associated with IRDs. MNV is a well-known complication of Sorsby fundus dystrophy and pseudoxanthoma elasticum. Those with late-onset Stargardt disease may masquerade as exudative age-related macular degeneration (AMD) when MNV is the presenting feature. Peripherinopathies may develop MNV that responds well to a short course of anti-vascular endothelial growth factor (anti-VEGF) therapy, while bestrophinopathies tend to develop MNV in the early stages of the disease without vision loss. Enhanced S-cone syndrome manifests type 3 MNV that typically regresses into a subfoveal fibrotic nodule. MNV is only a rare complication in choroideraemia and rod-cone dystrophies. Most IRD-related MNVs exhibit a favorable visual prognosis requiring less intensive regimens of anti-vascular endothelial growth factor therapy compared to age-related macular degeneration. We discuss the role of key imaging modalities in the diagnosis of MNV across a wide spectrum of IRDs and highlight the gaps in our knowledge with respect to the natural history and prognosis to pave the way for future directions of research. [ABSTRACT FROM AUTHOR]

Quantitative analysis of biomarkers in Optical Coherence Tomography (OCT) images plays an import role in the diagnosis and treatment of retinal diseases. However, biomarker segmentation in retinal OCT images is very hard due to the large variations in size and shape of retinal biomarkers, blurred boundaries, low contrast, and speckle interference. We proposed a novel M ulti- s cale L ocal- G lobal T ransformer network (MsLGT-Net) for biomarker segmentation in retinal OCT images. The network combines the proposed M ulti-scale F usion A ttention (MFA) module, L ocal- G lobal T ransformer (LGT) module, and C ontrastive L earning E nhancement (CLE) module to tackle the challenges of biomarker segmentation. Specifically, the proposed MFA module aims to enhance the network's ability to learn multi-scale features of retinal biomarkers by effectively combining the local detail information and contextual semantic information of biomarkers at different scales, and improve the representation ability for different classes of biomarkers. The LGT module is designed to learn local and global information adaptively from multi-scale fused features to address the challenge of small biomarker segmentation. In addition, to distinguish features between different types of retinal biomarkers, we propose the CLE module to enhance the feature representation of different biomarkers. Our proposed method is validated on one public dataset and one local dataset. The experimental results show that the proposed method is more effective than other state-of-the-art methods. [ABSTRACT FROM AUTHOR]

The retina, an important tissue of the eye, is essential in visual transmission and sustaining adequate eyesight. However, oxidative stress and inflammatory reactions can harm retinal structure and function. Recent studies have demonstrated that exposure to light can induce oxidative stress and inflammatory reactions in retinal cells, thereby facilitating the progression of retinal damage–related diseases and asthenopia. Plant bioactive compounds such as anthocyanin, curcumin, resveratrol, lutein, zeaxanthin, epigallocatechin gallate, and quercetin are effective in alleviating retinal damage and asthenopia. Their strong oxidation resistance and unique chemical structure can prevent the retina from producing reactive oxygen species and regulating eye muscle relaxation, thus alleviating retinal damage and asthenopia. Additionally, the combination of these active ingredients produces a stronger antioxidant effect. Consequently, understanding the mechanism of retinal damage caused by light and the regulation mechanism of bioactive compounds can better protect the retina and reduce asthenopia. Light causes retinal damage and asthenopia through oxidative stress, inflammatory reaction, mitochondrial damage, apoptosis, and autophagy. Anthocyanin, curcumin, resveratrol, lutein, zeaxanthin, epigallocatechin gallate, and quercetin can exert antioxidant and anti-inflammatory mechanisms and prevent retinal light damage. In addition, this bioavailability and preventive effect can be improved by embedding bioactive compounds and synergistic effect of bioactive compounds. Abbreviation: ROS, reactive oxygen species. [Display omitted] [ABSTRACT FROM AUTHOR]

To describe the largest, most phenotypically and genetically diverse cohort of patients with inherited retinal disease (IRD)-related Coats-like vasculopathy (CLV). Multicenter retrospective cohort study. A total of 67 patients with IRD-related CLV. Review of clinical notes, ophthalmic imaging, and molecular diagnosis from 2 international centers. Visual function, retinal imaging, management, and response to treatment were evaluated and correlated. The prevalence of IRD-related CLV was 0.5%; 54% of patients had isolated retinitis pigmentosa (RP), 21% had early-onset severe retinal dystrophy, and less frequent presentations were syndromic RP, sector RP, cone-rod dystrophy, achromatopsia, PAX6 -related dystrophy, and X-linked retinoschisis. The overall age of patients at CLV diagnosis was 30.7 ± 16.9 years (1–83). Twenty-one patients (31%) had unilateral CLV, and the most common retinal features were telangiectasia, exudates, and exudative retinal detachment (ERD) affecting the inferior and temporal retina. Macular edema/schisis was observed in 26% of the eyes, and ERD was observed in 63% of the eyes. Fifty-four patients (81%) had genetic testing, 40 of whom were molecularly solved. Sixty-six eyes (58%) were observed, 17 eyes (15%) were treated with a single modality, and 30 eyes (27%) had a combined approach. Thirty-five eyes (31%) were "good responders," 42 eyes (37%) were "poor responders," 22 eyes (19%) had low vision at baseline and were only observed, and 12 eyes (11%) did not have longitudinal assessment. Twenty-one observed eyes (62%) responded well versus 14 (33%) treated eyes. Final best-corrected visual acuity was significantly worse than baseline (P = 0.002); 40 patients (60%) lost 15 ETDRS letters or more over follow-up in 1 or both eyes, and 21 patients (31%) progressed to more advanced stages of visual impairment. Inherited retinal disease–related CLV is rare, sporadic, and mostly bilateral; there is no gender predominance, and it can occur in diverse types of IRD at any point of the disease, with a mean onset in the fourth decade of life. Patients with IRD-related CLV who have decreased initial visual acuity, ERD, CLV changes affecting 2 or more retinal quadrants, and CRB1 - retinopathy may be at higher risk of a poor prognosis. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article. [ABSTRACT FROM AUTHOR]

Lysosomes in photoreceptors (PRs), the retinal pigmented epithelium (RPE), and retinal ganglion cells (RGCs) are essential for maintaining retinal homeostasis. Phagocytosis of PR outer segments and autophagy in RPE are crucial for maintaining retinal health. Lysosomal impairments are involved in various retinal diseases: dysfunction in the RPE contributes to the biogenesis of drusen, a hallmark of early age-related macular degeneration (AMD); lysosomal dysfunction in PRs characterizes early stages of retinitis pigmentosa (RP), a constellation of blinding diseases caused by numerous genetic mutations; and development of glaucoma is linked to lysosomal abnormalities. Lysosomes interact with other organelles such as mitochondria. This coordination is vital to the cytoprotective responses of retinal cells and, when dysfunctional, contributes to the pathogenesis of blinding retinal diseases. Lysosomes play crucial roles in various cellular processes – including endocytosis, phagocytosis, and autophagy – which are vital for maintaining retinal health. Moreover, these organelles serve as environmental sensors and act as central hubs for multiple signaling pathways. Through communication with other cellular components, such as mitochondria, lysosomes orchestrate the cytoprotective response essential for preserving cellular homeostasis. This coordination is particularly critical in the retina, given its high metabolic rate and susceptibility to photo-oxidative stress. Consequently, impaired lysosomal function and dysregulated communication between lysosomes and other organelles contribute significantly to the pathobiology of major retinal degenerative diseases. This review explores the pivotal role of lysosomes in retinal cells and their involvement in retinal degenerative diseases. [ABSTRACT FROM AUTHOR]

Retromode scanning laser ophthalmoscopy imaging captures a pseudo-3-dimensional image of the ocular fundus. Retromode scanning laser ophthalmoscopy imaging was introduced first in 2008 using the Nidek F-10 scanning laser ophthalmoscope (F-10; Nidek Co., Gamagori, Japan). At that time, no major role was described for this imaging modality. The interest in retromode scanning laser ophthalmoscopy imaging is reemerging with the recent advent of the Mirante that combines scanning laser ophthalmoscopy and optical coherence tomography (Nidek Co., Gamagori, Japan) that can capture retromode images of the fundus. We summarize the findings and clinical implications of retromode imaging using the Nidek F-10 and the Mirante in retinal diseases with the aim of helping researchers direct their future studies. [ABSTRACT FROM AUTHOR]

It is known that metabolic defects in the retinal pigment epithelium (RPE) can cause degeneration of its neighboring photoreceptors in the retina, leading to retinal degenerative diseases such as age-related macular degeneration. However, how RPE metabolism supports the health of the neural retina remains unclear. The retina requires exogenous nitrogen sources for protein synthesis, neurotransmission, and energy metabolism. Using 15N tracing coupled with mass spectrometry, we found human RPE can utilize the nitrogen in proline to produce and export 13 amino acids, including glutamate, aspartate, glutamine, alanine, and serine. Similarly, we found this proline nitrogen utilization in the mouse RPE/choroid but not in the neural retina of explant cultures. Coculture of human RPE with the retina showed that the retina can take up the amino acids, especially glutamate, aspartate, and glutamine, generated from proline nitrogen in the RPE. Intravenous delivery of 15N proline in vivo demonstrated 15N-derived amino acids appear earlier in the RPE before the retina. We also found proline dehydrogenase, the key enzyme in proline catabolism is highly enriched in the RPE but not the retina. The deletion of proline dehydrogenase blocks proline nitrogen utilization in RPE and the import of proline nitrogen–derived amino acids in the retina. Our findings highlight the importance of RPE metabolism in supporting nitrogen sources for the retina, providing insight into understanding the mechanisms of the retinal metabolic ecosystem and RPE-initiated retinal degenerative diseases. [ABSTRACT FROM AUTHOR]

Chronic retinal diseases, such as age-related macular degeneration (AMD), are a major cause of global visual impairment. However, current treatment methods involving repetitive intravitreal injections pose financial and health burdens for patients. The development of controlled drug release systems, particularly for biological drugs, is still an unmet need in prolonging drug release within the vitreous chamber. To address this, green supercritical carbon dioxide (scCO 2) foaming technology was employed to manufacture porous poly(lactic- co -glycolic acid) (PLGA)-based intravitreal implants loaded with dexamethasone. The desired implant dimensions were achieved through 3D printing of customised moulds. By varying the depressurisation rates during the foaming process, implants with different porosities and dexamethasone release rates were successfully obtained. These implants demonstrated controlled drug release for up to four months, surpassing the performance of previously developed implants. In view of the positive results obtained, a pilot study was conducted using the monoclonal antibody bevacizumab to explore the feasibility of this technology for preparing intraocular implants loaded with biologic drug molecules. Overall, this study presents a greener and more sustainable alternative to conventional implant manufacturing techniques, particularly suited for drugs that are susceptible to degradation under harsh conditions. [Display omitted] • Intravitreal PLGA implants loaded with dexamethasone were successfully prepared using supercritical CO 2 foaming technology. • The dexamethasone implants showed enhanced release performance, ensuring controlled drug release for up to 4 months. • Implants prepared with different depressurisation conditions showed different physical and mechanical properties. • It was also possible to prepare bevacizumab intravitreal implants using supercritical CO 2 foaming. • The study introduces a greener and more sustainable alternative for implant manufacturing. [ABSTRACT FROM AUTHOR]

Timely and affordable computer-aided diagnosis of retinal diseases is pivotal in precluding blindness. Accurate retinal vessel segmentation plays an important role in disease progression and diagnosis of such vision-threatening diseases. To this end, we propose a Multi-resolution Contextual Network (MRC-Net) that addresses these issues by extracting multi-scale features to learn contextual dependencies between semantically different features and using bi-directional recurrent learning to model former-latter and latter-former dependencies. Another key idea is training in adversarial settings for foreground segmentation improvement through optimization of the region-based scores. This novel strategy boosts the performance of the segmentation network in terms of the Dice score (and correspondingly Jaccard index) while keeping the number of trainable parameters comparatively low. We have evaluated our method on three benchmark datasets, including DRIVE, STARE, and CHASE, demonstrating its superior performance as compared with competitive approaches elsewhere in the literature. [ABSTRACT FROM AUTHOR]

• Focal photoreceptor defects are alterations in foveal architecture due to loss or rarefaction of outer retinal layers (usually external limiting membrane, ellipsoid or interdigitation zone). • Etiologies include vitreomacular interface disorders, photic retinopathy, retinal dystrophies, drug toxicity, blunt trauma and acute retinal pigment epitheliopathy. • Optical coherence tomography imaging provides in-depth analysis of foveal photoreceptor defects, helpful in prognostication and understanding the course of this condition. Fovea centralis, located at the center of the macula, is packed with cone photoreceptors and is responsible for central visual acuity. Isolated foveal photoreceptor disruption may occur in a variety of hereditary, degenerative, traumatic, and toxic chorioretinal diseases. These have been known previously by multiple synonyms including macular microhole, foveal spot, and outer foveal microdefects. A common clinical feature underlying these conditions is the presence of apparently normal fovea or subtle hypopigmented lesion at the foveal or juxtafoveal area. A detailed history along with high-resolution optical coherence tomography is often helpful to derive a conclusive diagnosis in majority of these cases. Focal photoreceptor disruption usually involves loss or rarefaction of ellipsoid/interdigitation zone, either in isolation or associated with external limiting membrane or retinal pigment epithelium disruption in the fovea. Vitreomacular interface (VMI) disorders including vitreomacular traction, posterior vitreous detachment, epiretinal membrane, and impending macular hole possibly remain the most common cause. Retinal dystrophies such as cone dystrophy, occult macular dystrophy, and achromatopsia may present with diminution of vision and normal appearing fundus in a younger age group. Other causes include photic retinopathy (e.g., from a history of sun gazing or laser pointer exposure), blunt trauma, drug exposure (e.g., poppers maculopathy or tamoxifen retinopathy), and acute retinal pigment epitheliopathy (ARPE). Visual prognosis depends on the underlying etiology with complete recovery common in the subset of patients with VMI, and ARPE, whereas persistent outer retinal defects are the rule in other conditions. We discuss the differential diagnoses that lead to isolated foveal photoreceptor defects. Identifying and understanding the underlying disease processes that cause foveal photoreceptor disruption may help predict visual prognosis. [ABSTRACT FROM AUTHOR]

Vitelliform lesions (VLs) are associated with a wide array of macular disorders but are the result of one common pathway: retinal pigment epithelium (RPE) impairment and phagocytic dysfunction. VLs are defined by the accumulation of yellowish subretinal material. In the era of multimodal advanced retinal imaging, VLs can be further characterized by subretinal hyperreflectivity with optical coherence tomography and hyperautofluorescence with fundus autofluorescence. VLs can be the result of genetic or acquired retinal diseases. In younger patients, VLs usually occur in the setting of Best disease. Additional genetic causes of VL include pattern dystrophy or adult-onset vitelliform macular dystrophy. In older patients, acquired VLs can be associated with a broad spectrum of etiologies, including tractional, paraneoplastic, toxic, and degenerative disorders. The main cause of visual morbidity in eyes with VLs is the onset of macular atrophy and macular neovascularization. Histopathological studies have provided new insights into the location, nature, and lifecycle of the vitelliform material comprised of melanosomes, lipofuscin, melanolipofuscin, and outer segment debris located between the RPE and photoreceptor layer. Impaired phagocytosis by the RPE cells is the unifying pathway leading to VL development. We discuss and summarize the nature, pathogenesis, multimodal imaging characteristics, etiologies, and natural course of vitelliform maculopathies. [ABSTRACT FROM AUTHOR]

Near-infrared reflectance (NIR) retinal imaging aids in a better visualization of structures at the level of outer retina, retinal pigment epithelium, and choroid. It has multiple advantages, including easy acquisition in association with structural spectral domain optical coherence tomography, more comfort for patients, and enhanced contrast and spatial resolution. It helps in the diagnosis of chorioretinal diseases that present with minimal funduscopic findings and can be used to follow up many chorioretinal conditions. We describe the chorioretinal NIR imaging appearance and the clinical role of NIR imaging in ocular inflammatory disease, vascular and acquired disease, degenerative disease, tumors, associated systemic condition, toxic and traumatic disease, optic nerve head conditions, and physiological findings. [ABSTRACT FROM AUTHOR]

To develop a few-shot learning (FSL) approach for classifying optical coherence tomography (OCT) images in patients with inherited retinal disorders (IRDs). In this study, an FSL model based on a student–teacher learning framework was designed to classify images. 2,317 images from 189 participants were included. Of these, 1,126 images revealed IRDs, 533 were normal samples, and 658 were control samples. The FSL model achieved a total accuracy of 0.974–0.983, total sensitivity of 0.934–0.957, total specificity of 0.984–0.990, and total F1 score of 0.935–0.957, which were superior to the total accuracy of the baseline model of 0.943–0.954, total sensitivity of 0.866–0.886, total specificity of 0.962–0.971, and total F1 score of 0.859–0.885. The performance of most subclassifications also exhibited advantages. Moreover, the FSL model had a higher area under curves (AUC) of the receiver operating characteristic (ROC) curves in most subclassifications. This study demonstrates the effective use of the FSL model for the classification of OCT images from patients with IRDs, normal, and control participants with a smaller volume of data. The general principle and similar network architectures can also be applied to other retinal diseases with a low prevalence. [ABSTRACT FROM AUTHOR]

To review and describe in detail the clinical course, functional and anatomic characteristics of RP2 -associated retinal degeneration. Retrospective case series. Male participants with disease-causing variants in the RP2 gene. Review of all case notes and results of molecular genetic testing, retinal imaging (fundus autofluorescence [FAF] imaging, OCT), and electrophysiology assessment. Molecular genetic testing, clinical findings including best-corrected visual acuity (BCVA), qualitative and quantitative retinal imaging analysis, and electrophysiology parameters. Fifty-four molecularly confirmed patients were identified from 38 pedigrees. Twenty-eight disease-causing variants were identified, with 20 not previously clinically characterized. Fifty-three patients (98.1%) presented with retinitis pigmentosa. The mean age of onset (range ± standard deviation [SD]) was 9.6 years (1–57 ± 9.2 years). Forty-four patients (91.7%) had childhood-onset disease, with mean age of onset of 7.6 years. The most common first symptom was night blindness (68.8%). Mean BCVA (range ± SD) was 0.91 logarithm of the minimum angle of resolution (logMAR) (0–2.7 ± 0.80) and 0.94 logMAR (0–2.7 ± 0.78) for right and left eyes, respectively. On the basis of the World Health Organization visual impairment criteria, 18 patients (34%) had low vision. The majority (17/22) showed electroretinogram (ERG) evidence of a rod-cone dystrophy. Pattern ERG P50 was undetectable in all but 2 patients. A range of FAF findings was observed, from normal to advanced atrophy. There were no statistically significant differences between right and left eyes for ellipsoid zone width (EZW) and outer nuclear layer (ONL) thickness. The mean annual rate of EZW loss was 219 μm/year, and the mean annual decrease in ONL thickness was 4.93 μm/year. No patient with childhood-onset disease had an identifiable ellipsoid zone (EZ) after the age of 26 years at baseline or follow-up. Four patients had adulthood-onset disease and a less severe phenotype. This study details the clinical phenotype of RP2 retinopathy in a large cohort. The majority presented with early-onset severe retinal degeneration, with early macular involvement and complete loss of the foveal photoreceptor layer by the third decade of life. Full-field ERGs revealed rod-cone dystrophy in the vast majority, but with generalized (peripheral) cone system involvement of widely varying severity in the first 2 decades of life. Proprietary or commercial disclosure may be found after the references. [ABSTRACT FROM AUTHOR]

We aimed to characterize the ocular phenotype of patients with ROSAH (retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and headache) syndrome and their response to therapy. Single-center observational case study. Eleven patients with a diagnosis of ROSAH syndrome and mutation in ALPK1 were included. Patients with molecularly confirmed ROSAH syndrome underwent ophthalmic evaluation, including visual acuity testing, slit-lamp and dilated examinations, color fundus and autofluorescence imaging, fluorescein angiography, OCT, and electrophysiologic testing. Visual acuity, electrophysiology, fluorescein angiography, and OCT findings. Eleven individuals (6 female and 5 male patients) from 7 families ranging in age from 7.3 to 60.2 years at the time of the initial evaluation were included in this study. Seven patients were followed up for a mean of 2.6 years (range, 0.33–5.0 years). Best-corrected visual acuity at baseline ranged from 20/16 to no light perception. Variable signs or sequelae of intraocular inflammation were observed in 9 patients, including keratic precipitates, band keratopathy, trace to 2+ anterior chamber cells, cystoid macular edema, and retinal vasculitis on fluorescein angiography. Ten patients were observed to show optic disc elevation and demonstrated peripapillary thickening on OCT. Seven patients showed retinal degeneration consistent with a cone–rod dystrophy, with atrophy tending to involve the posterior pole and extending peripherally. One patient with normal electroretinography findings and visual evoked potential was found to have decreased Arden ratio on electro-oculography. Leveraging insights from the largest single-center ROSAH cohort described to date, this study identified 3 main factors as contributing to changes in visual function of patients with ROSAH syndrome: optic nerve involvement; intraocular inflammation, including cystoid macular edema; and retinal degeneration. More work is needed to determine how to arrest the progressive vision loss associated with ROSAH syndrome. Proprietary or commercial disclosure may be found after the references. [ABSTRACT FROM AUTHOR]

Retinopathy is a group of retinal diseases that causes severe retinal damage, resulting in partial visual impairment or complete vision loss. Due to the capability of optical coherence tomography in revealing early retinal abnormalities, many researchers have utilized it to develop autonomous retinal screening systems. However, to the best of our knowledge, the majority of these systems are vulnerable against diversified scanner specifications, hence, requiring extensive training supervision (on large-scale datasets) to accurately learn retinal screening tasks. In this paper, we present a novel self-supervised segmentation-driven classification pipeline that employs a proposed angular contrastive distillation scheme to extract retinal lesions (from the multi-vendor data) in order to give lesion-aware scanner independent screening and grading of retinopathy. The diagnostic capacity of the proposed framework is further enhanced by the integration of a novel co-attention mechanism, which enables the underlying network to focus its attention on retinal abnormalities to effectively grade retinal diseases without incurring supervision from the ground truth labels. The proposed framework is rigorously validated on seven public datasets, acquired with four different scanners, where it outperforms its competitors by achieving 9.22% improvement in terms of mean intersection-over-union for extracting retinal lesions and 10.71% improvement in terms of F1 score for grading retinopathy. • We present a contrastive learning-driven self-supervised retinal analysis scheme. • The proposed system gives a scanner-independent macular and ocular prognosis. • It employs a multi-scale fusion encoder–decoder-classifier to grade retinopathy. • It also leverages a novel co-attention mechanism to analyze disease patterns. • The proposed system is rigorously evaluated on seven public retinal OCT datasets. [ABSTRACT FROM AUTHOR]

Mesenchymal stem cell (MSCs)-derived extracellular vesicles (EVs) are emerging therapeutic tools. Hypoxic pre-conditioning (HPC) of MSCs altered the production of microRNAs (miRNAs) in EVs, and enhanced the cytoprotective, anti-inflammatory, and neuroprotective properties of their derivative EVs in retinal cells. EV miRNAs were identified as the primary contributors of these EV functions. Through miRNA seq analyses, miRNA-424 was identified as a candidate for the retina to overexpress in EVs for enhancing cytoprotection and anti-inflammatory effects. FEEs (functionally engineered EVs) overexpressing miR424 (FEE424) significantly enhanced neuroprotection and anti-inflammatory activities in vitro in retinal cells. FEE424 functioned by reducing inflammatory cytokine production in retinal microglia, and attenuating oxygen free radicals in retinal Muller cells and microvascular endothelial cells, providing a multi-pronged approach to enhancing recovery after retinal ischemic insult. In an in vivo model of retinal ischemia, native, HPC, and FEE424 MSC EVs robustly and similarly restored function to close to baseline, and prevented loss of retinal ganglion cells, but HPC EVs provided the most effective attenuation of apoptosis-related and inflammatory cytokine gene expression. These results indicate the potential for EV engineering to produce ameliorative effects for retinal diseases with a significant inflammatory component. We show that functionally engineered extracellular vesicles (FEEs) from mesenchymal stem cells (MSCs) provide cytoprotection in rat retina subjected to ischemia. FEEs overexpressing microRNA 424 (FEE424) function by reducing inflammatory cytokine production in retinal microglia, and attenuating oxygen free radicals in Muller cells and microvascular endothelial cells, providing a multi-pronged approach to enhancing recovery. In an in vivo model of retinal ischemia in rats, native, hypoxic-preconditioned (HPC), and FEE424 MSC EVs robustly and similarly restored function, and prevented loss of retinal ganglion cells, but HPC EVs provided the most effective attenuation of apoptosis-related and inflammatory cytokine gene expression. The results indicate the potential for EV engineering to produce ameliorative effects for retinal diseases with a significant inflammatory component. [Display omitted] [ABSTRACT FROM AUTHOR]

Visual phototransduction is the most extensively studied G protein-coupled receptor (GPCR) signaling pathway because of its quantifiable stimulus, non-redundancy of genes, and immense importance in vision. We summarize recent discoveries that have advanced our understanding of rod outer segment (ROS) morphology and the pathological basis of retinal diseases. We have combined recently published cryo-electron tomography (cryo-ET) data on the ROS with structural knowledge on individual proteins to define the precise spatial limitations under which phototransduction occurs. Although hypothetical, the reconstruction of the rod phototransduction system highlights the potential roles of phosphodiesterase 6 (PDE6) and guanylate cyclases (GCs) in maintaining the spacing between ROS discs, suggesting a plausible mechanism by which intrinsic optical signals are generated in the retina. Cryo-electron microscopy and cryo-electron tomography analysis of the rod outer segment (ROS) has characterized the functional components, specific molecular interactions, and physical boundaries for G protein-coupled receptor (GPCR) phototransduction. Rhodopsin is the only GPCR that has known structures of its intermolecular complexes with all three effectors in its signal transduction sequence. When activated, rhodopsin transiently binds to transducin to propagate the cascade of reactions that lead to vision; the activity is quenched by GRK1-mediated phosphorylation and binding of arrestin. Phototransduction constitutes interfacial catalysis; thus, lipids are important constituents and display remarkable microheterogeneity in support of signaling. Phototransduction changes the size of the ROS, generating the basis for the intrinsic optical signals (IOS) observed by optoretinography. These discoveries advance understanding of the structure–function relationships in GPCR signaling in vision and thus help in interpreting the cellular physiology and pathological basis of retinal diseases. [ABSTRACT FROM AUTHOR]

Rhodopsin is the key photoreceptor protein that mediates vision in low-light conditions. Mutations in rhodopsin are the cause of retinal degenerative diseases such as retinitis pigmentosa. Some of these mutations cause a decreased stability of the receptor. It is, therefore, of interest to find new approaches that can help improving rhodopsin conformational stability. In this study, we have analyzed the effect of retigabine, an anticonvulsant formerly used to treat epilepsy, on rhodopsin thermal stability, regeneration capacity, and signal transduction by means of UV–visible and fluorescence spectroscopic techniques. We find that retigabine enhances the thermal stability of dark-state rhodopsin and improves chromophore regeneration without disrupting the photobleaching process. Furthermore, retigabine does not significantly affect transducin activation. These results provide novel insights into the potential therapeutic applications of retigabine in the treatment of retinitis pigmentosa caused by rhodopsin mutations that cause a decreased stability of the mutated receptors. • Retigabine interacts with rhodopsin enhancing the thermal stability of its dark-adapted conformation. • Retigabine does not significantly alter the visual phototransduction process. • Retigabine could have potential therapeutic applications in the treatment of inherited retinal diseases. [ABSTRACT FROM AUTHOR]

Computer-aided diagnosis (CAD) of retinal fundus diseases is crucial for effective treatment planning and avoidance of vision deterioration and loss. Most existing CAD systems are focused on learning to differentiate between retinal fundus diseases, assuming that diseases are independent and ignoring disease co-occurrences. In this paper, we address this limitation in multi-label classification of retinal fundus diseases and introduce an end-to-end deep learning framework that accounts for label relationships via graph-theoretic regularization. Specifically, we trained convolutional neural networks for multi-label retinal disease classification. The training process for these networks embeds the graph prior in a scalable neighbor discriminative loss with binary cross entropy (SNDL-BCE). The proposed model was validated through extensive experiments on the RFMiD dataset. This model successfully identified the disease risk and classified 28 different retinal fundus diseases with a final score of 85% on the test set. In addition, Grad-CAM visualization exhibited high explainability and plausibility for the outcomes of our model. Moreover, our model compares well with other state-of-the-art methods for retinal disease classification. [Display omitted] • Retinal fundus diseases commonly occur together or share common symptoms. • Retinal disease relationships can be captured via graph representations. • Graph-regularized deep learning is used for multi-label retinal disease diagnosis. • An overall loss captures local feature structures and promotes class discriminability. • Model outcomes are experimentally validated and explained via Grad-CAM visualization. [ABSTRACT FROM AUTHOR]

Two retinal transcription factors, cone-rod homeobox (CRX) and neural retina leucine zipper (NRL), cooperate functionally and physically to control photoreceptor development and homeostasis. Mutations in CRX and NRL cause severe retinal diseases. Despite the roles of NRL and CRX, insight into their functions at the molecular level is lacking. Here, we have solved the crystal structure of the CRX homeodomain in complex with its cognate response element (Ret4) from the rhodopsin proximal promoter region. The structure reveals an unexpected 2:1 stoichiometry of CRX/Ret4 and unique orientation of CRX molecules on DNA, and it explains the mechanisms of pathogenic mutations in CRX. Mutations R41Q and E42K disrupt the CRX protein-protein contacts based on the structure and reduce the CRX/Ret4 binding stoichiometry, suggesting a novel disease mechanism. Furthermore, we show that NRL alters the stoichiometry and increases affinity of CRX binding at the rhodopsin promoter, which may enhance transcription of rod-specific genes and suppress transcription of cone-specific genes. [Display omitted] • Crystal structure of the CRX homeodomain in complex with its Ret4 response element • Complex displays a 2:1 stoichiometry and a unique orientation of CRX on the DNA • The CRX/Ret4 structure helps to elucidate the mechanisms of pathogenic CRX mutations • NRL alters the stoichiometry and strengthens CRX binding to the rhodopsin promoter Srivastava et al. determined the crystal structure of the CRX homeodomain in complex with its Ret4 response element from the rhodopsin promoter. This study provides structural insights into the recognition of DNA by CRX, its function, and the cooperative DNA binding by CRX and NRL. [ABSTRACT FROM AUTHOR]

The vasculature of the retina is exposed to systemic and local factors that have the capacity to induce several retinal vascular diseases, each of which may lead to vision loss. Prostaglandin signaling has arisen as a potential therapeutic target for several of these diseases due to the diverse manners in which these lipid mediators may affect retinal blood vessel function. Previous reports and clinical practices have investigated cyclooxygenase (COX) inhibition by nonsteroidal anti-inflammatory drugs (NSAIDs) to address retinal diseases with varying degrees of success; however, targeting individual prostanoids or their distinct receptors affords more signaling specificity and poses strong potential for therapeutic development. This review offers a comprehensive view of prostanoid signaling involved in five key retinal vascular diseases: retinopathy of prematurity, diabetic retinopathy, age-related macular degeneration, retinal occlusive diseases, and uveitis. Mechanistic and clinical studies of these lipid mediators provide an outlook for therapeutic development with the potential to reduce vision loss in each of these conditions. • Prostanoid levels are differentially regulated in retinal vascular diseases. • Each prostanoid has pleiotropic roles in the retinal vasculature. • Prostanoid receptors are more selective therapeutic targets than COX inhibition by NSAIDs. • Targeting individual prostanoids or their receptors has shown beneficial results for retinal diseases. • Receptor-level modulation of prostanoid signaling could help reduce vision loss in multiple conditions. [ABSTRACT FROM AUTHOR]

Glaucoma is a degenerative disease characterized by retinal ganglion cell (RGC) death and visual impairment caused by elevated intraocular pressure (IOP). Elevated IOP can activate microglia, which participate in ganglion cell injury. Based on the study of caveolin-1 (Cav-1) in glaucoma, we aimed to explore the effect and mechanism of Cav-1 on RGC apoptosis in mice with acute ocular hypertension (AOH). AOH mice were established, and Cav-1 was intravitreally injected. Retinal microglia and RGCs were isolated from neonatal mice. TUNEL staining, hematoxylin-eosin staining, immunohistochemistry, flow cytometry, PCR and western blotting were used to observe the effect of Cav-1 on RGCs and mouse retinas. The thickness of the whole retina and the inner retinal sublayer decreased significantly, retinal cell apoptosis increased after AOH injury, and Cav-1 treatment reversed the effect of AOH injury. In addition, Cav-1 treatment promoted the conversion of proinflammatory M1 microglia to anti-inflammatory M2 microglia. Microglia and RGCs were isolated from neonatal mice. Cav-1 protects RGCs from OGD/R-induced injury by changing the polarization status of retinal microglia in vitro. Further studies revealed that Cav-1 activated the Akt/PTEN signaling pathway and inhibited TLR4. Our study provides evidence that Cav-1 may be a promising therapeutic target for glaucoma. [ABSTRACT FROM AUTHOR]

Conventional gene therapy involving supplementation only treats loss-of-function diseases and is limited by viral packaging sizes, precluding therapy of large genes. The discovery of CRISPR/Cas has led to a paradigm shift in the field of genetic therapy, with the promise of precise gene editing, thus broadening the range of diseases that can be treated. The initial uses of CRISPR/Cas have focused mainly on gene editing or silencing of abnormal variants via utilising Cas endonuclease to trigger the target cell endogenous non-homologous end joining. Subsequently, the technology has evolved to modify the Cas enzyme and even its guide RNA, leading to more efficient editing tools in the form of base and prime editing. Further advancements of this CRISPR/Cas technology itself have expanded its functional repertoire from targeted editing to programmable transactivation, shifting the therapeutic focus to precise endogenous gene activation or upregulation with the potential for epigenetic modifications. In vivo experiments using this platform have demonstrated the potential of CRISPR-activators (CRISPRa) to treat various loss-of-function diseases, as well as in regenerative medicine, highlighting their versatility to overcome limitations associated with conventional strategies. This review summarises the molecular mechanisms of CRISPRa platforms, the current applications of this technology in vivo , and discusses potential solutions to translational hurdles for this therapy, with a focus on ophthalmic diseases. • Conventional exogeneous gene replacement cannot be used to treat inherited ocular conditions caused by large genes. • CRISPR/Cas technologies expand the treatment repertoire via specifically editing or knocking out specific mutations. • CRISPR activation can supplement haploinsufficient conditions and activate paralogs of large mutant genes. [ABSTRACT FROM AUTHOR]

In this paper, we propose a self-supervised CNN-GCN hybrid network (SCGHNet) based on latent graph representation by combining a convolutional neural network (CNN) and a graph convolutional network (GCN), and the Self-Supervised Learning (SSL) is achieved by collaborative tasks. We propose three components for the latent graph representation, including self-attention feature extraction module (SAFEM), latent instance graph representation (LIGR) and latent adaptable softmax (LASoftmax). The proposed SAFEM is used to extract the local and global features from retinal images to satisfy the requirement of the multiscale observation of pathologies. The proposed LIGR is used to explore the relationships among retinal images and promote the concentration of similar samples. The proposed LASoftmax is used to improve the optimization solution. Benefiting from the LASoftmax with LIGR, the latent graph representation can be used to improve the collaborative tasks, enlarge the distance between positvie and negative samples, and obtain more accurate retinal disease diagnosis. In the experiments, our model achieves the AUC of 79.5% and the accuracy of 88.5% for the iChanllenge-AMD dataset. The proposed model outperforms other state-of-the-art SSL models in retinal disease diagnosis of age-related macular degeneration (AMD) and pathological myopia (PM), and shows generalization with outstanding diagnosis performance. [ABSTRACT FROM AUTHOR]

Previously, researchers have employed Lipid nanoparticles (LNPs) to directly encapsulate medicines. In the realm of gene therapy, researchers have begun to employ lipid nanoparticles to encapsulate nucleic acids such as messenger RNA, small interfering RNA, and plasmid DNA, which are known as nucleic acid lipid nanoparticles. Recent breakthroughs in LNP-based medicine have provided significant prospects for the treatment of ocular disorders, such as corneal, choroidal, and retinal diseases. The use of LNP as a delivery mechanism for medicines and therapeutic genes can increase their effectiveness while avoiding undesired immune reactions. However, LNP-based medicines may pose ocular concerns. In this review, we discuss the general framework of LNP. Additionally, we review adjustable approaches and evaluate their possible risks. In addition, we examine newly described ocular illnesses in which LNP was utilized as a delivery mechanism. Finally, we provide perspectives for solving these potential issues. [Display omitted] • This paper reviewed the structure, function, synthesis method and administration mode of LNP. • This article focuses on describing the role of LNP in the treatment of eye diseases. • This review presents opportunities and challenges for the application of LNP inophthalmology. [ABSTRACT FROM AUTHOR]

Achromatopsia is an inherited retinal disease that affects 1 in 30,000–50,000 individuals and is characterised by an absence of functioning cone photoreceptors from birth. This results in severely reduced visual acuity, no colour vision, marked sensitivity to light and involuntary oscillations of the eyes (nystagmus). In most cases, a single gene mutation prevents normal development of cone photoreceptors, with mutations in the CNGB3 or CNGA3 gene being responsible for ∼80 % of all patients with achromatopsia. There are a growing number of studies investigating recovery of cone function after targeted gene therapy. These studies have provided some promise for patients with the CNGA3 mutation, but thus far have found limited or no recovery for patients with the CNGB3 mutation. Here, we developed colour-calibrated visual stimuli designed to isolate cone photoreceptor responses. We combined these with adapted fMRI techniques and pRF mapping to identify if cortical responses to cone-driven signals could be detected in 9 adult patients with the CNGB3 mutation after receiving gene therapy. We did not detect any change in brain activity after gene therapy when the 9 patients were analysed as a group. However, on an individual basis, one patient self-reported a change in colour perception, corroborated by improved performance on a psychophysical task designed to selectively identify cone function. This suggests a level of cone sensitivity that was lacking pre-treatment, further supported by a subtle but reliable change in cortical activity within their primary visual cortex. [Display omitted] • Gene therapy is providing new hope for patients with achromatopsia. • Colour calibrated visual stimuli can be used to probe individual photoreceptor types. • fMRI and pRF mapping can reveal retinotopic responses to rod and cone photoreceptors. • fMRI and pRF mapping can be used to detect change in cortical activity after gene therapy. • Evidence that gene therapy can restore cone function in Achromatopsia due to CNGB3 mutation. [ABSTRACT FROM AUTHOR]

Retinal fundus imaging contributes to monitoring the vision of patients by providing views of the interior surface of the eyes. Machine learning models greatly aided ophthalmologists in detecting retinal disorders from color fundus images. Hence, the quality of the data is pivotal for enhancing diagnosis algorithms, which ultimately benefits vision care and maintenance. To facilitate further research in this domain, we introduce the Eye Disease Diagnosis and Fundus Synthesis (EDDFS) dataset, comprising 28,877 fundus images. These include 15,000 healthy samples and a diverse range of images depicting various disorders such as diabetic retinopathy, age-related macular degeneration, glaucoma, pathological myopia, hypertension retinopathy, retinal vein occlusion, and Laser photocoagulation. In addition to providing the dataset, we propose a Transformer-joint convolution network for automated eye disease screening. Firstly, a co-attention structure is integrated to capture long-range attention information along with local features. Secondly, a cross-stage feature fusion module is designed to extract multi-level and disease-related information. By leveraging the dataset and our proposed network, we establish benchmarks for disease screening and grading tasks. Our experimental results underscore the network's proficiency in both multi-label and single-label disease diagnosis, while also showcasing the dataset's capability in supporting fundus synthesis. (The dataset and code will be available on https://github.com/xia-xx-cv/EDDFS_dataset.) [ABSTRACT FROM AUTHOR]

Juvenile X-linked retinoschisis (JXR), the most common inherited retinal disorder in young males, presents with a wide range of phenotypic variations. Acute angle closure in children with JXR has been reported in the literature only once before. We present a case of acute-angle closure, temporally associated with pharmacologic dilation, in a 12-year-old boy with JXR. [ABSTRACT FROM AUTHOR]

An optical coherence tomography images are used to visualize the retinal micro-architecture and perform an easy scan of its abnormalities. In this paper, a coherent convolutional neural network is proposed for four-class classification of retinal diseases and able to detect neovascularization (CNV), diabetic macular edema (DME), DRUSEN, and NORMAL class label in the OCT images. The new proposal overcomes three of the challenges by (1) more profoundly detect the irregular patterns of each class of retinal disease (2) manages consistency between input and output of the network (3) cohesively bound the layers of the network for easy flow of image features. The proposed convolution neural network model is having five layers. In order to adopt coherent behavior, the proposed model inculcating the batch normalization layer along with the every activity layer and obtained an accuracy of 97.19% for retinal disease detection. Moreover, the performance of this method is remarkably good as compared to other standard deep learning methods. This proposal is a promising step in revolutionizing the present scenario of ocular diagnostic system and has the potential to generate a significant clinical impact. [ABSTRACT FROM AUTHOR]

The COVID-19 pandemic disrupted the regular injections of anti-vascular endothelial growth factor (anti-VEGF) in patients with various retinal diseases globally. It is unclear to what extent delayed anti-VEGF injections have worsened patients' visual acuity. We performed a meta-analysis to assess the impact of delayed anti-VEGF injections on the best-corrected visual acuity (BCVA) in patients with neovascular age-related macular degeneration (nAMD), retinal vein occlusion (RVO), and diabetic macular edema (DME). We searched four computer databases (EMBASE, MEDLINE, Web of Science, Scopus) from inception to January 5, 2022. Data were pooled using the random-effects model. Results were reported by less than 4 months and 4 months or longer for the time period between the first injection during the pandemic and the last pre-pandemic injection. All BCVA measures were converted to the logarithm of the minimum angle of resolution (logMAR) for analyses. Among patients who received injections 4 months or longer apart, the mean difference in BCVA was 0.10 logMAR (or 5 ETDRS letters) (95% confidence interval [CI] 0.06∼0.14) for nAMD patients, 0.01 logMAR (or∼ 1 ETDRS letter) (95% CI -0.25∼0.27) for RVO patients, and 0.03 logMAR (or ∼1 ETDRS letters) (95% CI -0.06∼0.11) for DME patients. These results suggest that patients with nAMD needing scheduled anti-VEGF injections may require priority treatment over those with RVO and DME in the event of disturbed anti-VEGF injections from COVID-19 lockdowns or similar scenarios. [ABSTRACT FROM AUTHOR]

Retinal neovascularization is typically accompanied by hypoxia-induced oxidative injury in the vascular system. This study developed an ultrasmall (6–8 nm) platinum (Pt) nanozyme loaded mitochondria-targeted liposome (Pt@MitoLipo) to alleviate hypoxia and eliminate excess reactive oxygen species (ROS) for effective retinal neovascularization disease therapy. Pt nanozymes possess superoxide dismutase (SOD) and catalase (CAT) cascade enzyme-like activities, which convert cytotoxic O 2 •− and H 2 O 2 into nontoxic H 2 O and O 2. Triphenylphosphonium (TPP)-conjugated liposomes were coated on the surface of Pt nanozymes to increase their biocompatibility and help them penetrate the cell membrane, escape from the lysosomal barrier, and target mitochondria, thus achieving precise scavenging of mitochondrial O 2 •− and relief from hypoxia. Using an oxygen-induced retinopathy (OIR) mouse model, we demonstrated that Pt@MitoLipo nanozymes significantly suppressed hypoxia-induced abnormal neovascularization and facilitated avascular normalization of the retina in vivo without any noticeable toxicity. This study provides a promising way to break through cellular barriers and target scavenging mitochondrial O 2 •− and illustrates the potential of ROS-scavenging and hypoxia relief in retinal neovascularization disease therapy. [Display omitted] [ABSTRACT FROM AUTHOR]