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Purpose: Inherited retinal disease (IRD) causes progressive loss of visual function, degenerating towards complete blindness. Economic evaluation of gene therapies for rare forms of genetic IRDs have had to rely on health-related quality of life (HR-QoL) estimates from other diseases because there is limited data available for such a rare condition. This study aimed to estimate Australian societal-based utility values for IRD health states that can be used in cost-utility analyses (CUA) using a time trade-off (TTO) protocol adapted from a UK study. Methods: The EuroQol Valuation Technology (EQVT) protocol composite TTO (cTTO) framework was followed, which includes worse-than-death (WTD) states and quality control (QC) measures. Preferences were collected from a general population sample of 110 Australian adult participants. Five health state vignettes from the UK study which had been validated with patients and clinicians were presented randomly to participants during videoconferencing (VC) interviews with one of four interviewers. Technical and protocol feasibility were assessed in a pilot of 10 interviews. QC measures were used to monitor interviewers' performance during the study. Results: One participant withdrew consent. The final analysis was conducted on 109 respondents (including 4 non-traders). The average time to complete the interview was 44.2 minutes (SD 8.7). Participants reported mean visual analogue scale (VAS) scores between 63.15 for 'moderate impairment' and 17.98 for 'hand motion' to 'no light perception'. Mean health state utilities (HSU) varied between 0.76 (SD 0.26) in 'moderate impairment', and 0.20 (SD 0.58) in 'hand motion' to 'no light perception'. Of all HSU evaluations, 14% were considered WTD which most commonly occurred in the most severe visually impaired health state. Conclusion: This study provides valuable information on HSUs across a range of IRD health states from the Australian general population perspective. The utilities obtained in this study can be used as inputs into CUA of IRD therapies. [ABSTRACT FROM AUTHOR]

The family of pro-inflammatory and pro-angiogenic chemokines including Interleukin-8 (IL-8, aka CXCL8) and its homologues (CXCL1,2,3,5,6, and 7) exhibit promiscuous binding and activation of several G-protein-coupled receptors (i.e., CXCR2, CXCR1, and the atypical chemokine receptor (ACKR1)). A high proportion of their biological activity is attributed to CXCR2 activation, thus many CXCR2 inhibitors are in clinical trials for several chronic diseases. However, CXCR2 inhibition is often only investigated acutely in these trials or in Cxcr2−/− mice grown in gnotobiotic conditions. Since humans do not live in germ-free environments, our first goal is to highlight novel retinal and systemic observations in Cxcr2−/− mice grown in non-gnotobiotic conditions that suggest potential harmful consequences of long-term CXCR2 deficiency or blockade. Beyond confirmation of circulating blood/immune cell-related phenotypes, we report novel findings in Cxcr2−/− mice including: (1) delayed dye transit to the retinal vasculature, (2) alterations in the density and distribution of retinal vessels, astrocytes and microglia, (3) decreased electroretinogram a- and b-wave amplitudes, (4) reduced visual acuity, and (5) increased polymorphonuclear cell accumulation in vascular lumina abutting venular walls in the retina and in vital non-ocular tissues (lung and liver). Furthermore, PheWAS of CXCR2 CXCR1, and ACKR1 gene variants using data from UK Biobank participants suggest clinical associations with both retinal and vascular disease phenotypes. We conclude that chronic CXCR2 deficiency in mice contributes to functional damage to the retina and that the long-term safety of CXCR1/2 inhibitors designed for chronic use in humans should be explored before clinical adoption to safeguard sight and overall vascular health. [ABSTRACT FROM AUTHOR]

Recently, a founder Alu insertion in exon 4 of RP1 was detected in Japanese and Korean patients with inherited retinal diseases (IRDs). However, carrier frequency and diagnostic challenges for detecting AluY insertion are not established. We aim to investigate the frequency of AluY in individuals with or without IRDs and to overcome common diagnostic pitfalls associated with AluY insertion. A total of 1,072 subjects comprising 411 patients with IRD (IRD group) and 661 patients with other suspected Mendelian genetic disease (non-IRD group) was screened for AluY insertion. Targeted panel sequencing and whole-genome sequencing were used for detection of AluY insertion, and an optimized allele-specific PCR (AS-PCR) was used for validation. The AluY insertion was detected in 1.5% in IRD group (6/411). The AluY insertion was not observed in non-IRD group (0/661). All patients with AluY were confirmed to have RP1 pathogenic variants on the paired allele. We identified AluY allele dropout leading to false homozygosity for c.4196del pathogenic variant in Sanger sequencing. The allelic relationship between variants of RP1 was accurately determined by AluY AS-PCR. Delineating diagnostic challenges of AluY insertion and strategies to avoid potential pitfalls could aid clinicians in an accurate molecular diagnosis for patients with IRD. [ABSTRACT FROM AUTHOR]

Central serous chorioretinopathy (CSCR) is a retinal disease characterised by the accumulation of subretinal fluid, which often resolves spontaneously in acute cases. However, approximately one-third of patients experience recurrences that may cause severe and irreversible vision. This study aimed to identify parameters derived from optical coherence tomography (OCT) that are associated with CSCR recurrence. Our dataset included 5211 OCT scans from 344 eyes of 255 patients diagnosed with CSCR. 178 eyes were identified as recurrent, 109 as non-recurrent, and 57 were excluded. We extracted parameters using artificial intelligence algorithms based on U-Nets, convolutional kernels, and morphological operators. We applied inferential statistics to evaluate differences between the recurrent and non-recurrent groups, and we used a logistic regression predictive model, reporting the coefficients as a measure of biomarker importance. We identified nine predictive biomarkers for CSCR recurrence: age, intraretinal fluid, subretinal fluid, pigment epithelial detachments, choroidal vascularity index, integrity of photoreceptors and retinal pigment epithelium layer, choriocapillaris and choroidal stroma thickness, and thinning of the outer nuclear layer, and of the inner nuclear layer combined with the outer plexiform layer. These results could enable future developments in the automatic detection of CSCR recurrence, paving the way for translational medical applications. [ABSTRACT FROM AUTHOR]

The retina plays a crucial role in processing and decoding visual information, both in normal development and during myopia progression. Recent advancements have introduced a library-independent approach for data-independent acquisition (DIA) analyses. This study demonstrates deep proteome identification and quantification in individual mice retinas during myopia development, with an average of 6,263 ± 86 unique protein groups. We anticipate that the use of a predicted retinal-specific spectral library combined with the robust quantification achieved within this dataset will contribute to a better understanding of the proteome complexity. Furthermore, a comprehensive mice retinal-specific spectral library was generated, encompassing a total identification of 9,401 protein groups, 70,041 peptides, 95,339 precursors, and 761,868 transitions acquired using SWATH-MS acquisition on a ZenoTOF 7600 mass spectrometer. This dataset surpasses the spectral library generated through high-pH reversed-phase fractionation by data-dependent acquisition (DDA). The data is available via ProteomeXchange with the identifier PXD046983. It will also serve as an indispensable reference for investigations in myopia research and other retinal or neurological diseases. [ABSTRACT FROM AUTHOR]

Diabetic retinopathy (DR) is recognized as the most prevalent retinal degenerative disorder. Inflammatory response usually precedes microvascular alteration and is the primary factor of diabetic retinopathy. Activated microglia express many pro-inflammatory cytokines that exacerbate retina inflammation and disruption. In the present study, we found that MSCs alleviated blood–retina barrier (BRB) breakdown in diabetic rats, as evidenced by reduced retinal edema, decreased vascular leakage, and increased occludin expression. The MSC-treated retinal microglia exhibited reduced expression of M1-phenotype markers in the diabetic rats, including inducible nitric oxide synthase (iNOS), CD16, and pro-inflammatory cytokines. On the other hand, MSCs increased the expression of M2-phenotype markers, such as arginase-1 (Arg-1), CD206, and anti-inflammatory cytokines. HMGB1/TLR4 signaling pathway is activated in DR and inhibited after MSC treatment. Consistent with in vivo evidence, MSCs drove BV2 microglia toward M2 phenotype in vitro. Overexpression of HMGB1 in microglia reversed the effects of MSC treatment, suggesting HMGB1/TLR4 pathway is necessary for MSCs' regulatory effects on microglia polarization. Collectively, MSCs exert beneficial effects on DR by polarizing microglia from M1 toward M2 phenotype via inhibiting the HMGB1/TLR4 signaling pathway. [ABSTRACT FROM AUTHOR]

Retinal inflammation is a pivotal characteristic observed in various retinal degenerative disorders, notably age-related macular degeneration (AMD), primarily orchestrated by the activation of microglia. Targeting the inhibition of microglial activation has emerged as a therapeutic focal point. Quercetin (Qu), ubiquitously present in dietary sources and tea, has garnered attention for its anti-neuroinflammatory properties. However, the impact of Qu on retinal inflammation and the associated mechanistic pathways remains incompletely elucidated. In this study, retinal inflammation was induced in adult male C57BL/6 J mice through intraperitoneal administration of LPS. The results revealed that Qu pre-treatment induces a phenotypic shift in microglia from M1 phenotype to M2 phenotype. Furthermore, Qu attenuated retinal inflammation and stabilized the integrity of the blood-retina barrier (BRB). In vitro experiments revealed that Qu impedes microglial activation, proliferation, and migration, primarily via modulation the ERK/STAT3 signaling pathway. Notably, these actions of Qu significantly contributed to the preservation of photoreceptors. Consequently, Qu pre-treatment holds promise as an effective strategy for controlling retinal inflammation and preserving visual function. Exposure to LPS, microglia undergo activation and polarization towards the M1 phenotype. The activation of the cellular ERK/STAT3 signaling pathway resulted in the release of a multitude of cytokines. This cascade disrupts the BRB and damage the photoreceptors. In contrast, Qu intervenes in this process by inhibiting the ERK/STAT3 pathway, facilitating a transition in cellular polarization towards the anti-inflammatory M2 phenotype. [ABSTRACT FROM AUTHOR]

An important abnormality in Optical Coherence Tomography (OCT) images is Hyper-Reflective Foci (HRF). This anomaly can be interpreted as a biomarker of serious retinal diseases such as Age-related Macular Degeneration (AMD) and Diabetic Macular Edema (DME) or the progression of disease from an early stage to a late one. In this paper, a new method is proposed for the identification of HRFs. The new method divides the OCT B-scan into patches and separately verifies each patch to determine whether or not the patch contains an HRF. The procedure of patch verification contains a texture-based framework which assigns appropriate labels according to intensity changes to each column and row. Then, a feature vector is extracted for each patch based on the assigned labels. The feature vectors are utilized in the training step of well-known classifiers like Support Vector Machine (SVM). Then, the classifiers are used to produce the labels for the test OCT images. The new method is evaluated on a public dataset including HRF labels. The experimental results show that the new method is capable of providing outstanding results in terms of speed and accuracy. [ABSTRACT FROM AUTHOR]

Introduction: Digital exclusion is a growing challenge when deploying digital patient care pathways and a potential barrier to widespread implementation, especially in the field of smartphone-based self-monitoring of vision. This retrospective case series seeks to examine the characteristics of individuals who adhere to a smartphone home monitoring programme using the Alleye app for retinal disease, with a focus on digital exclusion, social deprivation and clinical outcomes. Methods: We conducted a retrospective analysis of 89 patients with retinal pathologies including diabetic retinopathy and retinal vein occlusions at Moorfields Eye Hospital participating in an Alleye home monitoring programme between April 2020 and November 2022. Postcodes were used to determine the Digital Exclusion Risk Index (DERI) and the Index of Multiple Deprivation (IMD) rebased for London. Clinical information from the electronic patient record and Alleye app usage data were extracted for each patient. Associations between the DERI/IMD, clinical parameters and app use were examined using multivariable regression models. Results: Mean DERI was 2.56 (standard deviation [SD] = 0.36), IMD was 6.25 (SD = 2.79), visual acuity (VA) in the better eye at study entry was 83.28 Early Treatment Diabetic Retinopathy Study (ETDRS) letters (SD = 7.92), and mean follow-up was 344.46 days (SD = 260.13). During the observation period, 36% received an intravitreal injection (IVI) and VA fell by at least ten letters in approximately one in four patients. In 87.5% of patients requiring IVI, the use of the app increased. We found no association between clinical parameters and programme adherence for DERI or IMD. Conclusions: We found no association between high digital exclusion risk and high social deprivation with monitoring adherence to smartphone-based self-monitoring of vision, contrary to the currently available evidence. This suggests that smartphone-based self-monitoring of vision is accessible to population groups of varying digital exclusion and social deprivation risk, and can be safely employed to monitor clinical progression. [ABSTRACT FROM AUTHOR]

Diabetic Retinopathy (DR) is termed as ever-lasting retinal disorders which can cause loss of vision and even blindness in most of the cases. The procedure to classify the level of severity in DR and is complex process as lesion features are complex to examine. The task of screening needs an effectual detection technique for classifying the subtle pathologies in retina. The deep models is considered as an imperative domain treating the disease caused in eye and help the ophthalmologists to make timely decisions. A new LeNet model is developed with Chronological Rat Swarm Optimization (CRSO) for detecting DR. The first step is the capturing retinal images through fundus photography, which further undergoes pre-processing with median filter. The segmentation is then achieved wherein lesion segmentation is completed with U-Net and blood vessel segmentation is performed with Dense U-Net. From input fundus image, lesion segmented output, and blood vessel segmented output, extraction of essential feature is performed. Finally, DR detection is executed with CRSO-based LeNet. The CRSO-based LeNet attained superior performance with highest accuracy of 89%, NPV of 87.2%, PPV of 87.0%, TNR of 89.0% and TPR of 89.5%. The proposed method is useful in various applications, such as medical applications and healthcare applications. [ABSTRACT FROM AUTHOR]

Purpose: Hydroxychloroquine is currently recommended for the treatment of systemic lupus erythematosus (SLE), but it can cause irreversible retinal toxicity. This study aimed to identify factors associated with early hydroxychloroquine-induced retinal toxicity in patients with SLE from a single centre for 20 years. Methods: SLE patients diagnosed between 1998 and 2017 and followed up for at least 1 year were included. Demographic, clinical, laboratory and therapeutic data were collected from the electronic medical records and retrospectively analysed. Early hydroxychloroquine-induced retinal toxicity was defined as the development of macular toxicity within the first 5 years of hydroxychloroquine treatment. Results: A total of 345 patients followed for a median of 15 years were analysed; 337 (97.7%) patients received hydroxychloroquine, 38 (11.3%) of them presented with retinal toxicity, and 10 (3%) developed early retinal toxicity. These patients had a mean treatment duration of 3.3 years with a mean cumulative dose of 241 g. Patients were diagnosed by visual field (VF) and fundoscopy, and two were also assessed using spectral domain optical coherence tomography (SD-OCT). The median (IQR) age of patients with early toxicity was 56 (51–66) years, and 80% were female. Factors independently associated with early hydroxychloroquine-induced retinal toxicity were lupus anticoagulant positivity (OR 4.2; 95% CI 1.2–15.5) and hypercholesterolaemia (OR 5.6; 95% CI 1.5–21.5). Conclusion: Our results suggest that lupus anticoagulant positivity and hypercholesterolaemia among SLE patients may be risk factors for early hydroxychloroquine-induced retinal toxicity, regardless of the dose or duration of treatment. [ABSTRACT FROM AUTHOR]

Purpose: Leber congenital amaurosis (LCA) is a group of early-onset retinal degenerative disorders, resulting in blindness in children. This study aimed to describe the clinical and genetic characteristics of a cohort of patients with LCA and to investigate the retinal vascular characteristics in LCA patients. Methods: Fifty-two children with LCA were included in the study. All patients underwent detailed ocular examinations. Electroretinography (ERG) was used to evaluate the retinal function. Optical coherence tomography (OCT) was used to assess the structure change of the retina for those patients who were able to cooperate very well. Panel-based next-generation sequencing was performed to identify pathogenic variants in genes associated with LCA. Diameters of the retinal vessels were measured using the EVision AI screening system with an artificial intelligence (AI) technique. An ultrasound Doppler was used to evaluate hemodynamic parameters, including peak systolic velocity (PSV), resistive index (RI), and pulsatility index (PI), in the ophthalmic, central retinal, posterior ciliary, carotid, and internal carotid as well as external carotid arteries in 12 patients aged from 3 to 14 years. Results: We detected 75 pathogenic variants from ten genes of RPGRIP1, CEP290, GUCY2D, LCA5, AIPL1, CRB1, RPE65, CRX, RDH12, and TULP1, including 29 novel and 36 previously reported variants in 52 affected children with LCA, with the highest detective rate in RPGRIP1 (26.9%). Fundus appearance is diverse in patients with LCA, ranging from normal to severe peripheral or central retinopathy. Retinal vasculature was evaluated in 12 patients with different gene variants, showing narrowed arteries with an average diameter of 43.6 ± 3.8 μm compared to that of 51.7 ± 2.6 μm in the normal controls (P < 0.001, n = 12). Meanwhile, their hemodynamic parameters were changed as well in the ophthalmic artery (OA), with a decreased PSV (P = 0.0132, n = 12) and slightly increased PI (P = 0.0488, n = 12) compared to the normal controls. However, the hemodynamic parameters did not change significantly in the other vessels. Conclusions: Blood supply to the eyeball is predicted to be reduced in patients with LCA, presumably due to photoreceptor cell degeneration. The novel identified variants will expand the spectrum of variants in LCA-related genes and be useful for studying the molecular mechanisms of LCA. [ABSTRACT FROM AUTHOR]

Gene therapies have emerged as promising treatments in clinical development for various retinal disorders, offering hope to patients with inherited degenerative eye conditions. Several gene therapies have already shown remarkable success in clinical trials, with significant improvements observed in visual acuity and the preservation of retinal function. A multitude of gene therapies have now been delivered safely in human clinical trials for a wide range of inherited retinal disorders but there are some gaps in the reported trial data. Some of the most exciting treatment options are not under peer review and information is only available in press release form. Whilst many trials appear to have delivered good outcomes of safety, others have failed to meet primary endpoints and therefore not proceeded to phase III. Despite this, such trials have enabled researchers to learn how best to assess and monitor patient outcomes, which will guide future trials to greater success. In this review, we consider recent and ongoing clinical trials for a variety of potential retinal gene therapy treatments and discuss the positive and negative issues related to these trials. We discuss the treatment potential following clinical trials as well as the potential risks of some treatments under investigation. As these therapies continue to advance through rigorous testing and regulatory approval processes, they hold the potential to revolutionise the landscape of retinal disorder treatments, providing renewed vision and enhancing the quality of life for countless individuals worldwide. [ABSTRACT FROM AUTHOR]

Objectives: To determine whether the types and rates of post-surgical complications associated with the Port Delivery System with ranibizumab (PDS) are comparable with those reported for other ocular implants that cross the sclera. Methods: Systematic literature reviews were conducted to determine the long-term (≥ 18-month) safety of ocular implants that cross the sclera in clinical trials and real-world studies. Complication types and rates were compared with those reported for the PDS in phase III clinical trials (Archway, Pagoda, and Pavilion). Results: Sixteen clinical trials (24 publications) and 43 real-world studies were identified reporting 30 complications in eyes with 15 implant types and 8 ocular diseases. Implants were associated with an acceptable, well-characterized safety profile, with most complications resolving spontaneously or with treatment. Device-related complications were reported in 0.7% (0.0–5.0%) of study eyes in clinical trials and 1.3% (0.0–14.5%) of eyes in real-world studies. Rates of conjunctival complications were 2.1% (0.0–22.8%) and 2.2% (0.9–4.6%), respectively. The overall types and rates of adverse events of special interest reported for the PDS in phase III trials (cataract, conjunctival bleb, vitreous hemorrhage, conjunctival erosion, conjunctival retraction, endophthalmitis, implant dislocation, retinal detachment, and hyphema) were within the ranges reported for other ocular implants. Conclusions: The rates of complications reported in phase III clinical trials for the PDS were within the ranges reported for other ocular implants that cross the sclera. This suggests that the long-term safety of the PDS is consistent with other ocular devices established in ophthalmology clinical practice. Trial Registration: PROSPERO international prospective register of systematic reviews: CRD5202234129, CRD42022343129. [ABSTRACT FROM AUTHOR]

Carbon quantum dots (CQDs), an emerging nanomaterial, are gaining attention in ophthalmological applications due to their distinctive physical, chemical, and biological characteristics. For example, their inherent fluorescent capabilities offer a novel and promising alternative to conventional fluorescent dyes for ocular disease diagnostics. Furthermore, because of the excellent biocompatibility and minimal cytotoxicity, CQDs are well-suited for therapeutic applications. In addition, functionalized CQDs can effectively deliver drugs to the posterior part of the eyeball to inhibit neovascularization. This review details the use of CQDs in the management of ophthalmic diseases, including various retinal diseases, and ocular infections. While still in its initial phases within ophthalmology, the significant potential of CQDs for diagnosing and treating eye conditions is evident. [ABSTRACT FROM AUTHOR]

Cell adhesion to the extracellular matrix and its natural outcome of cell spreading, along with the maintenance of barrier activity, are essential behaviors of epithelial cells, including retinal pigment epithelium (RPE). Disruptions in these characteristics can result in severe vision-threatening diseases such as diabetic macular edema and age-related macular degeneration. However, the precise mechanisms underlying how RPE cells regulate their barrier integrity and cell spreading are not fully understood. This study aims to elucidate the relative importance of upper glycolytic components in governing these cellular behaviors of RPE cells. Electric Cell-Substrate Impedance Sensing (ECIS) technology was utilized to assess in real-time the effects of targeting various upper glycolytic enzymes on RPE barrier function and cell spreading by measuring cell resistance and capacitance, respectively. Specific inhibitors used included WZB117 for Glut1 inhibition, Lonidamine for Hexokinase inhibition, PFK158 for PFKFB3/PFK axis inhibition, and TDZD-8 for Aldolase inhibition. Additionally, the viability of RPE cells was evaluated using a lactate dehydrogenase (LDH) cytotoxicity assay. The most significant decrease in electrical resistance and increase in capacitance of RPE cells were observed due to dose-dependent inhibition of Glut1 using WZB117, as well as Aldolase inhibition with TDZD-8. LDH level analysis at 24–72 h post-treatment with WZB117 (1 and 10 μM) or TDZD-8 (1 μM) showed no significant difference compared to the control, indicating that the disruption of RPE functionality was not attributed to cell death. Lastly, inhibition of other upper glycolytic components, including PFKFB3/PFK with PFK158 or Hexokinase with Lonidamine, did not significantly affect RPE cell behavior. This study provides insights into the varied roles of upper glycolytic components in regulating the functionality of RPE cells. Specifically, it highlights the critical roles of Glut1 and Aldolase in preserving barrier integrity and promoting RPE cell adhesion and spreading. Such understanding will guide the development of safe interventions to treat RPE cell dysfunction in various retinal disorders. [ABSTRACT FROM AUTHOR]

Pathologic myopia (PM) is the critical factor of irreversible visual artifacts and puts patients at risk of other severe retinal diseases such as glaucoma. Early intervention can help control the disease's progression and prevent vision loss. Due to its prevalence worldwide, automated detection of PM and its severity is essential. Deep learning-aided diagnosis has proven itself in the field of ophthalmology. The proposed study automatically classifies pathologic and non-pathologic myopia from the fundus images using a guided mini U-Net (GM-U-Net) for feature extraction integrated with a customized convolutional neural network (PMNet) explicitly designed for fundus images. The proposed GM-U-Net allows a deeper network with significantly reduced parameters than conventional U-Net for feature extraction. The proposed PMNet utilizes the features extracted by GM-U-Net to discriminate between PM and a normal retina image. The PMNet classification performance is compared with the other transfer learning models based on the features provided by the GM-U-Net. The combination of GM-U-Net and PMNet outperforms the different models for PM classification. In-depth ablation tests are conducted to realize the current form of PMNet and test its effectiveness. PMNet achieves an accuracy of 90%, average sensitivity of 93%, and specificity of 97% for binary class on the test set, demonstrating it as a valuable tool for early PM detection. Further, to localize the prominent regions in the images, colored heatmap techniques are applied to visualize the affected areas with a hotter color. [ABSTRACT FROM AUTHOR]

Retinal diseases that are not treated in time can cause irreversible, permanent damage, including blindness. Although a patient may suffer from more than one retinal disease at the same time, most of the studies focus on the diagnosis of a single disease only. Therefore, to detect multi-label retinal diseases from color fundus images, we developed an end-to-end deep learning architecture that combines the EfficientNet backbone with the ML-Decoder classification head in this study. While EfficientNet provides powerful feature extraction with fewer parameters via compound scaling, ML-Decoder further improves efficiency and flexibility by reducing quadratic dependency to a linear one and using a group decoding scheme. Also, with the use of sharpness-aware minimization (SAM) optimizer, which minimizes loss value and loss sharpness simultaneously, higher accuracy rates have been reached. In addition, a significant increase in EfficientNet performance is achieved by using image transformations and concatenation together. During the training phase, the random application of the image transformations allows for increasing the image diversity and makes the model more robust. Besides, fusing fundus images of left and right eyes at the pixel level extracts useful information about their relationship. The performance of the final model was evaluated on the publicly available Ocular Disease Intelligent Recognition (ODIR) dataset consisting of 10,000 fundus images, and superior results were obtained in all test set scenarios and performance metrics than state-of-the-art methods. The best results we obtained in the threefold cross-validation scenario for the kappa, F1, and AUC scores are 68.96%, 92.48%, and 94.80%, respectively. Moreover, it can be considered attractive in terms of floating point operations per second (FLOP) and a number of parameters. [ABSTRACT FROM AUTHOR]

Introduction: SB15 is a proposed biosimilar product of reference aflibercept (Eylea®), an approved biological drug product for retinal diseases including neovascular age-related macular degeneration (nAMD). This study aimed to assess the analytical similarity between SB15 and its commercially available reference product (RP) sourced from the United States (US-aflibercept) and European Union (EU-aflibercept) in terms of structural, physicochemical, and biological properties. Methods: A panel of state-of-the-art analytical methods was used for the comprehensive characterization of SB15 and US/EU-aflibercept. In terms of the structural and physicochemical properties, primary structure; post-translational modifications (PTM); higher-order structure; purity and impurities; charge variants; and glycosylation were compared. In addition, biological characterization including mechanism of action (MoA)-related and Fc-related biological activities was conducted. Results: Analytical similarity between SB15 and US/EU-aflibercept was demonstrated. The primary and higher-order structure of SB15 was confirmed to be comparable to that of US/EU-aflibercept. In addition, there were no meaningful differences in the physicochemical properties in terms of size and charge heterogeneity between SB15 and its RP. SB15 and RP were similar in biological activities including MoA-related binding activities, potencies, and Fc-related biological functions. Consequently, SB15 was confirmed to be highly similar to US/EU-aflibercept. Conclusions: Based on a comprehensive analytical similarity assessment of structural, physicochemical, and biological properties, SB15 was demonstrated to be highly similar to US/EU-aflibercept RP, supporting safe and effective use of SB15. [ABSTRACT FROM AUTHOR]

Branch retinal vein occlusion (BRVO) is the most prevalent retinal vascular disease that constitutes a threat to vision due to increased venous pressure caused by venous effluent in the space, leading to impaired visual function. Optical Coherence Tomography Angiography (OCTA) is an innovative non-invasive technique that offers high-resolution three-dimensional structures of retinal blood vessels. Most publicly available datasets are collected from single visits with different patients, encompassing various eye diseases for distinct tasks and areas. Moreover, due to the intricate nature of eye structure, professional labeling not only relies on the expertise of doctors but also demands considerable time and effort. Therefore, we have developed a BRVO-focused dataset named Soul (Source of ocular vascular) and propose a human machine collaborative annotation framework (HMCAF) using scrambled retinal blood vessels data. Soul is categorized into 6 subsets based on injection frequency and follow-up duration. The dataset comprises original images, corresponding blood vessel labels, and clinical text information sheets which can be effectively utilized when combined with machine learning. [ABSTRACT FROM AUTHOR]

Image segmentation is a crucial task in computer vision and image processing, with numerous segmentation algorithms being found in the literature. It has important applications in scene understanding, medical image analysis, robotic perception, video surveillance, augmented reality, image compression, among others. In light of this, the widespread popularity of deep learning (DL) and machine learning has inspired the creation of fresh methods for segmenting images using DL and ML models respectively. We offer a thorough analysis of this recent literature, encompassing the range of ground-breaking initiatives in semantic and instance segmentation, including convolutional pixel-labeling networks, encoder-decoder architectures, multi-scale and pyramid-based methods, recurrent networks, visual attention models, and generative models in adversarial settings. We study the connections, benefits, and importance of various DL- and ML-based segmentation models; look at the most popular datasets; and evaluate results in this Literature. [ABSTRACT FROM AUTHOR]

Age-related macular degeneration (AMD) is a common retinal neurodegenerative disease among the elderly. Neovascular AMD (nAMD), a leading cause of AMD-related blindness, involves choroidal neovascularization (CNV), which can be suppressed by anti-angiogenic treatments. However, current CNV treatments do not work in all nAMD patients. Here we investigate a novel target for AMD. Granzyme B (GzmB) is a serine protease that promotes aging, chronic inflammation and vascular permeability through the degradation of the extracellular matrix (ECM) and tight junctions. Extracellular GzmB is increased in retina pigment epithelium (RPE) and mast cells in the choroid of the healthy aging outer retina. It is further increased in donor eyes exhibiting features of nAMD and CNV. Here, we show in RPE-choroidal explant cultures that exogenous GzmB degrades the RPE-choroid ECM, promotes retinal/choroidal inflammation and angiogenesis while diminishing anti-angiogenic factor, thrombospondin-1 (TSP-1). The pharmacological inhibition of either GzmB or mast-cell degranulation significantly reduces choroidal angiogenesis. In line with our in vitro data, GzmB-deficiency reduces the extent of laser-induced CNV lesions and the age-related deterioration of electroretinogram (ERG) responses in mice. These findings suggest that targeting GzmB, a serine protease with no known endogenous inhibitors, may be a potential novel therapeutic approach to suppress CNV in nAMD. [ABSTRACT FROM AUTHOR]

Introduction: SB11 (Byooviz™; Samsung Bioepis Co., Ltd.) is a ranibizumab (Lucentis®; Genentech, Inc.) biosimilar targeting vascular endothelial growth factor A for the treatment of retinal diseases. The pre-filled syringe (PFS) presentation of SB11 offers an alternative administration method to the vial, with the potential for enhanced safety and efficient syringe preparation. The objective of this study was to assess the ability of healthcare professionals (HCPs) to follow the instructions for use to prepare and administer SB11 PFS intravitreal (IVT) injections to patients with neovascular age-related macular degeneration (nAMD) or macular edema secondary to retinal vein occlusion (RVO). Methods: This study was an open-label, single-arm, single-dose clinical study to evaluate the usability of the SB11 PFS in patients with nAMD or macular edema secondary to RVO. Four HCPs prepared and administered 0.5 mg SB11 PFS IVT injections to 34 patients. Product use task completion (12 tasks in total) was assessed by independent observers. Safety was assessed up to 7 days after injection of the investigational product. Results: A total of 34 patients were enrolled and completed the study. All 12 tasks were successfully completed in 34 (100%) patients without a use-related failure. Most patients (32 patients, 94.1%) experienced no adverse events (AEs), whereas 2 (5.9%) patients experienced three treatment-emergent AEs (TEAEs) which were mild to moderate in severity. There were no severe or serious TEAEs reported during the study. Conclusions: This study showed that HCPs were able to successfully prepare and administer the SB11 PFS via IVT injection. No unexpected safety issues were identified. The SB11 PFS is a promising alternative for therapeutic administration of SB11 in patients with retinal disease. Trial Registration: ClinicalTrials.gov identifier NCT06176963; EudraCT number 2021-003566-12. [ABSTRACT FROM AUTHOR]

Introduction: SB15 is a proposed biosimilar product of reference aflibercept (Eylea®), an approved biological drug product for retinal diseases including neovascular age-related macular degeneration (nAMD). This study aimed to assess the analytical similarity between SB15 and its commercially available reference product (RP) sourced from the United States (US-aflibercept) and European Union (EU-aflibercept) in terms of structural, physicochemical, and biological properties. Methods: A panel of state-of-the-art analytical methods was used for the comprehensive characterization of SB15 and US/EU-aflibercept. In terms of the structural and physicochemical properties, primary structure; post-translational modifications (PTM); higher-order structure; purity and impurities; charge variants; and glycosylation were compared. In addition, biological characterization including mechanism of action (MoA)-related and Fc-related biological activities was conducted. Results: Analytical similarity between SB15 and US/EU-aflibercept was demonstrated. The primary and higher-order structure of SB15 was confirmed to be comparable to that of US/EU-aflibercept. In addition, there were no meaningful differences in the physicochemical properties in terms of size and charge heterogeneity between SB15 and its RP. SB15 and RP were similar in biological activities including MoA-related binding activities, potencies, and Fc-related biological functions. Consequently, SB15 was confirmed to be highly similar to US/EU-aflibercept. Conclusions: Based on a comprehensive analytical similarity assessment of structural, physicochemical, and biological properties, SB15 was demonstrated to be highly similar to US/EU-aflibercept RP, supporting safe and effective use of SB15. [ABSTRACT FROM AUTHOR]

Nanomedicine has the potential to increase the biostability of drugs to treat retinal diseases, improving their performance and decreasing the required number of intravitreal injections. However, accurate pharmacokinetic studies of these nanoparticle-drug conjugates, nanoparticle motion across the vitreous humour and interaction with the retinal cell layers still need to be investigated. Existing nanoparticle tracking techniques require fluorescent labels, which can impact cytotoxicity, nanoparticles' motion, protein interactions, and cell internalization. In this study, a real-time label-free tracking technology, for single nanoparticles in an optical microscope based on the optical phenomena of caustics, was used to characterise the diffusion of nanoparticles in agar-hyaluronic acid hydrogels, previously validated as vitreous humour substitutes for in vitro models. The results demonstrated that the diffusion of nanoparticles through these hydrogels was heterogeneous, and that nanoparticle size had an important role in nanoparticle distribution across and within in vitro vitreous substitutes. These findings suggest that nanoparticle diameter is a critical parameter for designing novel therapeutics for retinal diseases. Moreover, nanoparticle charge did not affect nanoparticle diffusion or distribution in these synthetic hydrogels. The use of caustics in optical microscopy has been demonstrated to be a reproducible, inexpensive technique for screening novel therapeutics in eye in vitro models. [ABSTRACT FROM AUTHOR]

The development of treatments targeting the vascular endothelial growth factor (VEGF) signaling pathways have traditionally been firstly investigated in oncology and then advanced into retinal disease indications. Members of the VEGF family of endogenous ligands and their respective receptors play a central role in vasculogenesis and angiogenesis during both development and physiological homeostasis. They can also play a pathogenic role in cancer and retinal diseases. Therapeutic approaches have mostly focused on targeting VEGF-A signaling; however, research has shown that VEGF-C and VEGF-D signaling pathways are also important to the disease pathogenesis of tumors and retinal diseases. This review highlights the important therapeutic advances and the remaining unmet need for improved therapies targeting additional mechanisms beyond VEGF-A. Additionally, it provides an overview of alternative VEGF-C and VEGF-D signaling involvement in both health and disease, highlighting their key contributions in the multifactorial pathophysiology of retinal disease including neovascular age-related macular degeneration (nAMD). Strategies for targeting VEGF-C/-D signaling pathways will also be reviewed, with an emphasis on agents currently being developed for the treatment of nAMD. [ABSTRACT FROM AUTHOR]

Introduction: Neovascular age-related macular degeneration (nAMD) is a progressive retinal disease that causes severe and irreversible vision loss. The disease can therefore have a significant impact on the life of patients' and their families. The aim of this study was to evaluate the socio-economic burden of nAMD in Spain. Methods: The annual cost per patient with nAMD was estimated for the first, second, and third year (or beyond) of treatment since diagnosis. Several cost categories were considered including direct healthcare costs (DHC), direct non-healthcare costs (DNHC), labor productivity losses (LPL), and intangible costs (IC) related to loss of quality of life. The average annual cost per patient was estimated by assigning a unit price or financial proxy to the resources consumed per patient. Reference year of costs was 2021. Results: The mean annual cost of nAMD was estimated at €17,265, €15,403, and €14,465 per patient in the first, second, and third year of treatment after diagnosis. There was an additional one-off cost of €744 associated with the diagnosis of nAMD. DHC accounted for most of the total annual cost per patient independent of the year of treatment since diagnosis (48% in year 1; 42% in year 2; 39% in year 3). Similarly, DNHC had an important contribution to the total costs (32% in year 1; 35% in year 2; 37% in year 3), followed by IC (20% in year 1; 23% in year 2; 24% in year 3), while the contribution of patients' LPL was minimal. Conclusion: This study estimated a high economic burden associated with nAMD for patients and their families, the healthcare system, and society at large. There is a need to improve the management of these patients to reduce the impact of nAMD disease progression. [ABSTRACT FROM AUTHOR]

Optical coherence tomography (OCT) is a widely used imaging technique in ophthalmology for diagnosis and treatment. Recent advances in deep neural networks (DNNs) and vision transformers (ViTs) have paved the way for automated eye/retinal disease classifications and segmentations using OCT or spectral domain OCT (SD-OCT) images. Diabetic macular edema (DME), choroidal neovascularization (CNV), and Drusen are particularly challenging to accurately classify using OCT images because of their subtle differences and intricate features. Currently, the algorithms reported in the literature using DNNs or ViTs are computationally complex, consider fewer diseases, and are less accurate. This study proposes a hybrid SqueezeNet-vision transformer (SViT) model that combines the strengths of SqueezeNet and vision transformer (ViT), capturing local and global features of OCT images to achieve more accurate classification with less computational complexity. The proposed model uses the OCT2017 dataset for training, testing, and validation, and it performs both binary classification (normal vs disorders) as well as multiclass classification (DME, CNV, Drusen, and normal). As compared to state-of-the-art CNN-based and standalone Transformer models, the proposed SViT model achieves an overall classification accuracy of 99.90% for multiclass classification (CNV: 100%, DME: 99.9%, Drusen: 100%, and normal: 100%). With a good generalization ability, the model can be used to improve patient care and clinical decision-making across a broader range of applications. [ABSTRACT FROM AUTHOR]

Given the absence of approved treatments for pathogenic variants in Peripherin-2 (PRPH2), it is imperative to identify a universally effective therapeutic target for PRPH2 pathogenic variants. To test the hypothesis that formation of the elongated discs in presence of PRPH2 pathogenic variants is due to the presence of the full complement of rhodopsin in absence of the required amounts of functional PRPH2. Here we demonstrate the therapeutic potential of reducing rhodopsin levels in ameliorating disease phenotype in knockin models for p.Lys154del (c.458-460del) and p.Tyr141Cys (c.422 A > G) in PRPH2. Reducing rhodopsin levels improves physiological function, mitigates the severity of disc abnormalities, and decreases retinal gliosis. Additionally, intravitreal injections of a rhodopsin-specific antisense oligonucleotide successfully enhance the physiological function of photoreceptors and improves the ultrastructure of discs in mutant mice. Presented findings shows that reducing rhodopsin levels is an effective therapeutic strategy for the treatment of inherited retinal degeneration associated with PRPH2 pathogenic variants. Due to the abundance of pathogenic variants in Peripherin-2, causing peripherin-2-associated inherited retinal disorders, and the lack of any approved treatment, it is imperative to identify an effective therapeutic strategy. Here the authors show that reducing rhodopsin levels improves retinal function and structure and decreases inflammatory responses. [ABSTRACT FROM AUTHOR]

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Copyright of Die Ophthalmologie is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Classifying retinal diseases is a complex problem because the early problematic areas of retinal disorders are quite small and conservative. In recent years, Transformer architectures have been successfully applied to solve various retinal related health problems. Age-related macular degeneration (AMD) and diabetic macular edema (DME), two prevalent retinal diseases, can cause partial or total blindness. Diseases therefore require an early and accurate detection. In this study, we proposed Vision Transformer (ViT), Tokens-To-Token Vision Transformer (T2T-ViT) and Mobile Vision Transformer (Mobile-ViT) algorithms to detect choroidal neovascularization (CNV), drusen, and diabetic macular edema (DME), and normal using optical coherence tomography (OCT) images. The predictive accuracies of ViT, T2T-ViT and Mobile-ViT achieved on the dataset for the classification of OCT images are 95.14%, 96.07% and 99.17% respectively. Experimental results obtained from ViT approaches showed that Mobile-ViT have superior performance with regard to classification accuracy in comparison with the others. Overall, it has been observed that ViT architectures have the capacity to classify with high accuracy in the diagnosis of retinal diseases. [ABSTRACT FROM AUTHOR]

Screening techniques based on fundus imaging are very popular in diagnosing retinal diseases. In the field of fundus image classification, deep learning techniques, especially Convolutional Neural Networks (CNN), are the most popular choice. However, any deep neural network requires a large dataset for training the model, and the unavailability of data in such a large amount becomes a major hindrance in developing disease identification solutions for new and rare diseases. This research introduces a novel few-shot meta-learning strategy using a Siamese neural network with Triplet loss (Triplet Neural Network), along with a K-nearest Neighbour (KNN) classifier. The primary objective is to effectively classify new and rare retinal diseases, even when only a few samples are available. The Triplet Neural Network (TNN) is designed to learn a mapping function that places similar images in close proximity within an embedding space. This learned function is subsequently leveraged to map images from new classes. The embeddings produced by the TNN are then classified using the KNN algorithm. The proposed model is validated on two benchmark datasets, namely RFMiD and ODIR. The experimental results show an accuracy of above 90% with only a few samples of new classes. It is found that 24 samples per new class in the RFMiD dataset and 28 samples per new class in the ODIR dataset are enough to retrain the classifier using the embeddings learned during the meta-learning phase. [ABSTRACT FROM AUTHOR]

Diabetic Retinopathy (DR) refers to a retinal disease that happens due to high glucose levels in the blood, and it leads to blindness globally. In order to delay or avoid vision loss and degradation, early detection, and treatment are necessary. Hence, the conception of an automated technique for precise DR recognition is necessary. Thus, a Deep Q network (DQN) with a Gradient Descent-Sea Turtle Foraging Algorithm (GD-STFA) is proposed that inherits Gradient Descent (GD) in Sea Turtle Foraging Algorithm (STFA), to detect DR from images. This method involves various phases, like pre-processing, segmentation, as well as DR detection. Here, the DR image quality is enhanced in the pre-processing phase using a median filter. After that, the segmentation is done by utilizing Swin-UNet and it is trained using the proposed GD-STFA algorithm. Finally, the DQN trained with GD-STFA finds if a person has DR or normal from his retinal images. The experimentation is performed in detail and validated on the Indian Diabetic Retinopathy Image Dataset benchmark dataset. Ultimately, the experimental outcomes demonstrate that the model is better than traditional techniques regarding optimal accuracy of 0.98, sensitivity of 0.984 and specificity of 0.971. Also, regarding the segmentation accuracy, the proposed model is around 0.906 accurate with a Dice coefficient of 0.963. [ABSTRACT FROM AUTHOR]

Renal ciliopathies are a common cause of kidney failure in children and adults, and this study reviewed their ocular associations. Genes affected in renal ciliopathies were identified from the Genomics England Panels. Ocular associations were identified from Medline and OMIM, and the genes additionally examined for expression in the human retina (https://www.proteinatlas.org/humanproteome/tissue) and for an ocular phenotype in mouse models (http://www.informatics.jax.org/). Eighty-two of the 86 pediatric-onset renal ciliopathies (95%) have an ocular phenotype, including inherited retinal degeneration, oculomotor disorders, and coloboma. Diseases associated with pathogenic variants in ANK6, MAPKBP1, NEK8, and TCTN1 have no reported ocular manifestations, as well as low retinal expression and no ocular features in mouse models. Ocular abnormalities are not associated with the most common adult-onset "cystic" kidney diseases, namely, autosomal dominant (AD) polycystic kidney disease and the AD tubulointerstitial kidney diseases (ADTKD). However, other kidney syndromes with cysts have ocular features including papillorenal syndrome (optic disc dysplasia), Hereditary Angiopathy Nephropathy, Aneurysms and muscle Cramps (HANAC) (tortuous retinal vessels), tuberous sclerosis (retinal hamartomas), von Hippel-Lindau syndrome (retinal hemangiomas), and Alport syndrome (lenticonus, fleck retinopathy). Ocular abnormalities are associated with many pediatric-onset renal ciliopathies but are uncommon in adult-onset cystic kidney disease. However the demonstration of ocular manifestations may be helpful diagnostically and the features may require monitoring or treatment. [ABSTRACT FROM AUTHOR]

Spectral-domain optical coherence tomography (SDOCT) is the gold standard of imaging the eye in clinics. Penetration depth with such devices is, however, limited and visualization of the choroid, which is essential for diagnosing chorioretinal disease, remains limited. Whereas swept-source OCT (SSOCT) devices allow for visualization of the choroid these instruments are expensive and availability in praxis is limited. We present an artificial intelligence (AI)-based solution to enhance the visualization of the choroid in OCT scans and allow for quantitative measurements of choroidal metrics using generative deep learning (DL). Synthetically enhanced SDOCT B-scans with improved choroidal visibility were generated, leveraging matching images to learn deep anatomical features during the training. Using a single-center tertiary eye care institution cohort comprising a total of 362 SDOCT-SSOCT paired subjects, we trained our model with 150,784 images from 410 healthy, 192 glaucoma, and 133 diabetic retinopathy eyes. An independent external test dataset of 37,376 images from 146 eyes was deployed to assess the authenticity and quality of the synthetically enhanced SDOCT images. Experts' ability to differentiate real versus synthetic images was poor (47.5% accuracy). Measurements of choroidal thickness, area, volume, and vascularity index, from the reference SSOCT and synthetically enhanced SDOCT, showed high Pearson's correlations of 0.97 [95% CI: 0.96–0.98], 0.97 [0.95–0.98], 0.95 [0.92–0.98], and 0.87 [0.83–0.91], with intra-class correlation values of 0.99 [0.98–0.99], 0.98 [0.98–0.99], and 0.95 [0.96–0.98], 0.93 [0.91–0.95], respectively. Thus, our DL generative model successfully generated realistic enhanced SDOCT data that is indistinguishable from SSOCT images providing improved visualization of the choroid. This technology enabled accurate measurements of choroidal metrics previously limited by the imaging depth constraints of SDOCT. The findings open new possibilities for utilizing affordable SDOCT devices in studying the choroid in both healthy and pathological conditions. [ABSTRACT FROM AUTHOR]

Optical coherence tomography angiography (OCTA) is widely used for non-invasive retinal vascular imaging, but the OCTA methods used to assess retinal perfusion vary. We evaluated the different methods used to assess retinal perfusion between OCTA studies. MEDLINE and Embase were searched from 2014 to August 2021. We included prospective studies including ≥ 50 participants using OCTA to assess retinal perfusion in either global retinal or systemic disorders. Risk of bias was assessed using the National Institute of Health quality assessment tool for observational cohort and cross-sectional studies. Heterogeneity of data was assessed by Q statistics, Chi-square test, and I2 index. Of the 5974 studies identified, 191 studies were included in this evaluation. The selected studies employed seven OCTA devices, six macula volume dimensions, four macula subregions, nine perfusion analyses, and five vessel layer definitions, totalling 197 distinct methods of assessing macula perfusion and over 7000 possible combinations. Meta-analysis was performed on 88 studies reporting vessel density and foveal avascular zone area, showing lower retinal perfusion in patients with diabetes mellitus than in healthy controls, but with high heterogeneity. Heterogeneity was lowest and reported vascular effects strongest in superficial capillary plexus assessments. Systematic review of OCTA studies revealed massive heterogeneity in the methods employed to assess retinal perfusion, supporting calls for standardisation of methodology. [ABSTRACT FROM AUTHOR]

Retinal diseases such as Diabetic Retinopathy (DR), Hypertensive Retinopathy (HR), different types of Occlusions, etc., are associated with the deformity observed in the Retinal Vessel Structure (RVS). This paper proposes an automatic unsupervised vessel segmentation technique to separate the RVS with insignificant change in curvature of the vessel and eliminate the noises from the vessel structure and the background. The method involves three phases: preprocessing, where the fundus image is enhanced based on local information, and the noises are separated from the vessels. The second phase introduces a unique Bel–Hat transformation, which simultaneously uses two different groups of Structural Elements: the Neighbor Adaptive Line Structuring Element (NALSE) and the 2D Gaussian Structuring Element (2DGSE). These combined groups of Structural Elements can separate the vessel structure from the background by changing the size and orientation of the Structural Elements. Lastly, a novel robust statistical threshold is used, based on the statistical distribution of the area of the isolated objects, to segment the accurate noise-free Retinal Vessel Structure (RVS). This proposed method is more accurate than the recently proposed unsupervised and supervised methods. [ABSTRACT FROM AUTHOR]

Inherited and non-inherited retinopathies can affect distinct cell types, leading to progressive cell death and visual loss. In the last years, new approaches have indicated exciting opportunities to treat retinopathies. Cell therapy in retinitis pigmentosa, age-related macular disease, and glaucoma have yielded encouraging results in rodents and humans. The first two diseases mainly impact the photoreceptors and the retinal pigmented epithelium, while glaucoma primarily affects the ganglion cell layer. Induced pluripotent stem cells and multipotent stem cells can be differentiated in vitro to obtain specific cell types for use in transplant as well as to assess the impact of candidate molecules aimed at treating retinal degeneration. Moreover, stem cell therapy is presented in combination with newly developed methods, such as gene editing, Müller cells dedifferentiation, sheet & drug delivery, virus-like particles, optogenetics, and 3D bioprinting. This review describes the recent advances in this field, by presenting an updated panel based on cell transplants and related therapies to treat retinopathies. [ABSTRACT FROM AUTHOR]

Objective: Current gene therapy of inherited retinal diseases is achieved mainly by subretinal injection, which is invasive with severe adverse effects. Intravitreal injection is a minimally invasive alternative for gene therapy of inherited retinal diseases. This work explores the efficacy of intravitreal delivery of PEGylated ECO (a multifunctional pH-sensitive amphiphilic amino lipid) plasmid DNA (pGRK1-ABCA4-S/MAR) nanoparticles (PEG-ELNP) for gene therapy of Stargardt disease. Methods: Pigmented Abca4−/− knockout mice received 1 µL of PEG-ELNP solution (200 ng/uL, pDNA concentration) by intravitreal injections at an interval of 1.5 months. The expression of ABCA4 in the retina was determined by RT-PCR and immunohistochemistry at 6 months after the second injection. A2E levels in the treated eyes and untreated controls were determined by HPLC. The safety of treatment was monitored by scanning laser ophthalmoscopy and electroretinogram (ERG). Results: PEG-ELNP resulted in significant ABCA4 expression at both mRNA level and protein level at]6 months after 2 intravitreal injections, and a 40% A2E accumulation reduction compared with non-treated controls. The PEG-ELNP also demonstrated excellent safety as shown by scanning laser ophthalmoscopy, and the eye function evaluation from electroretinogram. Conclusions: Intravitreal delivery of the PEG-ELNP of pGRK1-ABCA4-S/MAR is a promising approach for gene therapy of Stargardt Disease, which can also be a delivery platform for gene therapy of other inherited retinal diseases. [ABSTRACT FROM AUTHOR]

Inherited retinal diseases (IRDs) are a clinically heterogeneous group of retinal pathologies associated with vision loss due to dysfunction or degeneration of photoreceptor and retinal pigment epithelium. Autosomal recessive forms of IRDs account for more than 55% of all diseases in this group on average worldwide. This study presents data on frequent pathogenic and likely pathogenic variants in recessive genes of IRDs obtained from a retrospective analysis of high-throughput sequencing data from a large Russian cohort of patients with suspected inherited nonsyndromic retinal pathology. Data from 1470 unrelated patients were analyzed. Pathogenic and likely pathogenic variants were identified in the zygosity required for the development of the disease in 643 patients (43.74%). It was found that nine genes (ABCA4, CNGB3, USH2A, RPE65, CRB1, CNGA3, CEP290, GUCY2D, PDE6H) account for 73.3% of all molecularly confirmed cases of IRDs in Russian patients. An analysis of the spectrum of nucleotide variants of these genes was carried out, and 17 variants were identified that occur with an allelic frequency of more than 1% for each gene. In light of the data obtained, diagnostic systems based on the multiplex ligation-dependent probe amplification reaction (MLPA) were developed. The informativity of the two systems for diagnosing autosomal recessive nonsyndromic forms of inherited retinal diseases is 16.4%, the informativity for all forms of nonsyndromic retinal diseases exceeds 7%. For a group of patients with achromatopsia, a study using one of the systems will make it possible to establish a diagnosis in 62.5% of cases. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to analyze the genetic results of inherited retinal diseases (IRDs) and evaluate the diagnostic usefulness of whole genome sequencing (WGS) in the Korean National Project of Bio Big Data. Methods: As part of the Korean National Project of Bio Big Data, WGS was performed on 32 individuals with IRDs with no identified pathogenic variants through whole or targeted exome sequencing. Results: Individuals with retinitis pigmentosa (n = 23), cone dystrophy (n = 2), cone-rod dystrophy (n = 2), familial exudative vitreoretinopathy (n = 2), pigmented paravenous chorioretinal atrophy (n = 1), North Carolina macular dystrophy (n = 1), and bull's-eye macular dystrophy (n = 1) were included. WGS revealed genetic mutations in the IQCB1, PRPF31, USH2A, and GUCY2D genes in five cases (15.6%). Two large structural variations and an intronic variant were newly detected in three cases. Two individuals had biallelic missense mutations that were not identified in previous exome sequencing. Conclusion: With WGS, the causative variants in 15.6% of unsolved IRDs from the Korean National Project of Bio Big Data were identified. Further research with a larger cohort might unveil the diagnostic usefulness of WGS in IRDs and other diseases. [ABSTRACT FROM AUTHOR]

Many important abnormalities of the vitreous, retina and choroid are predominantly located in the peripheral retina. In some retinal diseases with both central and peripheral manifestations, pathological structural or vascular changes can be apparent in the periphery before they are detectable in the central retina. Conventional optical coherence tomography (OCT) and optical coherence tomography angiography (OCT-A) imaging only cover the most posterior 30° of the retina. Wide-field OCT (WF-OCT), though offering detailed cross-sectional imaging of the peripheral retina, is not yet systematically used in clinical practice. This narrative review provides a presentation of the utilisation of WF-OCT and WF-OCT-A in the diagnosis and monitoring of a variety of ophthalmological diseases and discusses the advantages and limitations of the technology. With the rapidly developing technology, multiple WF-OCT and WF-OCT-A devices are now commercially available and enable the clinician to obtain scans within a field of view up to 200°. As detailed in this review, several studies have shown promising results in the application of WF-OCT and WF-OCT-A in diseases of the retina, choroid and vitreous, such as retinal vein occlusion, diabetic retinopathy, ocular oncology, paediatric ophthalmology, uveitis and lesions of the vitreo–retinal interface. In conclusion, WF-OCT and WF-OCT-A can reliably produce high-quality, non-invasive images of the vitreous, retinal, and choroidal structures and vascularity covering the posterior pole as well as the mid and far periphery. These methods can be a valuable part of a multimodal imaging approach in the management of a variety of ocular conditions. Future studies are warranted to investigate the patient outcome benefits of implementation of WF-OCT and WF-OCT-A imaging in a real-life clinical setting. [ABSTRACT FROM AUTHOR]

Geographic atrophy is an eye disease that greatly interferes with the daily lives of patients and their families, posing a serious threat to the aging European demographic. Over the past 30 months, this initiative has assembled leading experts in the field of ophthalmology to share insights on the necessary policy steps that need to be taken to overcome this challenge on an EU-wide scale. Through analyzing best practices in Germany, Italy, France, and Spain, this consensus paper sets out a series of policy recommendations, which, if implemented, could greatly benefit all individuals affected by geographic atrophy. Amongst other features, these countries have provided valuable examples of awareness campaigns and an overall commitment to inclusive and comprehensive policies. The policy recommendations emerging from this paper include the adoption of comprehensive screening programs, retinal disease screening in the EU Driving License Directive, the development of a white paper at the European Commission, and the creation of Council recommendations on eye health screening. Given the significant improvements made at the national level throughout the EU, countries will require unitary support at the European level to further develop their policies and successfully address the burden of geographic atrophy. [ABSTRACT FROM AUTHOR]

This study evaluated patient experiences with genetic testing for inherited retinal diseases (IRDs) and the association between underlying knowledge, testing outcomes, and the perceived value of the results. An online survey was distributed to adults with IRDs and parents/guardians of dependents with IRDs who had had genetic testing. Data included details of genetic testing, pre- and post- test perceptions, Decision Regret Scale, perceived value of results, and knowledge of gene therapy. Of 135 responses (85% from adults with IRDs), genetic testing was primarily conducted at no charge through public hospitals (49%) or in a research setting (30%). Key motivations for genetic testing were to confirm IRD diagnosis and to contribute towards research. Those who had received a genetic diagnosis (odds ratio: 6.71; p < 0.001) and those self-reported to have good knowledge of gene therapy (odds ratio: 2.69; p = 0.018) were more likely to have gained confidence in managing their clinical care. For over 80% of respondents, knowing the causative gene empowered them to learn more about their IRD and explore opportunities regarding clinical trials. Key genetic counselling information needs include resources for family communications, structured information provision, and ongoing genetic support, particularly in the context of emerging ocular therapies, to enhance consistency in information uptake. [ABSTRACT FROM AUTHOR]

Accurate discrimination of pathogenic and nonpathogenic variation remains an enormous challenge in clinical genetic testing of inherited retinal diseases (IRDs) patients. Computational methods for predicting variant pathogenicity are the main solutions for this dilemma. The majority of the state-of-the-art variant pathogenicity prediction tools disregard the differences in characteristics among different genes and treat all types of mutations equally. Since missense variants are the most common type of variation in the coding region of the human genome, we developed a novel missense mutation pathogenicity prediction tool, named Prediction of Deleterious Missense Mutation for IRDs (PdmIRD) in this study. PdmIRD was tailored for IRDs-related genes and constructed with the conditional random forest model. Population frequencies and a newly available prediction tool were incorporated into PdmIRD to improve the performance of the model. The evaluation of PdmIRD demonstrated its superior performance over nonspecific tools (areas under the curves, 0.984 and 0.910) and an existing eye abnormalities-specific tool (areas under the curves, 0.975 and 0.891). We also demonstrated the submodel that used a smaller gene panel further slightly improved performance. Our study provides evidence that a disease-specific model can enhance the prediction of missense mutation pathogenicity, especially when new and important features are considered. Additionally, this study provides guidance for exploring the characteristics and functions of the mutated proteins in a greater number of Mendelian disorders. [ABSTRACT FROM AUTHOR]

As retinitis pigmentosa (RP) is chronic and progressive, the chronological sequence of microvascular changes is important for understanding its pathophysiology. We aimed to investigate retinal and choroidal microvascular changes according to the RP stages. The stages of RP were classified into three stages according to the integrity and width of the inner segment ellipsoid zone: early, ≥ 2500 μm; moderate, < 2500 μm; advanced, absence. Using optical coherence tomography angiography, quantitative microvascular parameters were analyzed. In total, 91 eyes from 49 patients were included. For the superficial capillary plexus (SCP) and deep capillary plexus (DCP), perfusion densities (PDs) in the early stage (SCP: 37.32 ± 8.11%; DCP: 21.19 ± 9.15%) were greater than those in moderate (SCP: 34.16 ± 6.65%, P = 0.011; DCP: 15.67 ± 8.85%, P = 0.031) and advanced stages (SCP: 33.71 ± 9.02%, P = 0.030; DCP: 12.83 ± 6.29%, P < 0.001). The choroidal vascularity index in the early stage (0.58 ± 0.03) was greater than those in the moderate (0.57 ± 0.02, P = 0.017) and advanced stage (0.56 ± 0.02, P = 0.033). The area and perimeter of foveal avascular zone (FAZ) in advanced stage (0.44 ± 0.26 mm2, 2.96 ± 0.86 mm, respectively) were larger than those in early (0.26 ± 0.11 mm2, P = 0.020; 2.19 ± 0.53 mm, P = 0.006, respectively) and moderate stage (0.28 ± 0.13 mm2, P = 0.043; 2.24 ± 0.67 mm, P = 0.013, respectively). During RP disease progression, retinal and choroidal microvascular vessel density decreases in the early stage, followed by FAZ enlargement in the advanced stage. [ABSTRACT FROM AUTHOR]

The human eye is responsible for the visual reorganization of objects in the environment. The eye is divided into different layers and front/back areas; however, the most important part is the retina, responsible for capturing light and generating electrical impulses for further processing in the brain. Several manual and automated methods have been proposed to detect retinal diseases, though these techniques are time-consuming, inefficient, and unpleasant for patients. This research proposes a deep learning-based CSR detection employing two imaging techniques: OCT and fundus photography. These input images are manually augmented before classification, followed by training of DarkNet and DenseNet networks through both datasets. Moreover, pre-trained DarkNet and DenseNet classifiers are modified according to the need. Finally, the performance of both networks on their datasets is compared using evaluation parameters. After several experiments, the best accuracy of 99.78%, the sensitivity of 99.6%, specificity of 100%, and the F1 score of 99.52% were achieved through OCT images using the DenseNet network. The experimental results demonstrate that the proposed model is effective and efficient for CSR detection using the OCT dataset and suitable for deployment in clinical applications. [ABSTRACT FROM AUTHOR]

The purpose of this study was to screen Copy Number Variations (CNVs) in 35 unsolved Inherited Retinal Dystrophy (IRD) families. Initially, next generation sequencing, including a specific Hereditary Eye Disease Enrichment Panel or Whole exome sequencing, was employed to screen (likely) pathogenic Single-nucleotide Variants (SNVs) and small Insertions and Deletions (indels) for these cases. All available SNVs and indels were further validated and co-segregation analyses were performed in available family members by Sanger sequencing. If not, after excluding deep intronic variants, Multiplex ligation-dependent probe amplification (MLPA), quantitative fluorescence PCR (QF-PCR) and Sanger sequencing were employed to screen CNVs. We determined that 18 probands who had heterozygous SNVs/indels or whose parents were not consanguineous but had homozygous SNVs/indels in autosomal recessive IRDs genes had CNVs in another allele of these genes, 11 families had disease-causing hemizygous CNVs in X-linked IRD genes, 6 families had (likely) pathogenic heterozygous CNVs in PRPF31 gene. Of 35 families, 33 different CNVs in 16 IRD-associated genes were detected, with PRPF31, EYS and USH2A the most common disease-causing gene in CNVs. Twenty-six and 7 of them were deletion and duplication CNVs, respectively. Among them, 14 CNVs were first reported in this study. Our research indicates that CNVs contribute a lot to IRDs, and screening of CNVs substantially increases the diagnostic rate of IRD. Our results emphasize that MLPA and QF-PCR are ideal methods to validate CNVs, and the novel CNVs reported herein expand the mutational spectrums of IRDs. [ABSTRACT FROM AUTHOR]

Retinal diseases are leading causes of blindness globally. Developing new drugs is of great significance for preventing vision loss. Current drug discovery relies mainly on two-dimensional in vitro models and animal models, but translation to human efficacy and safety is biased. In recent years, the emergence of retinal organoid technology platforms, utilizing three-dimensional microenvironments to better mimic retinal structure and function, has provided new platforms for exploring pathogenic mechanisms and drug screening. This review summarizes the latest advances in retinal organoid technology, emphasizing its application advantages in high-throughput drug screening, efficacy and toxicity evaluation, and translational medicine research. The review also prospects the combination of emerging technologies such as organ-on-a-chip, 3D bioprinting, single cell sequencing, gene editing with retinal organoid technology, which is expected to further optimize retinal organoid models and advance the diagnosis and treatment of retinal diseases. [ABSTRACT FROM AUTHOR]