Digital ray: enhancing cataractous fundus images using style transfer generative adversarial networks to improve retinopathy detection.

BACKGROUND/AIMS: The aim of this study was to develop and evaluate digital ray, based on preoperative and postoperative image pairs using style transfer generative adversarial networks (GANs), to enhance cataractous fundus images for improved retinopathy detection. METHODS: For eligible cataract patients, preoperative and postoperative colour fundus photographs (CFP) and ultra-wide field (UWF) images were captured. Then, both the original CycleGAN and a modified CycleGAN (C2ycleGAN) framework were adopted for image generation and quantitatively compared using Frechet Inception Distance (FID) and Kernel Inception Distance (KID). Additionally, CFP and UWF images from another cataract cohort were used to test model performances. Different panels of ophthalmologists evaluated the quality, authenticity and diagnostic efficacy of the generated images. RESULTS: A total of 959 CFP and 1009 UWF image pairs were included in model development. FID and KID indicated that images generated by C2ycleGAN presented significantly improved quality. Based on ophthalmologists' average ratings, the percentages of inadequate-quality images decreased from 32% to 18.8% for CFP, and from 18.7% to 14.7% for UWF. Only 24.8% and 13.8% of generated CFP and UWF images could be recognised as synthetic. The accuracy of retinopathy detection significantly increased from 78% to 91% for CFP and from 91% to 93% for UWF. For retinopathy subtype diagnosis, the accuracies also increased from 87%-94% to 91%-100% for CFP and from 87%-95% to 93%-97% for UWF. CONCLUSION: Digital ray could generate realistic postoperative CFP and UWF images with enhanced quality and accuracy for overall detection and subtype diagnosis of retinopathies, especially for CFP.\ TRIAL REGISTRATION NUMBER: This study was registered with ClinicalTrials.gov (NCT05491798).

An artificial intelligence system for the whole process from diagnosis to treatment suggestion of ischemic retinal diseases.

Ischemic retinal diseases (IRDs) are a series of common blinding diseases that depend on accurate fundus fluorescein angiography (FFA) image interpretation for diagnosis and treatment. An artificial intelligence system (Ai-Doctor) was developed to interpret FFA images. Ai-Doctor performed well in image phase identification (area under the curve [AUC], 0.991-0.999, range), diabetic retinopathy (DR) and branch retinal vein occlusion (BRVO) diagnosis (AUC, 0.979-0.992), and non-perfusion area segmentation (Dice similarity coefficient [DSC], 89.7%-90.1%) and quantification. The segmentation model was expanded to unencountered IRDs (central RVO and retinal vasculitis), with DSCs of 89.2% and 83.6%, respectively. A clinically applicable ischemia index (CAII) was proposed to evaluate ischemic degree; patients with CAII values exceeding 0.17 in BRVO and 0.08 in DR may be associated with increased possibility for laser therapy. Ai-Doctor is expected to achieve accurate FFA image interpretation for IRDs, potentially reducing the reliance on retinal specialists.

Choroidal Vortex Vein Drainage System in Central Serous Chorioretinopathy Using Ultra-Widefield Optical Coherence Tomography Angiography.

Purpose: To evaluate differences in the choroidal vortex vein drainage system (VV) in eyes between patients with central serous chorioretinopathy (CSC) and unaffected individuals using ultra-widefield optical coherence tomography angiography (UWF-OCTA). Methods: In this cross-sectional observational study, 40 eyes of patients with CSC and 28 eyes of healthy volunteers were included. The analysis involved the use of UWF-OCTA to analyze the proportion of the choroidal vortex vein drainage system (VV%), choroidal thickness, choroidal vascular volume (CVV), and choroidal vascularity index (CVI) of the VV in each drainage quadrant. The location relationship between the leakage points in fluorescein angiography and the VV was also explored. Results: A within-group analysis of VV% showed a statistically significant difference in the CSC group (P < 0.001) but not in the control group (P = 0.270). Compared to healthy eyes, CSC eyes had a significantly larger CVV and higher CVI in all regions (all P < 0.05). The superotemporal (ST) drainage system had the largest CVV and thickest choroidal layer among the four drainage quadrants (all P < 0.05) in CSC eyes. The leakage rate in the ST quadrant was significantly higher than that in the inferotemporal quadrant (P < 0.001). Conclusions: CSC eyes have an asymmetric vortex vein drainage system, with relative hyperperfusion in all VV. Further, the preferential drainage route of the submacular choroid may be the ST drainage system in CSC eyes. Translational Relevance: Targeting the imbalanced drainage system could be a potential therapeutic approach for CSC.

Incidence, causes and risk factors of vision loss in rural Southern China: 6-year follow-up of the Yangxi Eye Study.

PURPOSE: To report the 6-year incidence, causes and risk factors for vision loss (visual impairment (VI) and blindness), among elderly adults in rural southern China. METHODS: Population-based, cohort study. Initiated in 2014, the study recruited participants aged 50 and older using random cluster sampling from Yangxi County. All eligible participants were invited to attend interviews and comprehensive eye examinations at the 6-year follow-up between November 2020 and March 2021. The WHO categories of vision loss were used to define incident cases of VI (3/60≤VA <6/12), moderate-to-severe VI (MSVI) (3/60≤VA<6/18) and blindness (VA <3/60) in the better-seeing eye. RESULTS: Among the 5825 baseline participants, 3187 (64.4%) of 4946 surviving subjects participated in the 6-year follow-up. Based on presenting and best-corrected VA, respectively, the crude incidence rate of blindness was 0.8% (95% CI 0.5% to 1.1%) vs 0.3% (95% CI 0.1% to 0.5%), for MSVI 6.7% (95% CI 5.7% to 7.6%) vs 4.6% (95% CI 3.8% to 5.4%) and for any VI 16.1% (95% CI 14.5% to 17.6%) vs 12.9% (95% CI 11.6% to 14.1%). Cataract (48.3%) and refractive errors (44.4%) were the most common causes of vision loss. Factors significantly associated with greater incident vision loss were older age, female sex, less education, living alone and longer axial length (all p<0.05). CONCLUSIONS: Substantial work is still required to reduce avoidable vision loss in rural China. Screening outreach and efforts to improve awareness which target the poorer and less educated are urgently needed to reduce the growing unmet need for eye care due to ageing.

Choroidal Vascularity Index as a Biomarker for Visual Response to Antivascular Endothelial Growth Factor Treatment in Diabetic Macular Edema.

PURPOSE: To investigate the choroidal vascularity index (CVI) as a prognostic factor for the visual efficacy of antivascular endothelial growth factor (VEGF) treatment in diabetic macular edema (DME). METHODS: We retrospectively reviewed 92 DME eyes receiving anti-VEGF treatment, which were stratified as responders (≥5 letters gained) and nonresponders (<5 letters gained or lost). Baseline systematic features and optical coherence tomography features, including the CVI, adjusted ellipsoid zone (EZ) reflectivity, subretinal fluid (SRF), and disorganization of the retinal inner layers (DRIL), were evaluated between the two groups. RESULTS: The baseline CVI was significantly lower in nonresponders than in responders (0.66 ± 0.05, 0.69 ± 0.05, and 0.72 ± 0.05, p = 0.014). After adjusting for other factors, the baseline CVI, DRIL, SRF, and adjusted EZ reflectivity were significantly associated with visual outcomes (CVI: odds ratio (OR) = 0.17, p = 0.006; adjusted EZ reflectivity: OR = 0.56, p = 0.007; DRIL: OR = 6.71, p = 0.001; and SRF: OR = 0.29, p = 0.008). CONCLUSION: DME patients with a higher CVI, higher adjusted EZ reflectivity, the presence of SRF, and the absence of DRIL at baseline were more likely to gain >5 letters in visual acuity after anti-VEGF treatment. CVI may serve as a novel biomarker for visual response to anti-VEGF treatment in DME.

The Relationship between Macular Vessel Density and Thickness with Light Sensitivity in Myopic Eyes.

Purpose: To investigate vasculature-function and structure-function relationship in healthy myopic eyes using optical coherence tomography angiography (OCT-A), optical coherence tomography (OCT) and microperimetry (MAIA). Methods: A total of 370 eyes from 190 participants were enrolled in this study. Subjects divided into three groups based on refractive status: low myopia (LM) (-3.00D ≤ spherical equivalent, SE ≤ -0.50D), moderate myopia (MM) (-6.00D ≤ SE < -3.00D) and high myopia (HM) (SE < -6.00D). The vessel density (VD), retinal thickness (RT) and light sensitivity (LS) were evaluated using OCT-A, OCT and MAIA. The global and regional vasculature-function and structure-function relationship were evaluated by the semi-partial correlation analysis according to ETDRS grid. The uni- and multivariate linear regression models were performed using LS as the dependent variable and covariates, included age, gender, intraocular pressure (IOP), axial length (AL), SE, ganglion cell complex thickness (GCCT), superficial (SVD) and deep vessel density (DVD) and RT as independent variables. Results: The LS negatively correlated with AL and positively correlated with SE, DVD, RT and GCCT (P < .05). The DVD was associated with the corresponding LS only in temporal and nasal sectors in HM (sr: 0.182-0.195, P < .05) but SVD not at all. The RT was associated with the corresponding LS in inferior and nasal sectors in MM (sr: 0.221-0.281, P < .005) and all sectors in HM (sr: 0.187-0.229, P < .05). Lower DVD and RT were independently associated with the declined LS in myopic eyes (P < .05). Conclusions: Reduced DVD and RT were independently associated with the declined LS in healthy myopic eyes, especially in HM.

Melatonin attenuated retinal neovascularization and neuroglial dysfunction by inhibition of HIF-1α-VEGF pathway in oxygen-induced retinopathy mice.

Retinopathy of prematurity (ROP) is a retinopathy characterized by retinal neovascularization (RNV) occurring in preterm infants treated with high concentrations of oxygen and may lead to blindness in severe cases. Currently, anti-VEGF therapy is a major treatment for ROP, but it is costly and may cause serious complications. The previous study has demonstrated that melatonin exerted neuroprotective effect against retinal ganglion cell death induced by hypoxia in neonatal rats. However, whether melatonin is anti-angiogenic and neuroglial protective in the progression of ROP remains unknown. Thus, this study was to investigate the effect of melatonin on RNV and neuroglia in the retina of oxygen-induced retinopathy (OIR) mice. The results showed a reduction in retinal vascular leakage in OIR mice after melatonin treatment. Besides, the size of retinal neovascular and avascular areas, the number of preretinal neovascular cell nuclei, and the number of proliferative vascular endothelial cells within the neovascular area were significantly decreased in mice treated with melatonin. After oxygen-induced injury, the density of astrocytes was decreased, accompanied by morphologic and functional changes of astrocytes. Besides, retinal microglia were also activated. Meanwhile, the levels of inflammatory factors were elevated. However, these pathologic processes were all hindered by melatonin treatment. Furthermore, HIF-1α-VEGF pathway was activated in the retina of OIR mice, yet was suppressed in melatonin-treated OIR mice retinas. In conclusion, melatonin prevented pathologic neovascularization, protected neuroglial cells, and exerts anti-inflammation effect via inhibition of HIF-1α-VEGF pathway in OIR retinas, suggesting that melatonin could be a promising therapeutic agent for ROP.

Salubrinal attenuated retinal neovascularization by inhibiting CHOP-HIF1α-VEGF pathways.

Retinal neovascularization (RNV) related disease is the leading cause of irreversible blindness in the world. The aim of this study is to identify whether salubrinal could attenuate RNV by inhibiting CCAAT/enhancer-binding protein (C/EBP) homologous protein (CHOP)- hypoxia inducible factors 1α (HIF1α) -vascular endothelial growth factor (VEGF) pathways in both mouse retinal microvascular endothelial cells (mRMECs) and oxygen-induced retinopathy (OIR) mouse model. After being treated with salubrinal (20µmol/L) or CHOP-siRNA, mRMECs were exposed to a hypoxia environment. OIR mice were intraperitoneally injected with salubrinal (0.5 mg/kg/day) from P12 to P17. With salubrinal or CHOP-siRNA treatment, the elevated CHOP protein and mRNA levels in hypoxia-induced mRMECs were significantly decreased. HIF1α-VEGF pathways were activated under hypoxia condition, then HIF1α protein was degraded and VEGF secretion was down-regulated after salubrinal or CHOP-siRNA treatment. In OIR mice, the areas of RNV were markedly decreased with salubrinal treatment. Moreover, elevated expressions of CHOP, HIF1α and VEGF in retinas of OIR mice were all reduced after salubrinal treatment. It suggested that salubrinal attenuated RNV in mRMECs and OIR mice by inhibiting CHOP-HIF1α-VEGF pathways and could be a potential therapeutic target for hypoxia-induced retinal microangiopathy.

FK506 suppresses hypoxia­induced inflammation and protects tight junction function via the CaN­NFATc1 signaling pathway in retinal microvascular epithelial cells.

The present study aimed to identify whether FK506 suppresses hypoxia­induced inflammation and protects tight junction function via the calcineurin­nuclear factor of activated T­cells 1 (CaN­NFATc1) signaling pathway in mouse retinal microvascular endothelial cells (mRMECs). The mRMECs were treated with FK506 at different concentrations following the induction of hypoxia. Trans­epithelial electrical resistance (TEER) and cell permeability were examined to measure the integrity of the tight junctions. The concentrations of inflammatory cytokines were measured using reverse transcription­quantitative polymerase chain reaction analysis and enzyme­linked immunosorbent assays. The protein expression levels of zonula occludens­1 (ZO­1) and nuclear factor of activated T­cell 1 (NFATc1) were identified using immunofluorescent microscopy and western blot analysis. The TEER value was decreased following hypoxia, but increased following treatment with FK506 (1 and 10 µM) for 24 and 48 h. The protein expression of ZO­1 was also increased following FK506 treatment for 24 h at 1 and 10 µM. By contrast, following treatment with FK506 (1 and 10 µM) for 24 and 48 h, the elevated cell permeability in the hypoxia group was significantly downregulated. Similarly, the concentrations of inflammatory cytokines, including cyclooxygenase­2, inducible nitric oxide synthase, monocyte chemoattractant protein­1, interleukin­6, intercellular adhesion molecule­1 and vascular cell adhesion molecule­1, were downregulated following treatment with FK506 for 24 h at 1 and 10 µM. Following treatment with FK506, the level of total NFATc1 was downregulated and the level of phosphorylated NFATc1 was upregulated. Taken together, FK506 suppressed injury to the tight junctions and downregulated the expression of inflammatory cytokines in hypoxia­induced mRMECs via the CaN­NFATc1 signaling pathway. This suggests a potentially effective therapy for hypoxia­induced retinal microangiopathy.

Madecassic Acid protects against hypoxia-induced oxidative stress in retinal microvascular endothelial cells via ROS-mediated endoplasmic reticulum stress.

Madecassic acid (MA) is an abundant triterpenoid in Centella asiatica (L.) Urban. (Apiaceae) that has been used as a wound-healing, anti-inflammatory and anti-cancer agent. Up to now, the effects of MA against oxidative stress remain unclear. In this study, we investigated the effect of MA and its mechanisms on hypoxia-induced human Retinal Microvascular Endothelial Cells (hRMECs). hRMECs were pre-treated with different concentrations of MA (0-50µM) for 30min before being incubated under hypoxia condition (37°C, 5% CO2 and 95% N2). Cell apoptosis was evaluated with MTT assay and TUNEL staining, and the expression of apoptosis- and endoplasmic reticulum (ER) stress-related molecules was assessed with western blotting and RT-PCR analysis. Intracellular ROS level was evaluated using DCFH-DA. Intracellular malondialdehyde (MDA), dehydrogenase (LDH), glutathione peroxidase (GSH-PX) and superoxide dismutase (SOD) were evaluated using related Kits. Activating transcription factor 4 (ATF4) nuclear translocation was assessed with western blotting analysis and immunofluorescence staining. MA significantly reduced oxidative stress in hypoxia-induced hRMECs, as shown by increased cell viability, SOD and GSH-PX leakage, decreased TUNEL- and ROS-positive cell ratio, LDH and MDA leakage, caspase-3 and -9 activity, and Bax/Bcl-2 ratio. In addition, MA also attenuated hypoxia-induced ER stress in hRMECs, as shown by reduced mRNA levels of glucose-regulated protein 78 (GRP78), C/EBP homologous transcription factor (CHOP), protein levels of cleaved activating transcription factor 6 (ATF6) and inositol-requiring kinase/endonuclease 1 alpha (IRE1α), phosphorylation of pancreatic ER stress kinase (PERK) and eukaryotic initiation factor 2 alpha (eIF2α), cleaved caspase-12 and ATF4 translocation to nucleus. The current study indicated that the regulation of oxidative stress and ER stress by MA would be a promising therapy to reverse the process and development of hypoxia-induced hRMECs dysfunction.