Purpose:To develop diffusion-based fundus fluorescein angiography (DiFFA), a noninvasive method for generating high-quality FFA images from color fundus (CF) photographs using diffusion models, addressing the limitations of invasive FFA examinations in detecting diabetic microvascular complications. Methods:DiFFA was trained on paired CF and FFA images from 4032 patients across 3 hospitals, with external validation using 2000 CF images from the UK Biobank. Four systematic evaluations were conducted: (1) objective image quality assessment using the mean absolute error, peak signal-to-noise ratio, structural similarity index measure, and Fréchet inception distance metrics, (2) subjective authenticity evaluation by ophthalmologists, (3) diagnostic efficiency assessment, and (4) automated classification accuracy for diabetic retinopathy and diabetic kidney disease using VGG16 with and without synthetic FFA images. Results:DiFFA achieved strong objective performance (mean absolute error, 109.25,; peak signal-to-noise ratio, 27.677; Fréchet inception distance, 38.466; structural similarity index measure, 0.694). Ophthalmologists showed limited ability to distinguish synthetic from real FFA images (area under the curve, 0.52 ± 0.06 for junior ophthalmologists and 0.57 ± 0.05 for senior ophthalmologists), with no significant quality score differences (P > 0.05). Combining synthetic FFA with CF images improved automated classification, achieving an area under the curve of 0.933 for diabetic retinopathy and 0.849 for diabetic kidney disease internally, compared with 0.891 and 0.792 using CF photographs alone. External validation confirmed improvements (diabetic retinopathy, 0.858 to 0.879; diabetic kidney disease, 0.731 to 0.814). Conclusions:DiFFA successfully generates clinically authentic FFA images from non-invasive CF photographs, enhancing diagnostic accuracy while overcoming the invasiveness limitations of traditional FFA examinations. Translational Relevance:Diffusion-based fundus fluorescein angiography enables noninvasive early detection of diabetic microvascular complications, improving patient compliance and diagnostic accessibility while reducing examination risks in diabetes screening and monitoring.

Ocular fundus neovascularization (OFN) is a leading cause of irreversible vision loss. Conventional antivascular endothelial growth factor (anti-VEGF) therapies indiscriminately suppress pathological and reparative angiogenesis and fail to correct the senescence- and inflammation-driven microenvironment that sustains disease progression. Senescent endothelial cells (ECs) form the structural scaffold of pathological vessels, while neighboring senescent microglia exacerbate inflammatory signaling, together deteriorating the reactive oxygen species (ROS)-rich vascular-immune microenvironment. Here, we develop an injectable ROS-responsive senolytic hydrogel (PCC1/PHCF-Gel) that enables lesion-activated, sustained intraocular release of procyanidin C1 (PCC1), overcoming rapid clearance, oxidative degradation, and poor lesion retention associated with free PCC1. In oxygen-induced retinopathy and choroidal neovascularization models, PCC1/PHCF-Gel markedly reduces retinal senescence, suppresses pathological neovascularization, and restores neuroretinal function, outperforming symptom-directed therapies anti-VEGF therapy. Single-cell RNA sequencing reveals selective elimination of two pathogenic senescent cell subpopulations-CXCR4+ ECs and IFITM3+ microglia-thereby disrupting the reinforcing cycle of vascular and immune senescence and promoting reparative vascular regeneration. These findings establish a multifunctional, spatiotemporally controlled therapeutic paradigm and highlight PCC1/PHCF-Gel as a promising translational strategy for the precision treatment of OFN.

Neovascular age-related macular degeneration (nAMD) is a major aetiology of vision loss characterized by lipid metabolism dysregulation. This study investigated the alterations in lipid profiles associated with wet AMD (wAMD) and its subtype, polypoidal choroidal vasculopathy (PCV). A cross-sectional lipidomic analysis was derived from a prospective longitudinal study in China (2017–2019). Serum samples from 195 wAMD patients, 130 PCV patients and 119 controls were analysed using ultra-performance liquid chromatography‒tandem mass spectrometry (UPLC‒MS/MS), focusing on acylcarnitines, glycerophospholipids and sphingolipids. Training and test sets were randomly generated after sample size matching. Orthogonal partial least squares-discriminant (OPLS-DA), univariate and multivariate analyses were performed. The selection criteria for differential lipids were a variable importance in projection (VIP) > 1.0, a fold change (FC) > 1.2 or < 0.83, and a false discovery rate (FDR) < 0.05. Key lipids were refined using the Boruta algorithm and evaluated through Firth regression and receiver operating characteristic (ROC) analysis. Spearman’s rank correlation analysis was used to assess the relationships between the differential lipids and ocular indicators, including central retinal thickness (CRT), central retinal volume (CRV) and best-corrected visual acuity (BCVA). No significant Lipid profile differences were detected between wAMD and PCV. Compared with the controls, wAMD patients had 53 differential lipids (52 upregulated, 1 downregulated), whereas PCV patients had 34 (31 upregulated, 3 downregulated). Upregulated PC ae C42:0 was consistently associated with ocular indicators in both groups. A 9-lipid panel for wAMD and a 6-lipid panel for PCV showed moderate diagnostic performance in the ROC models. Significant correlations with macular structure and BCVA were observed in PCV patients for 12 phosphatidylcholines, 3 sphingomyelins and 2 acylcarnitines and in wAMD patients for one phosphatidylcholine and one acylcarnitine. Downregulated lipids were negatively correlated with CRT or CRV, whereas upregulated lipids showed the opposite trend. Age-related lipid associations were found in wAMD but not in PCV patients. PCV and wAMD had shared and distinct lipidomic dysregulations, with stronger systemic–retinal associations in PCV, suggesting that subtype-specific metabolic reprogramming may affect nAMD pathology, offering new perspectives regarding early diagnosis and intervention strategies to mitigate disease burden. NCT03128463 ( www.ClinicalTrial.gov ) was registered on 9 March 2017.

Pathological retinal and choroidal neovascularization is a hallmark of several blinding diseases, including diabetic retinopathy and age-related macular degeneration. While intravitreal anti-VEGF therapies remain the standard of care, they necessitate frequent injections, posing risks such as endophthalmitis and elevated intraocular pressure, alongside economic and adherence challenges. Here, we present Pene/LQ015, a novel eye drop formulation comprising the anti-VEGFA nanobody (LQ015) and a proprietary penetratin analog for noninvasive delivery. LQ015 demonstrates superior VEGF-blocking activity, broad binding specificity across species, and robust stability and scalability using a yeast expression system. Topical administration of Pene/LQ015 achieved effective retinal-choroid complex drug levels and suppressed neovascularization in preclinical models. Notably, in the cynomolgus monkey laser-induced choroidal neovascularization model, 30 days of continuous topical application significantly reduced neovascularization and vascular leakage, with excellent safety and tolerability. These findings highlight Pene/LQ015's potential as a game-changer in treating neovascular eye diseases. It offers a groundbreaking, noninvasive alternative to intravitreal injections, addressing key limitations of current therapies by enabling continuous dosing, improving patient adherence, and reducing treatment burden. These findings underscore its potential to transform the management of neovascular retinal and choroidal diseases, with promising implications for clinical application.

Age-related macular degeneration (AMD) is the leading cause of blindness; however, its underlying pathogenesis remains unclear. This study investigated the role of the neuropeptide VF (NPVF) in AMD. Transcriptome profiling in retinal-choroid tissues was analyzed using a public dataset. There was an increase in NPVF expression in the retinal-choroid tissues of eyes with AMD, which was more significant in wet AMD. Serological validation was conducted to verify the expression of NPVF in 30 wet AMD patients and 30 controls, and a statistically significant increase in serum NPVF concentration was observed in wet AMD patients. The role of NPVF in AMD was then investigated through in vitro experiments involving the overexpression of NPVF in a human retinal pigment epithelium (RPE) cell line. Overexpression of NPVF resulted in a marked upregulation of hypoxia-inducible factor-1 alpha (HIF-1 alpha), a key regulator implicated in the pathogenesis of AMD and associated neovascularization, and further promotes the secretion of vascular endothelial growth factor and enhances endothelial tube formation. By integrating transcriptomic and metabolomic data, it was found that aldehyde dehydrogenase 2 (ALDH2) was upregulated, whereas its substrate, D-glycerate, was downregulated in NPVF-overexpressing RPE cells. Further experimental validation confirmed that NPVF regulates HIF-1 alpha expression through the ALDH2/D-glycerate axis. In summary, the present findings suggest that NPVF contributes to AMD pathogenesis via the ALDH2/D-glycerate/HIF-1 alpha pathway.

Background: Retinal vascular occlusion (RVO) and retinal artery occlusion (RAO) have been reported as rare adverse events following COVID-19 vaccination, raising concerns about vaccine safety. This review synthesizes cohort and case–control studies assessing the association between COVID-19 vaccines and RVO/RAO, while exploring potential pathophysiological mechanisms. Methods: We analyzed large-scale population-based studies from South Korea, Europe, and the TriNetX database, focusing on odds ratios (OR), hazard ratios (HR), and relative risks (RR) across mRNA and adenoviral vector vaccines. Pathological processes were hypothesized based on molecular and clinical evidence. Results: Studies investigating the association between COVID-19 vaccination and retinal vascular occlusion show conflicting results; some studies report no association (e.g., OR 0.93, 95% CI 0.60–1.45), others suggest reduced risk (e.g., OR 0.80, 95% CI 0.64–0.99), and one indicates increased risk over two years (HR 2.19, 95% CI 2.00–2.39). Adenoviral vector vaccines, particularly ChAdOx1, show higher RAO incidence in specific cohorts. Proposed mechanisms include vaccine-induced immune thrombotic thrombocytopenia (VITT) via anti-PF4 antibodies, spike protein-mediated endothelial dysfunction, and adjuvant-driven inflammation. Conclusions: While causality remains unproven, temporal heterogeneity and vaccine type-specific risks warrant further investigation. Longitudinal studies with robust controls are needed to clarify these associations in the post-pandemic context.

To assess the association between serum uric acid (SUA) level and the prevalence of diabetic retinopathy (DR) and chronic kidney disease (CKD) in patients with long-term diabetes. A cross-sectional analysis was conducted involving diabetic patients from Shanghai General hospital during October 2018 and October 2021. Participants underwent measurements of SUA, renal function test and DR assessments via fundus photography. Multivariable ordinal logistic regression models assessed odd ratios (ORs) and 95

Aims To find potential relation between retrobulbar vessels and fundus microvessels and to detect sensitive and effective clinical indicators in predicting the progress of diabetic retinopathy (DR), ocular hemodynamics were measured using superb microvascular imaging (SMI) and ultrawide-field optical coherence tomography angiography (UWF-OCTA). Methods Observational, cross-sectional study evaluating ocular hemodynamics in patients with DR by SMI (Aplio i900, Canon Medical) and UWF-OCTA (BM-400 K BMizar, Tupai Medical Technology). The peak systolic velocity (PSV), end-diastolic velocity (EDV), and resistive index (RI) of the central retinal artery (CRA), posterior ciliary artery (PCA), and ophthalmic artery (OA) were measured by SMI. UWF-OCTA evaluated the fundus vascular parameters. A correlation analysis was used to determine the correlation between SMI and UWF-OCTA parameters. Results One hundred thirty-nine eyes of 139 diabetic patients were included: 29 without DR (NDR), 36 with mild to moderate nonproliferative DR (M-NPDR), 37 with severe NPDR (S-NPDR), and 37 with proliferative DR (PDR). PSV and EDV of retrobulbar vessels decreased from NDR to S-NPDR while increasing PDR. RI of OA showed a decreasing trend in the progression of DR, but other vessels didn’t show the same trend. ROC curve analysis showed that CRA PSV , CRA EDV , PCA EDV , OA PSV, and OA EDV had diagnostic value distinguishing M-NPDR and S-NPDR. The correlation analysis observed a significant association between the SMI parameters of CRA and PCA and UWF-OCTA parameters. CRA hemodynamics were more associated with fundus vascular parameters, especially the retina, in the NDR group than in the M-NPDR group. In contrast, PCA consistently correlated with fundus vascular parameters, especially in the choroid, from the NDR to the M-NPDR group. However, OA showed a poor correlation with OCTA parameters. Conclusion The velocity of retrobulbar vessels, mainly the CRA, may serve as a valuable predictor for assessing the progress of DR. The use of SMI in diabetic patients may help identify patients at risk of developing retinopathy.

Chen, Chong MD; Liu, Kun MD, PhD; Gong, Yuanyuan MD; Yu, Suqin MD; Xu, Xun MD; Su, Li MD, PhDEditor(s): Grewal, Dilraj; Valikodath, Nita; Justin, Grant A. Author Information

Introduction: This study aimed to compare anatomical outcomes of air and perfluoropropane gas (C3F8) tamponade in pars plana vitrectomy for the treatment of rhegmatogenous retinal detachment (RRD). Methods: In this retrospective study, data were gathered from 578 patients (578 eyes) with RRD. The follow-up records of all 578 patients that underwent primary vitrectomy for RRD with air or C3F8 were examined and analyzed. Surgical outcomes of the two groups were compared. Results: A total of 342 eyes were treated with air and 236 with C3F8. The mean follow-up period was 37.65 ± 2.33 months. Baseline and preoperative clinical characteristics were similar between groups, but the period to intraocular bubble disappearance (p < 0.0001), intraocular pressure on the first postoperative day (p < 0.0001), number of cases with intraocular pressure >21 mm Hg within 3 days post-surgery (p < 0.0001), and the number with intraocular pressure >21 mm Hg during follow-up (p = 0.0002) differed significantly between groups. Primary reattachment rates for air and C3F8 groups were 95.03% and 95.34%, respectively. Clinical characteristics were similar in those with and without successful reattachment, and the frequency of new or unclosed breaks was similar between the two groups. There was no significant difference in two groups according to the presence or absence of inferior retinal breaks and inferior detached quadrants. Univariate and multivariate logistic regression identified no risk factor for surgical failure. Conclusions: Air showed equivalent effects to C3F8, with a shorter period to intraocular bubble disappearance, less risk of postoperative intraocular hypertension, and less expense.

Purpose: Human trabecular meshwork cell (HTMC) dysfunction results in imbalanced aqueous humor inflow and outflow, leading to an increase in intraocular pressure (IOP). Uncontrolled high IOP can promote the occurrence of glaucoma, an irreversible optic neuropathy. Here, we explored whether the long non-coding RNA plasmacytoma variant translocation 1 (lncRNA PVT1)/microRNA-29a-3p (miR-29a-3p) axis could ameliorate HTMC dysfunction under oxidative stress by modulating the expression of the proangiogenic factor vascular endothelial growth factor (VEGFA) and the profibrotic factor metalloproteinase-2 (MMP-2). Methods: HTMCs were cultured under H2O2-induced oxidative stress for 48 h. The expression of lncRNA PVT1, miR-29a-3p, VEGFA, MMP-2, intracellular adhesion molecule-1 (ICAM-1), and alpha-smooth muscle actin (α-SMA) was detected by reverse transcription quantitative real-time polymerase chain reaction, western blotting, and immunofluorescence. Interference experiments were conducted via the transfection of HTMCs with small interfering RNA (siRNA) targeting lncRNA PVT1 or miR-29a-3p mimics. A luciferase reporter assay was undertaken to identify the presence of a miR-29a-3p binding site in lncRNA PVT1. Flow cytometry and Transwell and Cell Counting Kit-8 assays were employed to evaluate HTMC functions under oxidative stress with different treatments. Results: In HTMCs, the expression of lncRNA PVT1 was induced by H2O2 treatment, whereas that of miR-29a-3p was inhibited. The levels of angiogenic factors (VEGFA, ICAM-1) and fibrosis-associated mediators (MMP-2, α-SMA) were upregulated in HTMCs under oxidative stress. The siRNA-mediated suppression of lncRNA PVT1 or the upregulation of miR-29a-3p significantly suppressed the expression of VEGFA, MMP-2, ICAM-1, and α-SMA. A luciferase reporter assay confirmed that lncRNA PVT1 directly targeted miR-29a-3p and acted as a miR-29a-3p sponge. The knockdown of lncRNA PVT1 restored the level of miR-29a-3p in H2O2-treated HTMCs, thereby inhibiting VEGFA and MMP-2, its target mRNAs. HTMC dysfunction, including increased apoptosis and decreased cell mobility and viability, could be effectively ameliorated by lncRNA PVT1 downregulation or miR-29a-3p overexpression under oxidative stress. Conclusion: LncRNA PVT1 has potential as a therapeutic target for inhibiting VEGFA and MMP-2, thus protecting HTMCs, suppressing the progression of fibrosis, and, consequently, improving the outcome of glaucoma filtration surgery.

Chen, Chong MD; Hu, Guangyi MD, PhD; Chen, Feng'e MD; Liu, Kun MD, PhD; Yu, Suqin MD; Xu, Xun MDEditor(s): Grewal, Dilraj; Valikodath, Nita; Justin, Grant A. Author Information

Background:Retinal disorders cause substantial visual burden globally. Accurate estimates of the vision loss due to retinal diseases are pivotal to inform optimal eye health care planning and allocation of medical resources. The purpose of this study is to describe the proportion of visual impairment and blindness caused by major retinal diseases in China.Methods:A nationwide register-based study of vitreoretinal disease covering all 31 provinces (51 treating centres) of mainland China. A total of 28 320 adults diagnosed with retinal diseases were included. Participants underwent standardised ocular examinations, which included best-corrected visual acuity (BCVA), dilated-fundus assessments, and optical coherence tomography. Visual impairment and blindness are defined using BCVA according to the World Health Organization (WHO) (visual impairment: <20/63-≥20/400; blindness: <20/400) and the United States (visual impairment: <20/40-≥20/200; blindness: <20/200) definitions. The risk factors of vision loss were explored by logistic regression analyses.Results:Based on the WHO definitions, the proportions for unilateral visual impairment and blindness were 46% and 18%, respectively, whereas those for bilateral visual impairment and blindness were 31% and 3.3%, respectively. Diabetic retinopathy (DR) accounts for the largest proportion of patients with visual impairment (unilateral visual impairment: 32%, bilateral visual impairment: 60%) and blindness (unilateral blindness: 35%; bilateral blindness: 64%). Other retinal diseases that contributed significantly to vision loss included age-related macular degeneration, myopic maculopathy, retinal vein occlusion, and rhegmatogenous retinal detachment and other macular diseases. Women (bilateral vision loss: P = 0.011), aged patients (unilateral vision loss: 45-64 years: P < 0.001, ≥65 years: P < 0.001; bilateral vision loss: 45-64 years: P = 0.003, ≥65 years: P < 0.001 (reference: 18-44 years)) and those from Midwest China (unilateral and bilateral vision loss: both P < 0.001) were more likely to suffer from vision loss.Conclusions:Retinal disorders cause substantial visual burden among patients with retinal diseases in China. DR, the predominant retinal disease, is accountable for the most prevalent visual disabilities. Better control of diabetes and scaled-up screenings are warranted to prevent DR. Specific attention should be paid to women, aged patients, and less developed regions.

Purpose: To assess the anti-neovascularization effect of a novel peptide NT/K-CRS derived from the kringle domain of neurotrypsin in vitro and in vivo. Methods: Primary human umbilical vein endothelial cells (HUVECs) were treated with vascular endothelial growth factor (VEGF) in advance. Cell migration, lumen formation, and cell proliferation assays were performed to determine the anti-neovascularization effect of NT/K-CRS in HUVECs. TUNEL and 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium tests were conducted to evaluate cell viability. Chick chorioallantoic membrane and oxygen-induced retinopathy model were established to assess the anti-angiogenic role of NT/K-CRS in vivo. Results: The in vitro results showed that NT/K-CRS effectively decreased VEGF-induced cell migration and endothelial tube formation, with no significant effect on cell proliferation and cell viability. In addition, NT/K-CRS showed great efficacy in angiogenesis inhibition in chicken embryos. The cytokine release syndrome (CRS) peptide also inhibited retinal neovascularization and improved retinal blood perfusion in oxygen-treated mouse pups through intravitreal injection. Conclusions: NT/K-CRS peptide derived from the kringle domain of neurotrypsin can strongly inhibit neovascularization in vitro and vivo. This novel peptide may become a promising therapeutic agent for neovascular-related ocular diseases.

Background: Neovascular age-related macular degeneration (nAMD) and polypoidal choroidal vasculopathy (PCV) are major causes of blindness in aged people. 30% of the patients show unsatisfactory response to anti-vascular endothelial growth factor (anti-VEGF) drugs. This study aims to investigate the relationship between serum metabolome and treatment response to anti-VEGF therapy.Methods: A prospective longitudinal study was conducted between March 2017 and April 2019 in 13 clinical sites in China. The discovery group were enrolled from Shanghai General Hospital. The validation group consisted of patients from the other 12 sites. Participants received at least one intravitreal injection of 0.5 mg anti-VEGF drug, conbercept, and were divided into two groups - responders and non-responders. Serum samples of both groups were processed for UHPLC-MS/MS analysis. We constructed principal component analysis (PCA) and partial least squares discriminant analysis (PLS-DA) models to investigate the metabolic differences between two groups using SIMCA-P. Area under curve (AUC) was calculated to screen the biomarkers to predict treatment response. Metabolites sub-classes and enriched pathways were obtained using MetaboAnalyst5.0.Results: 219 eyes from 219 patients (nAMD = 126; PCV = 93) were enrolled. A total of 248 metabolites were detected. PCA and PLS-DA models of the discovery group demonstrated that the metabolic profiles of responders and non-responders clearly differed. Eighty-five differential metabolites were identified, including sub-classes of diacylglycerophosphocholines, lysophosphatidylcholine (LPC), fatty acids, phosphocholine, etc. Responders and non-responders differed most significantly in metabolism of LPC (p = 7.16 × 10^-19) and diacylglycerophosphocholine (p = 6.96 × 10^-17). LPC 18:0 exhibited the highest AUC, which is 0.896 with 95% confidence internal between 0.833 and 0.949, to discriminate responders. The predictive accuracy of LPC 18:0 was 72.4% in the validation group.Conclusions: This study suggests that differential metabolites may be useful for guiding treatment options for nAMD and PCV. Metabolism of LPC and diacylglycerophosphocholine were found to affect response to conbercept treatment. LPC 18:0 was a potential biomarker to discriminate responders from non-responders.

As a type of local anaesthesia, retrobulbar nerve block is often used in vitrectomy, with patients remaining conscious during the operation. The increase in systolic blood pressure (SBP) caused by tension and fear during the operation—especially in patients with a history of hypertension—can negatively impact the safety of the procedure, resulting in suprachoroidal haemorrhage or retinal haemorrhage. Diazepam has a sedative effect and can relieve tension during surgery. This study aims to evaluate the efficacy and safety of diazepam for intraoperative BP stabilisation in hypertensive patients under retrobulbar anaesthesia during surgery. This single-centre, double-blind, randomised controlled and parallel clinical trial will include 180 hypertensive patients who will undergo vitrectomy with nerve block anaesthesia. Study participants will be randomly allocated in a 1:1 ratio to intervention (patients receiving oral diazepam before the operation) and control (patients receiving oral placebo before the operation) groups. The primary outcome is the effective rate of intraoperative BP control (systolic BP during operation maintained at <160mmHg at all timepoints). The secondary outcomes are the proportion of patients with SBP ≥180 mmHg at any timepoint from operation to 1 h post-operation, the change of mean systolic blood pressure and mean heart rate during operation from baseline, as well as the number of patients with intraoperative and post-operative adverse reactions within 12 weeks of surgery. The logistic regression model will be performed to compare the outcomes. This study will evaluate the efficacy and safety of diazepam for intraoperative BP stabilisation in hypertensive patients under nerve block anaesthesia during surgery. The results of this trial will reveal whether diazepam has a significant effect on intraoperative BP stability in patients with a history of hypertension who require vitrectomy. If the results of this trial are significant, a large-scale multi-centre clinical trial can be designed. Chinese Clinical Trial Registry (ChiCTR) ChiCTR2100041772 . Registered on 5 January 2021.