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To identify predictors of extension of the injection interval beyond 8 weeks at the 24-month visit after switching to brolucizumab in aflibercept-resistant polypoidal choroidal vasculopathy (PCV). Retrospective observational study. 17 eyes of 16 patients with persistent or recurrent exudation on aflibercept were switched to intravitreal brolucizumab and managed with a treat-and-extend (T&E) regimen with a minimum 8-week interval after loading. The primary outcome contrasted extension (>8 weeks) versus non-extension (≤8 weeks) at month 24. Prespecified predictors were early central choroidal thickness (CCT) change from baseline to the switch visit (A0 to A1; ≥ 40% reduction) and pachychoroid. Associations were tested with Fisher's exact tests and Firth-penalized logistic regression with the event defined as extension. At 24 months, 6 of 17 eyes (35%) achieved extension. A ≥ 40% early CCT reduction occurred in 0 of 6 extension eyes versus 7 of 11 non-extension eyes (Fisher exact two-sided P ≈ 0.035). In the Firth model (event = extension), < 40% CCT reduction strongly predicted extension (odds ratio 38.5; profile-likelihood 95% CI 2.0-10,000; LR P = 0.004). Non-pachychoroid showed the same direction with wide CIs (odds ratio 14.3; 95% CI 0.99-2,174; LR P = 0.006). Model fit was significant (LR χ² = 15.19, P = 0.0005) and discrimination was good (apparent AUC ≈ 0.97). We prespecified a parsimonious two-predictor model to limit overfitting; adding age, sex, prior photodynamic therapy, or number of prior aflibercept injections did not materially change coefficients or improve AICc (ΔAICc < 2). Eyes without marked early choroidal thinning (<40% CCT reduction at A1) were more likely to extend, whereas marked thinning (≥40%) signaled difficulty extending under T&E regimen after switching to brolucizumab. Given the small sample and few events, estimates should be interpreted cautiously and considered hypothesis-generating, and warrant prospective external validation studies.

Lutein slows the progression of age-related macular degeneration (AMD), a leading cause of blindness in ageing societies. However, the underlying mechanisms remain elusive. Here, we evaluated lutein’s effects on light-induced AMD-related pathological events. Balb/c mice exposed to light (2000 lux, 3 h) showed tight junction disruption in the retinal pigment epithelium (RPE) at 12 h, as detected by zona occludens-1 immunostaining. Substantial disruption remained 48 h after light exposure in the vehicle-treated group; however, this was ameliorated in the mice treated with intraperitoneal lutein at 12 h, suggesting that lutein promoted tight junction repair. In the photo-stressed RPE and the neighbouring choroid tissue, lutein suppressed reactive oxygen species and increased superoxide dismutase (SOD) activity at 24 h and produced sustained increases in sod1 and sod2 mRNA levels at 48 h. SOD activity was induced by lutein in an RPE cell line, ARPE19. We also found that lutein suppressed upregulation of macrophage-related markers, f4/80 and mcp-1 , in the RPE-choroid tissue at 18 h. In ARPE19, lutein reduced mcp-1 mRNA levels. These findings indicated that lutein promoted tight junction repair and suppressed inflammation in photo-stressed mice, reducing local oxidative stress by direct scavenging and most likely by induction of endogenous antioxidant enzymes.

The annual increase in myopia prevalence poses a significant economic and health challenge. Our study investigated the effect of calcitriol role in myopia by inducing the condition in guinea pigs through form deprivation for four weeks. Untargeted metabolomics methods were used to analyze the differences in metabolites in the vitreous body, and the expression of vitamin D receptor (VDR) in the retina was detected. Following form deprivation, the guinea pigs received intraperitoneal injections of calcitriol at different concentrations. We assessed myopia progression using diopter measurements and biometric analysis after four weeks. Results indicated that form deprivation led to a pronounced shift towards myopia, characterized by reduced choroidal and scleral thickness, disorganized collagen fibers, and decreased scleral collagen fiber diameter. Notably, a reduction in calcitriol expression in vitreous body, diminished vitamin D and calcitriol levels in the blood, and decreased VDR protein expression in retinal tissues were observed in myopic guinea pigs. Calcitriol administration effectively slowed myopia progression, preserved choroidal and scleral thickness, and prevented the reduction of scleral collagen fiber diameter. Our findings highlight a significant decrease in calcitriol and VDR expressions in myopic guinea pigs and demonstrate that exogenous calcitriol supplementation can halt myopia development, enhancing choroidal and scleral thickness and scleral collagen fiber diameter.

Background Since there is evidence that the Fc domain of antivascular endothelial growth factor drugs may cause unexpected consequences in retinal and choroidal vessels, the effects of intravitreal ranibizumab and aflibercept on monkey eyes were investigated. Methods Four cynomolgus monkeys were intravitreally injected with 0.5 mg of ranibizumab and another four with 2 mg of aflibercept. Two untreated monkeys served as controls. Funduscopy, fluorescein angiography (FA), spectral-domain-optical coherence tomography (SD-OCT) and measurement of intraocular pressure (IOP) were performed. The eyes were inspected by light, fluorescence and electron microscopy. The diameter of the choriocapillaris (CC) was measured by morphometry, and the areas of the CC with free haemoglobin, CC fenestrations and endothelial thickness were quantified. Results Analysis showed ranibizumab permeated the retina via intercellular clefts, whereas aflibercept was taken up by ganglion cells, cells of the inner and outer retinal layers and the retinal pigment epithelium (RPE). Stasis and haemolysis in the choriocapillaris and choroidal vessels were more frequent after aflibercept treatment, which caused hypertrophy and death of individual RPE cells. The area of the CC was significantly reduced after both drugs compared with controls, but the reduction of the CC endothelium thickness, number of fenestrations and the areas with haemolysis were more pronounced after aflibercept. Conclusions Ranibizumab permeated the retina through intercellular spaces, whereas aflibercept was taken up by neuronal and RPE cells. Aflibercept induced protein complex formation and more haemolysis in the choriocapillaris, leading to individual RPE cell death. The clinical significance and relation of these findings to the Fc domain or to other characteristics of aflibercept remain to be investigated.

Aim of this study was to evaluate the efficacy of switching treatment to faricimab in neovascular age-related macular degeneration (nAMD) from other anti-VEGF agents. Fifty-eight eyes of fifty-one patients with nAMD and a full upload series of four faricimab injections were included. Demographic data, multimodal imaging and treatment parameters were recorded. The primary outcome measures were changes in central subfield thickness (CST) and subfoveal choroidal thickness (SFCT). A subgroup analysis was performed for eyes with prior ranibizumab (R) or aflibercept (A) treatment. Mean injection intervals before and after switching were comparable (33.8 ± 11.2 vs. 29.3 ± 2.6 days; p  = 0.08). Mean CST of 361.4 ± 108.1 µm prior to switching decreased significantly to 318.3 ± 97.7 µm ( p  < 0.01) after the third faricimab injection, regardless of prior anti-VEGF treatment ( p  < 0.01). Although SFCT slightly improved for the whole cohort from 165.8 ± 76.8 µm to 161.0 ± 82,8 µm ( p  = 0.029), subgroup analysis did not confirm this positive effect (subgroup R: p  = 0.604; subgroup A: p  = 0.306). In patients with a suboptimal response to aflibercept or ranibizumab in nAMD, farcimab can improve CST and slightly improve or maintain SFCT. Further prospective randomized trials are warranted.

The purpose of the current study was to investigate the effect of topical atropine on choroidal thickness using spectral-domain optical coherence tomography. A total of 30 healthy eyes from 30 children were analyzed in this study. A single drop of 1% atropine gel was administered twice daily for a week. Choroidal thickness (CT) was measured using SD-OCT, and changes in CT before and after administration of the eye drops were analyzed at the subfovea and at 1.0-mm intervals (up to 3.0 mm) from the fovea at superior, inferior, nasal, and temporal locations. Pre- and post-cycloplegic axial length (AL) was also measured using the IOLMaster. We observed that administration of 1% atropine gel led to a significant increase in the choroidal thickness under the fovea and at all intervals from the fovea. The greatest change in CT was observed in the inferior meridian, while the nasal meridian exhibited the least change. AL did not significantly differ before and after cycloplegia, and there was no significant correlation between the changes in AL and subfoveal CT. It was concluded that administration of 1% atropine gel can significantly increase CT in the eyes of young Chinese children, albeit with different magnitude at different locations.

The angiogenic sprout has been compared to the growing axon, and indeed, many proteins direct pathfinding by both structures 1 . The Roundabout (Robo) proteins are guidance receptors with well-established functions in the nervous system 2 , 3 ; however, their role in the mammalian vasculature remains ill defined 4 , 5 , 6 , 7 , 8 . Here we show that an endothelial-specific Robo, Robo4, maintains vascular integrity. Activation of Robo4 by Slit2 inhibits vascular endothelial growth factor (VEGF)-165–induced migration, tube formation and permeability in vitro and VEGF-165–stimulated vascular leak in vivo by blocking Src family kinase activation. In mouse models of retinal and choroidal vascular disease, Slit2 inhibited angiogenesis and vascular leak, whereas deletion of Robo4 enhanced these pathologic processes. Our results define a previously unknown function for Robo receptors in stabilizing the vasculature and suggest that activating Robo4 may have broad therapeutic application in diseases characterized by excessive angiogenesis and/or vascular leak.

Purpose In this work, we tested the hypothesis that microneedles provide a minimally invasive method to inject particles into the suprachoroidal space for drug delivery to the back of the eye. Methods A single, hollow microneedle was inserted into the sclera, and infused nanoparticle and microparticle suspensions into the suprachoroidal space. Experiments were performed on whole rabbit, pig, and human eyes ex vivo. Particle delivery was imaged using brightfield and fluorescence microscopy as well as microcomputed tomography. Results Microneedles were shown to deliver sulforhodamine B as well as nanoparticle and microparticle suspensions into the suprachoroidal space of rabbit, pig, and human eyes. Volumes up to 35 μL were administered consistently. Optimization of the delivery device parameters showed that microneedle length, pressure, and particle size played an important role in determining successful delivery into the suprachoroidal space. Needle lengths of 800-1,000 μm and applied pressures of 250-300 kPa provided most reliable delivery. Conclusions Microneedles were shown for the first time to deliver nanoparticle and microparticle suspensions into the suprachoroidal space of rabbit, pig and human eyes. This shows that microneedles may provide a minimally invasive method for controlled drug delivery to the back of the eye.

Background/aimsTo investigate the changes in the intrachoroidal structures after half-dose verteporfin photodynamic therapy (PDT) for central serous chorioretinopathy (CSC).MethodsSwept-source optical coherence tomography cross-sectional images of 22 eyes of 22 patients with CSC were retrospectively analysed by a manual delineation technique and binarisation method.ResultsIn the 22 eyes, the mean subfoveal choroidal thickness decreased from 412.9±112.9 μm at baseline to 340.0±111.0 μm at 3 months (p<0.0001). The mean thickness of the large choroidal vessel layer decreased from 368.7±112.7 μm at baseline to 292.2±118.0 μm at 3 months (p<0.0001), but the mean choriocapillaris-medium choroidal vessel layer thickness did not change from 44.2±29.2 μm at baseline to 47.8±25.7 μm at 3 months (p=0.85). Analyses of the binarised choroidal images showed that a 3 mm subfoveal choroidal area decreased from 1.141±0.290 mm2 at baseline to 0.962±0.320 mm2 at 3 months after PDT (p=0.0001). The mean luminal areas decreased from 0.826±0.246 mm2 at baseline to 0.665±0.234 mm2 at 3 months (p=0.0001), however, the mean stromal areas did not change from 0.315±0.066 mm2 at baseline to 0.297±0.095 mm2 at 3 months (p=0.60).ConclusionsHalf-dose PDT reduces subfoveal choroidal thickness and alters the intrachoroidal structures in eyes with CSC.

ABSTRACT Anti‐vascular endothelial growth factor (VEGF) drugs suppress choroidal neovascularisation (CNV), thus improving vision. However, some patients may have a poor response or develop resistance to anti‐VEGF drugs. Geraniin (GE), a polyphenol isolated from an herb called Phyllanthus amarus, possesses anti‐angiogenic properties. This study aimed to explore the mechanism of action of GE in CNV. GE was found to activate the angiotensin‐converting enzyme 2 (ACE2)/angiotensin 1–7 (Ang‐[1–7])/MAS1 proto‐oncogene, G protein‐coupled receptor (MasR)/interleukin‐10 (IL‐10) pathway in hypoxic human choroidal endothelial cells (HCECs) in vitro and mouse models of laser‐induced CNV in vivo. Activation of the ACE2/Ang‐(1–7)/MasR/IL‐10 pathway by GE attenuated the proliferative, migratory, and tube‐forming abilities of hypoxic HCECs and prevented the development of CNV in mice. Notably, GE did not cause ocular or systemic toxicity in mice with CNV. These findings suggest that GE alleviates CNV by activating the ACE2/Ang‐(1–7)/MasR/IL‐10 pathway in choroidal endothelial cells (CECs).