Autophagy in drusen biogenesis secondary to age-related macular degeneration.

Age-related macular degeneration (AMD) is an emerging cause of blindness in aged people worldwide. One of the key signs of AMD is the degeneration of the retinal pigment epithelium (RPE), which is indispensable for the maintenance of the adjacent photoreceptors. Because of impaired energy metabolism resulting from constant light exposure, hypoxia, and oxidative stress, accumulation of drusen in AMD-affected eyes is observed. Drusen contain damaged cellular proteins, lipoprotein particles, lipids and carbohydrates and they are related to impaired protein clearance, inflammation, and extracellular matrix modification. When autophagy, a major cellular proteostasis pathway, is impaired, the accumulations of intracellular lipofuscin and extracellular drusen are detected. As these aggregates grow over time, they finally cause the disorganisation and destruction of the RPE and photoreceptors leading to visual loss. In this review, the role of autophagy in drusen biogenesis is discussed since impairment in removing cellular waste in RPE cells plays a key role in AMD progression. In the future, means which improve intracellular clearance might be of use in AMD therapy to slow the progression of drusen formation.

One-Year Functional and Morphological Prognosis After Intravitreal Injection Treatments According to Different Morphological Patterns of Diabetic Macular Edema in Real-Life: MARMASIA Study Group Report No.13.

PURPOSE: To evaluate the responses of different optical coherence tomography (OCT) patterns of diabetic macular edema (DME) to intravitreal injection therapy. METHODS: In this retrospective, comparative, and multicenter study, patients who had previously untreated DME, who received intravitreal ranibizumab (IVR) or aflibercept (IVA) and/or steroid treatment with the pro re nata (PRN) treatment regimen after a 3-month loading dose, and had a 12-month follow-up in the MARMASIA Study Group were included. Morphological patterns of DME were divided into four groups based on OCT features diffuse/spongious edema (Group 1), cystoid edema (Group 2), diffuse/spongious edema+subretinal fluid (SRF) (Group 3), and cystoid edema+SRF (Group 4). Changes in central macular thickness (CMT) and best-corrected visual acuity (BCVA) at months 3, 6, and 12, and the number of injections at month 12 were compared between the DME groups. RESULTS: 455 eyes of 299 patients were included in the study. The mean baseline BCVAs [Logarithm of the Minimum Angle of Resolution (logMAR)] in groups 1, 2, 3, and 4 were 0.54 ± 0.24, 0.52 ± 0.25, 0.55 ± 0.23, and 0.57 ± 0.27, respectively. There was no significant difference between the baseline mean BCVAs between the groups (p = .35). The mean BCVAs were significantly improved to 0,47 ± 0,33 in group 1, 0,42 ± 0,33 in group 2, 0,47 ± 0,31 in group 3, and 0,45 ± 0,43 at month 12. There was no significant difference between the groups in terms of BCVA change at month 12 (p = .71). The mean baseline CMTs in groups 1, 2, 3, and 4 were 387,19 ± 128,19, 447,02 ± 132,39, 449,12 ± 109,24, and 544,19 ± 178,61, respectively. At baseline, the mean CMT was significantly higher in Group 4 than in the other groups (p = .000). The mean CMTs were significantly decreased to 325,16 ± 97,55, 334,94 ± 115,99, 324,33 ± 79,20, and 332,08 ± 150,40 in four groups at month 12 respectively (p > .05). The groups had no significant difference in mean CMT at month 12 (p = .835). The change in CMT was significantly higher in Group 4 than in the other groups at month 12 (p = .000). The mean number of intravitreal anti-VEGF injections at month 12 was 4.51 ± 1.57 in Group 1, 4.63 ± 1.54 in Group 2, 4.88 ± 1.38 in Group 3, and 5.07 ± 1.49 in Group 4. The mean number of anti-VEGF injections in Group 1 and Group 2 was significantly lower than in Group 4 (p = 0,014 and p = 0,017). CONCLUSIONS: In real life, there was no significant difference between the DME groups in terms of visual improvement at month 12. However, better anatomical improvement was achieved in Group 4 than in the other DME groups.

Structural, blood flow and functional changes in the macular area and the expression of aqueous humor factors in myopia.

Objective: To compare the macular area parameters and aqueous humor factors between myopia and emmetropia. Methods: Convenience sampling was used to select patients who visited the Changzhi Aier Eye Hospital's department of ophthalmology from December 2018 to December 2022 as the study participants. They were divided into three groups according to whether they were diagnosed as mild myopia myopic, highly myopic or not as follows: the mild myopia group (60 cases, 108 eyes), the high myopia group (46 cases, 78 eyes) and the healthy emmetropia group (40 cases, 65 eyes). The differences in the macular integrity (MI) assessment, optical coherence tomography and optical coherence tomography angiography parameters and aqueous humor factors were compared between the three groups. Results: AL in high myopia group was the highest, and that in emmetropia group was the lowest. The BCVA of mild myopia group was the highest. The RS in the high myopia group were significantly lowest in the three groups (26.42 ± 1.04 vs. 28.34 ± 0.76 vs. 31.92 ± 0.77) (F = 5.374, p = 0.013). The 63% BCEA, 95% BCEA and MI in the high myopia group were significantly highest (p < 0.05). The mean RPE thickness, mean CT and mean RT in the high myopia group were lowest (p < 0.05). The blood flow density were lowest in the superficial fovea, paracentral fovea and different subdivisions of the paracentral fovea in the high myopia group (p < 0.05). The VEGF concentration in the aqueous humor of the high myopia group was lowest (25.62 ± 17.43 vs. 32.45 ± 24.67 vs. 64.37 ± 21.14) (F = 9.237, p < 0.001). The MMP-2 concentration was highest (483 ± 201.48 vs. 410 ± 142.37 vs. 386 ± 154.34) (F = 5.542, p = 0.018). The VEGF concentration in the aqueous humor factor was negatively correlated with the AL in the myopia group (r = -0.438, p = 0.002), the MMP-2 concentration was positively correlated with the AL (r = 0.484, p = 0.010). Conclusion: Patients with high myopia showed decreased retinal light sensitivity, fixation stability, superficial blood flow density and retinal thickness compared with people with emmetropia. A decreased VEGF concentration and increased MMP-2 concentration in the aqueous humor factor have potential associations with the development of high myopia.

Using multi-modal imaging to refine the phenotype of PRPH2-associated retinal degeneration.

OBJECTIVE: To refine retinal PRPH2-associated retinal degeneration (PARD) phenotypes using multimodal imaging. DESIGN: Retrospective review of clinical records and multimodal imaging. SUBJECTS: Patients who visited the inherited retinal degeneration (IRD) clinic at two tertiary referral eye centers with molecularly confirmed IRD due to PRPH2 variants. METHODS: Retinal imaging was reviewed using ultra-widefield (UWF) pseudocolor, UWF fundus autofluorescence (FAF), and spectral-domain optical coherence tomography (SD-OCT). Phenotypes were identified in the macular or peripheral region. A combined phenotype was considered if any phenotypes were present in both macular and peripheral regions. Mixed phenotypes in the macula or peripheral retina were considered if there were two distinct phenotypes identified in the same eye. The presence or absence of atrophy in the macular or peripheral area was also noted. MAIN OUTCOME MEASURE: Grading of multimodal imaging by phenotype and atrophy. RESULTS: A total of 144 eyes of 72 patients were included in this study. The majority of the eyes had combined macular and peripheral phenotypes (89/14, 61.8%), while 44 (30.6%) eyes had isolated macular findings, and 11 (7.6%) had isolated peripheral findings. Twenty-five eyes were classified with mixed macular phenotypes while fundus flavimaculatus dystrophy type was the most common combined macular and peripheral phenotype (54/144, 37.5%): n = 10 with macular dystrophy and macular flavimaculatus dystrophy, and n = 15 with butterfly pattern dystrophy and macular flavimaculatus dystrophy. Nearly half of the eyes (71/144, 49.3%) were identified to have concomitant outer retinal atrophy. Fundus flavimaculatus type dystrophy was also associated with the highest proportion of concomitant atrophy (57/71, 80.3%). CONCLUSION: PARD demonstrates a wide array of phenotypes using multimodal imaging. We report that combinations of classically described phenotypes were often seen. Additionally, macular and peripheral atrophy were often associated with PARD phenotypes. Refinement of PARD phenotypes using newer multimodal imaging techniques will likely assist diagnosis and future clinical trials.

Nocturnal hypoxia and age-related macular degeneration.

BACKGROUND: Nocturnal hypoxia is common, under-diagnosed and is found in the same demographic at risk of age-related macular degeneration (AMD). The objective of this study was to determine any association between nocturnal hypoxia and AMD, its severity, and the high-risk sub-phenotype of reticular pseudodrusen (RPD). METHODS: This cross-sectional study included participants aged ≥50 years with AMD, or normal controls, exclusive of those on treatment for obstructive sleep apnoea. All participants had at home, overnight (up to 3 nights) pulse oximetry recordings and multimodal imaging to classify AMD. Classification of Obstructive Sleep Apnea (OSA) was determined based on oxygen desaturation index [ODI] with mild having values of 5-15 and moderate-to-severe >15. RESULTS: A total of 225 participants were included with 76% having AMD, of which 42% had coexistent RPD. Of the AMD participants, 53% had early/intermediate AMD, 30% had geographic atrophy (GA) and 17% had neovascular AMD (nAMD). Overall, mild or moderate-to-severe OSAwas not associated with an increased odds of having AMD nor AMD with RPD (p ≥ 0.180). However, moderate-to-severe OSA was associated with increased odds of having nAMD (odds ratio = 6.35; 95% confidence interval = 1.18 to 34.28; p = 0.032), but not early/intermediate AMD or GA, compared to controls (p ≥ 0.130). Mild OSA was not associated with differences in odds of having AMD of any severity (p ≥ 0.277). CONCLUSIONS: There was an association between nocturnal hypoxia as measured by the ODI and nAMD. Hence, nocturnal hypoxia may be an under-appreciated important modifiable risk factor for nAMD.

Exploring the role of granzyme B in subretinal fibrosis of age-related macular degeneration.

Age-related macular degeneration (AMD), a prevalent and progressive degenerative disease of the macula, is the leading cause of blindness in elderly individuals in developed countries. The advanced stages include neovascular AMD (nAMD), characterized by choroidal neovascularization (CNV), leading to subretinal fibrosis and permanent vision loss. Despite the efficacy of anti-vascular endothelial growth factor (VEGF) therapy in stabilizing or improving vision in nAMD, the development of subretinal fibrosis following CNV remains a significant concern. In this review, we explore multifaceted aspects of subretinal fibrosis in nAMD, focusing on its clinical manifestations, risk factors, and underlying pathophysiology. We also outline the potential sources of myofibroblast precursors and inflammatory mechanisms underlying their recruitment and transdifferentiation. Special attention is given to the potential role of mast cells in CNV and subretinal fibrosis, with a focus on putative mast cell mediators, tryptase and granzyme B. We summarize our findings on the role of GzmB in CNV and speculate how GzmB may be involved in the pathological transition from CNV to subretinal fibrosis in nAMD. Finally, we discuss the advantages and drawbacks of animal models of subretinal fibrosis and pinpoint potential therapeutic targets for subretinal fibrosis.

Decreased Circulating Very Small Low-Density Lipoprotein is Likely Causal for Age-Related Macular Degeneration.

Objective: Abnormal changes in metabolite levels in serum or plasma have been highlighted in several studies in age-related macular degeneration (AMD), the leading cause of irreversible vision loss. Specific changes in lipid profiles are associated with an increased risk of AMD. Metabolites could thus be used to investigate AMD disease mechanisms or incorporated into AMD risk prediction models. However, whether particular metabolites causally affect the disease has yet to be established. Design: A 3-tiered analysis of blood metabolites in the United Kingdom (UK) Biobank cohort to identify metabolites that differ in AMD patients with evidence for a putatively causal role in AMD. Participants: A total of 72 376 donors from the UK Biobank cohort including participants with AMD (N = 1353) and non-AMD controls (N = 71 023). Methods: We analyzed 325 directly measured or derived blood metabolites from the UK Biobank for 72 376 donors to identify AMD-associated metabolites. Genome-wide association studies for 325 metabolites in 98 316 European participants from the UK Biobank were performed. The causal effects of these metabolites in AMD were tested using a 2-sample Mendelian randomization approach. The predictive value of these measurements together with sex and age was assessed by developing a machine learning classifier. Main Outcome Measures: Evaluating metabolic biomarkers associated with AMD susceptibility and investigating their potential causal contribution to the development of the disease. Results: This study noted age to be the prominent risk factor associated with AMD development. While accounting for age and sex, we identified 84 metabolic markers as significantly (false discovery rate-adjusted P value < 0.05) associated with AMD. Lipoprotein subclasses comprised the majority of the AMD-associated metabolites (39%) followed by several lipoprotein to lipid ratios. Nineteen metabolites showed a likely causative role in AMD etiology. Of these, 6 lipoproteins contain very small, very low-density lipoprotein (VLDL), and phospholipids to total lipid ratio in medium VLDL. Based on this we postulate that depletion of circulating very small VLDLs is likely causal for AMD. The risk prediction model constructed from the metabolites, age and sex, identified age as the primary predictive factor with a much smaller contribution by metabolites to AMD risk prediction. Conclusions: This study underscores the pronounced role of lipids in AMD susceptibility and the likely causal contribution of particular subclasses of lipoproteins to AMD. Our study provides valuable insights into the metabopathological mechanisms of AMD disease development and progression.

Different Vortex Vein Anomalies Observed in a Single Case: Macular Vortex Vein in One Eye and Varix of Vortex Vein Ampulla in the Other Eye.

We present a 56-year-old female with a macular vortex vein in her right eye and a varix of vortex vein ampulla in the inferior nasal fundus of her left eye. The choroidal lesions were evaluated by multimodal imaging including fundoscopy with contact lens, ultra-widefield fundus photography, swept-souse optical coherence tomography (SS-OCT), enface image of widefield optical coherence tomography (widefield enface-OCT), and ultra-widefield fundus angiography. Widefield enface-OCT revealed submacular large choroidal vessels in the right eye. Ultra-widefield indocyanine green fluorescence angiography (UWICGA) of the right eye showed the dye of those submacular choroidal vessels drained from the ampullae beneath the macula. Fundoscopy revealed an elevated lesion with crescent shadows in the inferior nasal fundus of the left eye. Dynamic fundoscopy with compression of the left eye resulted in a diminishing of the elevation and release of the compression resulted in an enlargement of the elevation. Ultra-widefield fundus photography of the left eye in the right inferior gaze revealed an elevated lesion with a crescent shadow in the inferior nasal fundus, while it is not prominent in the primary gaze. The B-scan of SS-OCT revealed a hyporeflective lesion in the choroid beneath the elevated lesion of the left eye. The elevated lesion was consistent with the vortex vein ampulla on UWICGA. This is the first case where two different choroidal vascular anomalies, macular vortex vein and varix of vortex ampulla, coexist in a single patient. Multimodal imaging is useful to visualize and diagnose choroidal vascular anomalies.

Calculated Drug Concentrations in Currently Available Intravitreal Therapies: Determination of Dilution Factor and Deviation From Recommended Doses.

In ophthalmology, intravitreal therapies are currently not personalized/customized and are not adjusted to the individual vitreous volume. With reference to the recently published calculation formula for a more accurate estimation of the vitreous body, we determined the dose of intravitreal medication for different vitreous volumes and compared them with the average volume. Using the axial length of the eye, the formula for the vitreous volume exact (VIVEX) can provide a more accurate indication of the vitreous volume in individual cases than an assumed standard volume of 4 mL. The concentration of active substances in small eyes may be twice as high as that in normal-sized emmetropic eyes. In contrast, large eyes may show less than half of the recommended drug concentration. The calculated concentrations of the investigated intravitreal drugs in small and large eyeballs showed impressive differences with large deviations from the recommended doses. Further systematic studies should follow to find out whether this has any impact on the effectiveness or side effects of the injected drugs.

Macular thickness and visual acuity are characterized by a quadratic nonlinear relation in previously treated neovascular AMD eyes.

PURPOSE: To assess the associations between visual acuity (VA) and retinal thickness in age-related macular degeneration (AMD) eyes treated with anti-vascular endothelial growth factor (VEGF) therapy. METHODS: Sixty-eight patients with neovascular AMD (68 eyes) undergoing anti-VEGF therapy with two years of follow-up imaging data after the initiation of treatment were retrospectively included. Linear and nonlinear regression analyses with curve fitting estimation were performed to explore the relationship between visual acuity and OCT-based parameters at the 3-month and 24-month follow-up visits. Regression analyses were also performed between visual acuity and the retinal thickness deviation which was calculated as the absolute value of the difference between measured and normative retinal thickness values. RESULTS: The VA was not associated with either foveal (R2 = 0.011 and p = .401 at 3 months; R2 = 0.032 and p = .142 at 24 months) or parafoveal (R2 = 0.045 and p = .081 at 3 months; R2 = 0.050 and p = .055 at 24 months) retinal thicknesses. Compared with the linear models, a quadratic function yielded a relative increase in the R2 coefficients. Conversely, the VA was linearly associated with foveal retinal thickness deviation (R2 = 0.041 and p = .037 at 24 months) and parafoveal retinal thickness deviation (R2 = 0.062 and p = .040 at 3 months; R2 = 0.088 and p = .014 at 24 months) values. CONCLUSIONS: Although there was no linear relationship between retinal thickness and VA, a weak but statistically significant linear relationship could be observed when a retinal thickness deviation was considered. This suggests that deviation-based parameters may be beneficial for structure-function correlations in the context of anti-VEGF therapy for neovascular AMD.

Association of serum lipid profile and other systemic risk factors with retinal hard exudates in diabetic retinopathy.

PURPOSE: Diabetic macular edema is one of the leading causes of vision loss across the world. Hard exudates at the macula can lead to structural abnormalities in the retina leading to irreversible vision loss. Systemic dyslipidemia and other modifiable risk factors when identified and treated early may help prevent substantial vision loss. The purpose of this study was to study the association between serum lipid levels and other systemic risk factors like hemoglobin, HbA1c, and serum creatinine with hard exudates and macular edema in patients with diabetic retinopathy. METHODS: It is a prospective cross-sectional study conducted in a tertiary health care center in South India. 96 patients having diabetic retinopathy with hard exudates were included. Modified Airlie house classification was used to grade the hard exudates. Blood investigations including serum lipid profile, hemoglobin, HbA1c, and serum creatinine were carried out. Central subfield macular thickness was measured using optical coherence tomography. RESULTS: 96 patients of type II DM with diabetic retinopathy were divided into three groups of hard exudates. A statistically significant correlation was observed between the severity of hard exudates and total cholesterol (p = 0.00), triglycerides (p = 0.00), LDL (p = 0.00), and VLDL (p = 0.00). HbA1c levels showed a statistically significant correlation with the severity of hard exudates (p = 0.09), no significant correlation was noted between hard exudates and hemoglobin levels (p = 0.27) and with serum creatinine (p = 0.612). A statistically significant association between CSMT and hard exudates (p = 0.00) was noted. CONCLUSION: In our study, we concluded that the severity of hard exudates is significantly associated with increasing levels of serum total cholesterol, triglycerides, LDL, VLDL, and HbA1c levels in type II DM patients presenting with diabetic retinopathy. The increasing duration of diabetes is significantly associated with increasing severity of hard exudates. Central subfield macular thickness increases with increasing severity of hard exudates in diabetic retinopathy.

Efficacy and Safety of Anti-VEGF Injections and Surgery for AMD-Related Submacular Hemorrhage: A Systematic Review & Meta-Analysis.

TOPIC: This systematic review and meta-analysis investigates the efficacy and safety of anti-vascular endothelial growth factor (anti-VEGF) injections compared to surgical intervention in improving visual acuity (VA) and reducing complications for patients with submacular hemorrhage (SMH) due to neovascular age-related macular degeneration (AMD). CLINICAL RELEVANCE: Determining the optimal intervention for SMH in AMD is crucial for patient care. METHODS: We included studies on anti-VEGF injections or surgical interventions for SMH in AMD from 7 databases, searched up to May 2024. Data extraction and quality assessment were done by two independent reviewers. Certainty of evidence was assessed GRADE approach. Meta-analysis employed random-effects models. Primary outcomes were pooled mean logMAR VA difference (initial examination minus last follow-up VA) and adverse events rates. RESULTS: A total of 43 observational studies were included: 21 (960 eyes) on anti-VEGF and 22 (455 eyes) on surgery. Comparisons were made across separate studies due to lack of head-to-head studies. Meta-analysis included 11 anti-VEGF studies (444 eyes) and 12 surgical studies (195 eyes) for VA outcomes. The mean difference (MD) in VA was -0.16 (95%CI: -0.26,-0.07) for anti-VEGF and -0.36 (95%CI: -0.68,-0.04) for surgery, with no significant difference between groups (X2=1.70, df =1, p=0.19). Heterogeneity was high in surgical studies (I2=96.2%, tau2=0.23, p<0.01) and negligible in anti-VEGF studies (I2=7%, tau2=0.003, p=0.38). GRADE certainty was moderate for anti-VEGF and low for surgery. Anti-VEGF had lower rates of cataract (0% vs 4.6%), proliferative vitreoretinopathy (PVR, 0.1% vs 2.0%), and retinal detachment (RD, 0.1% vs 10.6%), but similar rates of recurrent hemorrhage (5.4% vs 5.3%). Complications were summarized descriptively due to zero cell problem. CONCLUSION: Both anti-VEGF and surgery treat SMH in AMD with similar VA outcomes but different safety profiles. Anti-VEGF is preferred for less severe hemorrhage, while surgery is suited for extensive hemorrhage. Despite uncertain comparative VA outcomes, treatment should be guided by clinical judgment and patient factors.

Changing Reimbursement Criteria on Anti-VEGF Treatment Patterns Among Wet Age-Related Macular Degeneration and Diabetic Macular Edema Patients: An Interrupted Time Series Analysis.

BACKGROUND: To evaluate the impact of reimbursement criteria change on the utilization pattern of anti-vascular endothelial growth factor (anti-VEGF) among patients with wet age-related macular degeneration (wAMD) and diabetic macular edema (DME) separately in Taiwan. METHODS: An interrupted time series analysis (ITSA) was performed using Taiwan's National Health Insurance (NHI) database, and patients with wAMD or DME diagnosis at the first injection of anti-VEGF agents was identified from 2011 to 2019. The outcome of interest was treatment gaps between injections of anti-VEGF. This outcome was retrieved quarterly, and the study period was divided into three phases in wAMD (two criteria changed in August 2014 [intervention] and December 2016 [intervention]) and two phases in DME (three consecutive criteria changed in 2016 [intervention]). Segmented regression models adjusted for autocorrelation were used to estimate the change in level and the change in slope of the treatment gaps between each anti-VEGF injection. RESULTS: The treatment gaps between each anti-VEGF injection decreased from 2011 to 2019. The cancellation of the annual three needles limitation was associated with significantly shortened treatment gaps between the third and fourth needles (wAMD change in level: -228 days [95% CI -282, -173], DME change in level: -110 days [95% CI -141, -79]). The treatment gap between the fifth and sixth needles revealed a similar pattern but without significant change in DME patients. Other treatment gaps revealed considerable change in slopes in accordance with criteria changes. CONCLUSION: This is the first nationwide study using ITSA to demonstrate the impact of reimbursement policy on treatment gaps between each anti-VEGF injection. After canceling the annual limitation, we found that the treatment gaps significantly decreased among wAMD and DME patients. The shortened treatment gaps might further link to better visual outcomes according to previous studies. The different impacts from criteria changes can assist future policy shaping. Future studies were warranted to explore whether such changes are associated with the benefits of visual effects.

Corneal application of SOCS1/3 peptides for the treatment of eye diseases mediated by inflammation and oxidative stress.

Several blinding diseases affecting the retina and optic nerve are exacerbated by or caused by dysregulated inflammation and oxidative stress. These diseases include uveitis, age related macular degeneration, diabetic retinopathy and glaucoma. Consequently, despite their divergent symptoms, treatments that reduce oxidative stress and suppress inflammation may be therapeutic. The production of inflammatory cytokines and their activities are regulated by a class of proteins termed Suppressors of Cytokine Signaling (SOCS). SOCS1 and SOCS3 are known to dampen signaling via pathways employing Janus kinases and signal transducer and activator of transcription proteins (JAK/STAT), Toll-like Receptors (TLR), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), mitogen activated kinase (MAPK) and NLR family pyrin domain containing 3 (NLRP3). We have developed cell-penetrating peptides from the kinase inhibitory region of the SOCS1 and SOCS3 (denoted as R9-SOCS1-KIR and R9-SOCS3-KIR) and tested them in retinal pigment epithelium (RPE) cells and in macrophage cell lines. SOCS-KIR peptides exhibited anti-inflammatory, anti-oxidant and anti-angiogenic properties. In cell culture, both Th1 and Th17 cells were suppressed together with the inhibition of other inflammatory markers. We also observed a decrease in oxidants and a simultaneous rise in neuroprotective and anti-oxidant effectors. In addition, treatment prevented the loss of gap junction proteins and the ensuing drop in transepithelial electrical resistance in RPE cells. When tested in mouse models by eye drop instillation, they showed protection against autoimmune uveitis, as a prophylactic as well as a therapeutic. Mice with endotoxin-induced uveitis were protected by eye drop administration as well. R9-SOCS3-KIR was particularly effective against the pathways acting through STAT3, e.g. IL-6 and VEGF-A mediated responses that lead to macular degeneration. Eye drop administration of R9-SOCS3-KIR stimulated production of antioxidant effectors and reduced clinical symptoms in mouse model of oxidative stress that replicates the RPE injury occurring in AMD. Because these peptides suppress multiple pathogenic stimuli and because they can be delivered topically to the cornea, they are attractive candidates for therapeutics for uveitis, macular degeneration, diabetic retinopathy and glaucoma.

Comparative analysis of macular characteristics in mCNV and contralateral eyes.

Purpose: To illustrate the characteristics of perforating scleral vessels in macular regions between mCNV eyes and contralateral eyes in unilateral mCNV patients. Methods: This was a retrospective study that included patients with unilateral naive mCNV. The study aimed to identify and analyze the distribution of perforating scleral vessels (PSVs) in the macular region of mCNV eyes and contralateral eyes. The central macular choroidal thicknesses (mChT) were measured using optical coherence tomography angiography (OCTA). The grades of myopic atrophic maculopathy (MAM) and macular myopic diffuse chorioretinal atrophy (DCA) were evaluated within groups. The number of PSVs and mChT were compared between contralateral and mCNV eyes based on the grade of DCA. The ROC curves were utilized to explore the diagnostic indexes for mCNV. Results: A total of 102 eyes from 51 patients with unilateral mCNV were included. There was no significance in the severity of MAM or the grade of DCA between mCNV eyes and contralateral eyes (p = 0.074, p = 0.054, respectively). The mean number of PSVs in mCNV eyes was fewer than the contralateral eyes [1.00 (1.00-2.00) vs. 2.00 (0.75-3.00), p = 0.030]. The mChT in mCNV eyes was thinner than the contralateral eyes [36.00 (25.00-53.75) µm vs. 46.00 (31.00-75.25) µm, p = 0.001]. The mean grade of DCA in mCNV eyes was higher than that in contralateral eyes [3.00 (3.00-3.00) vs. 3.00 (2.00-3.00), p = 0.004]. When DCA involved the macular region, there were more PSVs in contralateral eyes than in mCNV eyes [1.50 (1.00-2.00) vs. 2.00 (1.00-3.00), p = 0.042]. Similarly, when DCA involved the foveal region, there were more PSVs in contralateral eyes than in mCNV eyes [1.50 (1.00-2.00) vs. 3.00 (2.00-4.00), p = 0.004]. The grade of DCA and mChT were valuable factors for predicting mCNV eyes (AUC = 0.6566, p = 0.021; AUC = 0.6304, p = 0.029; respectively). When the extent of DCA exceeded the foveal region, the count of PSVs was a good diagnostic factor for predicting mCNV (AUC = 0.7430, p = 0.003). Conclusion: The mean amount of PSVs was significantly lower in the mCNV eyes compared to the contralateral eyes. When the extent of DCA exceeded the foveal region, the count of PSVs was a good diagnostic factor for predicting mCNV. Myopic eyes with a higher grade of DCA and a thinner mChT were more likely to develop mCNV.

Reproducibility of SIMPLE classification for diabetic retinopathy screening and its comparison to current Italian guidelines.

PURPOSE: To evaluate the reproducibility of SIMPLE (Single field Image Multi Parameters defined Lesions Extent), a new Diabetic Retinopathy (DR) classification for screening of 45° single field fundus pictures of patients with diabetes (PwDM), assessing DR, Diabetic Maculopathy (DMac) and referral rate agreement and comparing it to current Italian Guidelines (IG). MATERIALS AND METHODS: We conducted a retrospective, observational, multicentre study, collecting 1000 retinal 45° single field images of PwDM obtained during routine visits in two diabetes clinics. Three ophthalmologists evaluated each image, determining the presence and number of specific DR lesions and then assigning a stage according to the current IG for screening. SIMPLE staging was performed automatically via Excel software, based on the pre-specified DR characteristics observed by the graders. We analysed intra-centre, inter-centre and total inter-grader agreement for DR and DMac stage and referral rate of the two classifications. RESULTS: Agreement amongst the three graders was consistently higher when using SIMPLE classification than when using current IG classification. For DR, kappa (k) was 0.86 with IG and 0.95 with SIMPLE classification; for DMac, k-IG was 0.78, while k-SIMPLE was 0.96; concordance on the referral rate was 0.91 with IG and 0.99 with SIMPLE. Similar results were obtained in sub-analyses for the evaluation of intra-centre and inter-centre concordance. CONCLUSIONS: Our results suggest that the new SIMPLE classification has an excellent reproducibility amongst graders, comparable or superior to the current IG for DR screening proposed in 2015, improving the standardisation of the decision on referability.

Alisol A, the Eye-Entering Ingredient of Alisma orientale, Relieves Macular Edema Through TNF-α as Revealed by UPLC-Triple-TOF/MS, Network Pharmacology, and Zebrafish Verification.

Purpose: Alisma orientale (AO, Alisma orientale (Sam). Juzep) has been widely employed for the treatment of macular edema (ME) in traditional Chinese medicine due to its renowned water-relief properties. Nonetheless, the comprehensive investigation of AO in alleviating ME remained unexplored. This study aims to identify the active components of AO that target the eye and investigate its pharmacological effects and mechanisms on ME. Methods: The study commenced with UPLC-Triple-TOF/MS analysis to identify the primary constituents of AO. Zebrafish eye tissues were then analyzed after a five-day administration of AO to detect absorbed components and metabolites. Subsequently, network pharmacology, molecular docking, and molecular dynamics simulations were employed to predict the mechanisms of ME treatment via biological target pathways. In vivo experiments were conducted to corroborate the pharmacological actions and mechanisms. Results: A total of 7 compounds, consisting of 2 prototype ingredients and 5 metabolites (including isomers), were found to traverse the blood-eye barrier and localized within eye tissues. Network pharmacology results showed that AO played a role in the treatment of ME mainly by regulating the pathway network of PI3K-AKT and MAPK with TNF-α centered. Computational analyses suggested that 11-dehydro-16-oxo-24-deoxy-alisol A, a metabolite of alisol A, mitigates edema through TNF-α inhibition. Furthermore, zebrafish fundus confocal experiments and HE staining of eyes confirmed the attenuating effects of alisol A on fundus angiogenesis and ocular edema, representing the first report of AO's ME-inhibitory effects. Conclusion: In this study, computational analyses with experimental validation were used to understand the biological activity and mechanism of alisol A in the treatment of ME. The findings shed light on the bioactive constituents and pharmacological actions of AO, offering valuable insights and a theoretical foundation for its clinical application in managing ME.

The Macular Pigment Optical Density (MPOD) Decrease in Chinese Primary Angle Closure Glaucoma Using the One-Wavelength Reflectometry Method.

PURPOSE: The objective of this study was to observe the macular pigment optical density (MPOD) and the relationship between MPOD and retinal thickness in Chinese primary angle-closure glaucoma (PACG) patients by the one-wavelength reflectometry method. METHODS: This study was a prospective comparative observational study, including 39 eyes from 39 PACG patients (15 men and 24 women, mean age 61.89 ± 12.30) and 41 eyes from 41 controls (20 men and 21 women, mean age 63.24 ± 14.02). We measured the MPOD 7-degree area by the one-wavelength reflectometry method and analyzed both the max and mean optical density (OD). The central retinal thickness (CRT) and the total thickness of the macular ganglion cell layer (GCL), and inner plexiform layer (IPL)were measured by spectral-domain-optical coherence tomography (SD-OCT). Statistical methods such as Shapiro-Wilk test, Fisher's exact test, chi-square test, two independent samples test and Spearman's correlation coefficient were used to observe the differences in the MPOD between normal subjects and PACG patients and the correlation between the MPOD and retinal thickness. RESULTS: The max optical density (Max OD) (PACG group: 0.302 ± 0.067d.u, control group: 0.372 ± 0.059d.u., p < .001) and mean optical density (Mean OD) (PACG group: 0.124 ± 0.035d.u., control group: 0.141 ± 0.028d.u., p < 0.05) were significantly reduced in PACG patients compared with control subjects. Significant decreases in GCL + IPL thickness (PACG group: 74.71 ± 39.56 µm, control group:113.61 ± 8.14 µm, p < 0.001) and CRT (PACG group: 254.49 ± 41.47 µm, control group:329.10 ± 18.57 µm, p < 0.001) were also observed in PACG eyes. There was no statistically significant correlation between the MPOD and GCL + IPL thickness (p = .639, p = .828). CONCLUSIONS: MPOD was significantly lower in Chinese PACG patients than in the control group, potentially due to thinning of the GCL + IPL thickness. This study provides insights for the pathophysiology, assessment of PACG and potential guidance for lifestyle modifications.

In this study, we measured the MPOD values of Chinese PACG patients for the first time using the one-wavelength reflectance method and clarified that the MPOD of PACG patients was significantly lower than that of the normal group. This study provides insights for the pathophysiology, assessment of PACG and potential guidance for lifestyle modifications.

The effect of topical tranexamic acid with micro-needling and micro-needling alone in treatment of macular amyloidosis.

BACKGROUND: Macular amyloidosis is a form of primary localized cutaneous amyloidosis presented by pruritic pigmented macules in rippled or reticulate pattern. The aim of this study was to assess the efficacy of using topical tranexamic acid with micro-needling comparing to micro-needling alone in patients with macular amyloidosis. MATERIALS AND METHODS: Patients with bilaterally located macular amyloidosis on trunk or upper extremities were recruited in this trial. The skin lesions in all patients were divided into two parts which were randomly assigned to the group of treatment with micro-needling plus tranexamic acid and the group of micro-needling alone. There were four sessions of treatment with 2 weeks interval. The percentage of improvement in pigmentation (based on photographs and dermoscopy) and rippling of each group was determined by three blinded dermatologists. The level of patient satisfaction and reduction of pruritus was measured by a questionnaire and defined as a percentage. RESULTS: Twenty females were enrolled in this study. The mean (SD) patients' age was 39.7 (±10.13) years. Both groups showed improvement in pigmentation based on images, dermoscopy, and rippling pattern. Patients' satisfaction was 46.5% in tranexamic acid group and 47.5% in micro-needling alone. Nevertheless, there was no significant difference between both groups (p value >0.05). Interestingly, the pruritus improved 61.66% after four sessions of treatment in both groups. CONCLUSION: Micro-needling is a suitable modality for decreasing pruritus and pigmentation in macular amyloidosis. However, topical application of tranexamic acid does not lead to additional improvement.

Economic Assessment in Resource-Constrained Systems: Individual-Level Simulation Model in Wet Age-Related Macular Degeneration and Diabetic Macular Oedema.

INTRODUCTION: Cost-effectiveness analyses typically ignore healthcare system resource constraints. Ophthalmology is affected by resource constraints because of increasing disease prevalence and the use of resource-intensive treatments. This study evaluated the impact of resource constraints on the cost-effectiveness of faricimab 6 mg, compared with aflibercept 2 mg and ranibizumab biosimilar 0.5 mg, for treating wet age-related macular degeneration (wAMD) or diabetic macular oedema (DMO) over a 5-year horizon. METHODS: A microsimulation model estimated the impact of resource constraints on patients visits, delays, costs and quality-adjusted life-year (QALY) losses due to treatment delays at a typical UK National Health Service eye hospital treating 1500 patients with wAMD and 500 patients with DMO. Patient characteristics, treatment regimens and treatment intervals were informed using published literature and expert opinion. Resource constraint was represented by limiting the number of available intravitreal injection appointments per week, with growing demand caused by rising disease prevalence. The model compared outcomes across three scenarios; each scenario involved treating all patients with one of the three treatments. RESULTS: Over 5 years, in a resource-constrained hospital, compared with aflibercept, faricimab use resulted in the avoidance of 12,596 delays, saved GBP/£15,108,609 in cost and avoided the loss of 60.06 QALYs. Compared with ranibizumab biosimilar, faricimab use resulted in the avoidance of 18,910 delays, incurred £2,069,088 extra cost and avoided the loss of 105.70 QALYs, resulting in an incremental cost-effectiveness ratio of £19,574/QALY. CONCLUSIONS: Accounting for resource constraints in health economic evaluation is crucial. Emerging therapies that are more durable and require less frequent clinic visits can reduce treatment delays, leading to improved QALY outcomes and reduced burden on healthcare systems. Faricimab reduced the number of delayed injections, leading to improved QALY outcomes for patients in a healthcare system with resource constraints. Faricimab is cost-saving when compared with aflibercept and cost-effective when compared with ranibizumab biosimilar.