A single-cell transcriptome atlas of the adult human retina.

The retina is a specialized neural tissue that senses light and initiates image processing. Although the functional organization of specific retina cells has been well studied, the molecular profile of many cell types remains unclear in humans. To comprehensively profile the human retina, we performed single-cell RNA sequencing on 20,009 cells from three donors and compiled a reference transcriptome atlas. Using unsupervised clustering analysis, we identified 18 transcriptionally distinct cell populations representing all known neural retinal cells: rod photoreceptors, cone photoreceptors, Müller glia, bipolar cells, amacrine cells, retinal ganglion cells, horizontal cells, astrocytes, and microglia. Our data captured molecular profiles for healthy and putative early degenerating rod photoreceptors, and revealed the loss of MALAT1 expression with longer post-mortem time, which potentially suggested a novel role of MALAT1 in rod photoreceptor degeneration. We have demonstrated the use of this retina transcriptome atlas to benchmark pluripotent stem cell-derived cone photoreceptors and an adult Müller glia cell line. This work provides an important reference with unprecedented insights into the transcriptional landscape of human retinal cells, which is fundamental to understanding retinal biology and disease.

OUTCOMES OF SWITCHING FROM PROACTIVE TO REACTIVE TREATMENT AFTER DEVELOPING ADVANCED CENTRAL NEOVASCULAR AGE-RELATED MACULAR DEGENERATION.

PURPOSE: We assessed outcomes of eyes with neovascular age-related macular degeneration (nAMD) that switched from proactive (treat-and-extend) to reactive (pro re nata) treatment regimen after developing macular atrophy (MA) or submacular fibrosis (SMFi). METHODS: Data were collected from a retrospective analysis of a prospectively designed, multinational registry of "real-world" nAMD treatment outcomes. Eyes without MA or SMFi when starting treatment with a vascular endothelial growth factor inhibitor regimen that subsequently developed MA or SMFi were included. RESULTS: Macular atrophy developed in 821 eyes and SMFi in 1,166 eyes. Seven percent of eyes that developed MA and 9% of those that developed SMFi were switched to reactive treatment. Vision was stable at 12 months for all eyes with MA and inactive SMFi. Active SMFi eyes that switched to reactive treatment had significant vision loss. No eyes that continued proactive treatment developed ≥15 letter loss, but 8% of all eyes that switched to a reactive regimen and 15% of active SMFi eyes did. CONCLUSION: Eyes that switch from proactive to reactive treatment after developing MA and inactive SMFi can have stable visual outcomes. Physicians should be aware of the risk of a significant loss of vision in eyes with active SMFi that switch to reactive treatment.

Twenty-four-month real-life treatment outcomes of polypoidal choroidal vasculopathy versus type 1 macular neovascularization in Caucasians.

BACKGROUND: To compare 24-month real-world outcomes of Vascular Endothelial Growth Factor (VEGF) inhibitors for Polypoidal Choroidal Vasculopathy (PCV) and type 1 Macular Neovascularization (MNV) in a Caucasian population. METHODS: Retrospective analysis from a prospectively designed observational database. Data from Italian centres participating in the Fight Retinal Blindness! (FRB!) project were collected. Treatment-naïve PCV or type 1 MNV commencing treatment after January 2009 were included. The primary outcome was 24-month visual acuity (VA) change; other outcomes included baseline characteristics, number of anti-VEGF injections, time to lesion inactivation and proportion of active visits. RESULTS: A total of 322 eyes (114 PCVs) from 291 patients were included. Median [Q1, Q3] VA at baseline was comparable (70 [55, 75.8] vs. 70 [58.8, 75] letters, p = 0.95). Adjusted VA change at 2 years was higher in PCV (mean [95% CI], +1.2 [-1.6, 4.1] vs. -3.6 [-6, -1.2] letters, p = 0.005). PCV received fewer anti-VEGF injections over the first 24 months of treatment than type 1 MNV (median [Q1, Q3], 8 [5, 10] vs. 9 [7, 12.2] injections, p = 0.001), inactivated earlier (median [Q1, Q3], 235 [184, 308] vs. 252 [169, 343] days, p = 0.04) and was less frequently graded 'active' (62% vs. 68% of visits, p = 0.001). CONCLUSIONS: PCV had slightly better VA outcomes over 24 months of treatment than type 1 MNV after receiving less anti-VEGF injections. These results suggest a possible overlap of the two clinical entities with similar visual prognosis in Caucasians.

Serine and Lipid Metabolism in Macular Disease and Peripheral Neuropathy.

BACKGROUND: Identifying mechanisms of diseases with complex inheritance patterns, such as macular telangiectasia type 2, is challenging. A link between macular telangiectasia type 2 and altered serine metabolism has been established previously. METHODS: Through exome sequence analysis of a patient with macular telangiectasia type 2 and his family members, we identified a variant in SPTLC1 encoding a subunit of serine palmitoyltransferase (SPT). Because mutations affecting SPT are known to cause hereditary sensory and autonomic neuropathy type 1 (HSAN1), we examined 10 additional persons with HSAN1 for ophthalmologic disease. We assayed serum amino acid and sphingoid base levels, including levels of deoxysphingolipids, in patients who had macular telangiectasia type 2 but did not have HSAN1 or pathogenic variants affecting SPT. We characterized mice with low serine levels and tested the effects of deoxysphingolipids on human retinal organoids. RESULTS: Two variants known to cause HSAN1 were identified as causal for macular telangiectasia type 2: of 11 patients with HSAN1, 9 also had macular telangiectasia type 2. Circulating deoxysphingolipid levels were 84.2% higher among 125 patients with macular telangiectasia type 2 who did not have pathogenic variants affecting SPT than among 94 unaffected controls. Deoxysphingolipid levels were negatively correlated with serine levels, which were 20.6% lower than among controls. Reduction of serine levels in mice led to increases in levels of retinal deoxysphingolipids and compromised visual function. Deoxysphingolipids caused photoreceptor-cell death in retinal organoids, but not in the presence of regulators of lipid metabolism. CONCLUSIONS: Elevated levels of atypical deoxysphingolipids, caused by variant SPTLC1 or SPTLC2 or by low serine levels, were risk factors for macular telangiectasia type 2, as well as for peripheral neuropathy. (Funded by the Lowy Medical Research Institute and others.).

IMPAIRMENTS IN CONE PIGMENT REGENERATION AND ABSOLUTE THRESHOLD IN MACULAR TELANGIECTASIA TYPE 2.

PURPOSE: To test the hypothesis that Müller cell dysfunction in macular telangiectasia type 2 (MacTel) results in delayed cone adaptation kinetics and to assess absolute cone and rod thresholds in this condition. METHODS: Adaptation after an approximate 63.5% full-field cone photopigment bleach was assessed for Goldmann size V (1.7° diameter) 640 nm (red) and 480 nm (blue) targets presented at a retinal locus corresponding to 2° temporal to fixation. The cone time constant of adaptation and absolute cone and rod thresholds were calculated from exponential functions fitted to the resultant dark adaptation curves. RESULTS: Eighteen eyes with MacTel (from 11 patients) were compared with 19 control eyes (from 16 normal subjects). Cone adaptation kinetics were significantly impaired in MacTel, as was the absolute cone threshold. Final thresholds for blue targets were also significantly elevated in MacTel, consistent with impaired rod absolute threshold. Losses in sensitivity observed in MacTel were consistent with a so-called d1/2 mechanism (i.e., receptoral) site of sensitivity loss. CONCLUSION: In addition to previously documented impairments in rod dark adaptation, MacTel results in a significant elevation in cone thresholds because of pathology at the level of the photoreceptors. The delays in cone adaptation that we found in eyes with MacTel may reflect impairment of the Müller cell-mediated cone-specific visual cycle.

IMPAIRMENTS OF L-CONE/M-CONE AND S-CONE-MEDIATED COLOR DISCRIMINATION IN MACULAR TELANGIECTASIA TYPE II.

PURPOSE: To characterize red-green and tritan color discrimination in eyes with macular telangiectasia Type II (MacTel). METHODS: Color discrimination was assessed by metameric matching methods using an Oculus MR Anomaloscope. Red-green color discrimination was assessed using the Rayleigh equation, and tritan color discrimination was assessed using the Moreland equation. Results were expressed as anomalquotient (AQ) and tritanomalquotient (TAQ) units, respectively. RESULTS: Seventeen eyes with MacTel were compared with 16 control eyes with normal vision. Twelve eyes with MacTel demonstrated abnormal color matches; except for two eyes with red-shifted Rayleigh matches, the primary abnormality evident was reduced color discrimination. On average, Rayleigh matching ranges were significantly widened in MacTel (0.518 ± 0.066 AQ units) compared with normal (0.14 ± 0.03 AQ units; P < 0.0001). Similarly, Moreland matching ranges were significantly wider (0.794 ± 0.109 TAQ units) than normal control subjects (0.204 ± 0.070 TAQ units; P < 0.0001). Losses in color discrimination did not correlate significantly with the best-corrected visual acuity, although Moreland matching ranges were significantly correlated to Rayleigh matching ranges. CONCLUSION: MacTel results in a combined acquired red-green and tritan color vision deficiency. A minority of eyes demonstrated red-shifted Rayleigh matches, consistent with decreases in cone photopigment optical density.

THE IMPACT OF DISEASE ACTIVITY ON 5-YEAR OUTCOMES IN PATIENTS UNDERGOING TREATMENT FOR NEOVASCULAR AGE-RELATED MACULAR DEGENERATION.

PURPOSE: To assess the impact of disease activity on clinical outcomes in a "real-world" cohort with neovascular age-related macular degeneration over 5 years. METHODS: Data were obtained from the prospectively defined Fight Retinal Blindness! registry. Eyes were divided into tertiles based on the proportion of visits where choroidal neovascular lesion was active (low, moderate, and high) up until 5 years. RESULTS: Data from 2,109 eyes were included. The adjusted mean (95% confidence interval) visual acuity change was -0.5 letters (-1.8 to 1.1), 1.8 letters (0.2 to 3.4), and -2.5 letters (-4.2 to -1.3) in the low, moderate, and high activity groups respectively, P < 0.001. Eyes in the low activity group were more likely to develop macular atrophy (56, 47 and 26% in the low, moderate, and high activity groups respectively, P < 0.001) but less likely to develop subretinal fibrosis (27, 35 and 42% in the low, moderate, and high activity groups respectively, P < 0.001). CONCLUSION: Eyes with higher and lower levels of disease activity had poorer outcomes than eyes with moderate activity over 5 years, apparently because of the development of subretinal fibrosis or macular atrophy.

THREE-YEAR TREATMENT OUTCOMES OF AFLIBERCEPT VERSUS RANIBIZUMAB FOR DIABETIC MACULAR EDEMA: Data from the Fight Retinal Blindness! Registry.

PURPOSE: Compare the 3-year outcomes of ranibizumab versus aflibercept in eyes with diabetic macular edema in daily practice. METHODS: This was a retrospective analysis of naive diabetic macular edema eyes starting intravitreal injections of ranibizumab (0.5 mg) or aflibercept (2 mg) from January 1, 2013 to December 31, 2017 that were collected in the Fight Retinal Blindness! Registry. RESULTS: We identified 534 eyes (ranibizumab-267 and aflibercept-267) of 402 patients. The adjusted mean (95% confidence interval) visual acuity change of +1.3 (-0.1 to 4.2) letters in the ranibizumab group and +2.4 (-0.2 to 5.1) letters (P = 0.001) in the aflibercept group at 3 years was not clinically different. However, the adjusted mean CST change seemed to remain significantly different throughout the 3-year period with higher reductions in favor of aflibercept (-87.8 [-108.3 to -67.4] µm for ranibizumab vs. -114.4 [-134.4 to -94.3] for aflibercept; P < 0.01). When baseline visual impairment was moderate (visual acuity ≤68 Early Treatment Diabetic Retinopathy Study letters), we found a faster improvement in visual acuity in eyes treated with aflibercept up until 18 months of treatment than eyes treated with ranibizumab, which then stayed similar until 36 months of treatment, whereas there was no apparent difference when baseline visual impairment was mild (visual acuity ≥69 Early Treatment Diabetic Retinopathy Study letters). The rate of serious adverse events was low. CONCLUSION: Aflibercept and ranibizumab were both effective and safe for diabetic macular edema over 3 years.

INTERNATIONAL IMPACT OF THE COVID-19 PANDEMIC LOCKDOWN ON INTRAVITREAL THERAPY OUTCOMES: Fight Retinal Blindness Registry.

PURPOSE: To evaluate the impact of the COVID-19 pandemic lockdowns on the outcomes of eyes treated for neovascular age-related macular degeneration, diabetic macular edema, and retinal vein occlusion in eight countries. METHODS: A multicenter international database study of 5,782 eyes (4,708 patients) receiving intravitreal antivascular endothelial growth factor injections before, during, and after national lockdowns. The baseline visit was defined as the last visit within 3 months before lockdown, and prelockdown and postlockdown periods were defined as 6 months before and after the lockdown date. RESULTS: Eyes with neovascular age-related macular degeneration (n = 4,649) lost vision in all countries in proportion to the reduced number of injections. The mean visual acuity change postlockdown ranged from -0.4 to -3.8 logarithm of the minimum angle of resolution letters, and the median number of injections/visits decreased from 4-5/4-7 to 2-4/2-4 postlockdown. The diabetic macular edema (n = 654) and retinal vein occlusion (n = 479) eyes' mean visual acuity change ranged from -2.8 to +1.7 letters and -1.6 to +0.1 letters, and the median number of injections/visits decreased from 2.5-5/4-6 to 1-3/2-4 and from 3-5.5/4-5 to 1-3.5/2-3.5, respectively. The 6-month dropout rates postlockdown were 20% for neovascular age-related macular degeneration, 27% for diabetic macular edema, and 28% for retinal vein occlusion. CONCLUSION: This international study provides estimates of the impact of COVID-19 pandemic lockdown on intravitreal therapy and suggests that prioritizing neovascular age-related macular degeneration eyes seems appropriate.

Quality of life impact of eye diseases: a Save Sight Registries study.

BACKGROUND: The objectives of this study were to evaluate the quality-of-life (QoL) impact of eye diseases (keratoconus; neovascular age-related macular degeneration, AMD; retinal vein occlusion, RVO; and diabetic macular edema, DME) using the Impact of Vision Impairment (IVI) questionnaire, and to determine the relationship between the IVI scores and visual acuity. METHODS: This cross-sectional, multicentre, real-world study utilised the prospective, web-based Save Sight Registries. The IVI was completed by 1557 patients: 307 with keratoconus, 1049 with AMD, 148 with RVO and 53 with DME. Statistical analysis included Rasch analysis, Welch t-test, one-way ANOVA, Tukey's test, Pearson correlation, and multiple regression. RESULTS: The IVI scales (Overall; Visual Function, VF; Emotional, EM) had robust psychometric properties. The keratoconus patients had the worst Overall (adjusted mean: 48.2 vs. DME 58.8, RVO 64.6, AMD 67.6 units), VF (47.7 vs. DME 59.4, RVO 65.9, AMD 68.9 units) and EM (50.8 vs. DME 63.1, RVO 69.2, AMD 71.8 units) scores (all p < 0.05). The IVI scales scores weakly correlated with better and worse eye visual acuity (Pearson's r 0.24-0.39, all p < 0.05). The correlations were similar in the better eye (Overall 0.35, VF 0.39, EM 0.24) and the worse eye (Overall 0.31, VF 0.33, EM 0.25) visual acuity. Correlations with visual acuity were stronger for VF than for the EM scores. CONCLUSIONS: The IVI was a psychometrically robust QoL questionnaire. Keratoconus patients had worse IVI scores than patients with retinal diseases. The low strength of correlations between visual acuity and QoL scores, although statistically significant, suggested that a complex relationship exists.

One-year real-world outcomes of bevacizumab for the treatment of macular oedema secondary to retinal vein occlusion.

BACKGROUND: Bevacizumab is the only agent that many people can afford, yet there are only limited data on whether it improves macular oedema (MO) secondary to retinal vein occlusion (RVO) in real-world clinical practice. Here we studied 12-month real-world treatment outcomes of bevacizumab for RVO-related MO. METHODS: This was a multicentre, observational study analysing 12-month data from the Fight Retinal Blindness! (FRB) database. We studied treatment-naïve eyes with MO secondary to RVO commencing bevacizumab therapy between June 2009 and June 2019. Visual acuity (VA) and central subfield thickness (CST) were measured at baseline, 6 and 12 months. The primary outcome was a change in VA from baseline to 12 months. RESULTS: Two hundred and twenty treatment naive eyes were analyzed. The baseline VA for BRVO was better than CRVO (55.8 vs. 42.6 LogMAR letters) and this gap widened over the 12-month period, with a 12-month VA change of +14.0 (95% CI 11.1, 16.8) letters for BRVO and + 11.9 (95% CI 6.4, 17.4) for CRVO. The mean CST at baseline was 511 µm for BRVO and 627 µm for CRVO, falling at 12 months by -155 µm (-190, -121) in BRVO and -198 µm (-252, -145) in CRVO. The median number of injections for BRVO and CRVO completers was 7 (5, 9). CONCLUSIONS: Bevacizumab can be an effective treatment of RVO-MO in a real-world setting with outcomes approaching those reported by the seminal clinical trials. The functional and anatomical outcomes of intravitreal therapy were better for BRVO than CRVO.

Creation of a neovascular age-related macular degeneration national database using a web-based platform: Fight Retinal Blindness Spain. Report 1: Visual outcomes.

BACKGROUND: To study the visual outcomes of neovascular AMD (nAMD) treated with anti-vascular endothelial growth factor (VEGF) drugs at national level. METHODS: Multicenter national database of nAMD eyes treated with anti-VEGF intravitreal injections (ranibizumab, aflibercept, bevacizumab) in fixed bimonthly (FB) or treat-and-extend (TAE) regimens. Demographics, visual acuity (VA) in logarithm of the minimum angle of resolution (logMAR) ETDRS letters at baseline and subsequent visits, number of injections and visits data were collected using a validated web-based tool (Fight Retinal Blindness!). RESULTS: 1273 eyes (1014 patients) were included, 971 treatment naïve (TN) and 302 previously treated (PT). Baseline VA (mean ± SD) was 57.5 (±19.5) and 62.2 (±17) (p > 0.001), and 24 months final VA was 60.4 (±21.2) and 58.8 (±21.1) (p = 0.326), respectively. Mean VA change at 12/24 months was +4.2/+2.9 letters in TN eyes and +0.1/-3.4 letters in PT eyes (p < 0.001/p < 0.001). The percentage of ≥15 letters gainers/losers at 24 months was 24.8%/14.5% in TN, and 10.3%/15.7% in PT eyes. The median number of injections/visits at 12 months was 7/9 in TN and 6/8 in PT (p = 0.002/p < 0.001) and at 24 months was 11/16 in TN and 11/14 in PT (p = 0.329/p < 0.001). Study drugs included ranibizumab (39.5%), aflibercept (41.2%) and bevacizumab (19.3%). CONCLUSION: Independent, large-scale national audits are feasible if committed health care professionals are provided with efficient information technology systems to do them. The results described here represent an adequate measurement of the quality of care delivered nationwide and benchmark the clinical management of nAMD at a country level compared to other real-world international cohorts.

Inhibition of Mitochondrial Respiration Impairs Nutrient Consumption and Metabolite Transport in Human Retinal Pigment Epithelium.

Mitochondrial respiration in mammalian cells not only generates ATP to meet their own energy needs but also couples with biosynthetic pathways to produce metabolites that can be exported to support neighboring cells. However, how defects in mitochondrial respiration influence these biosynthetic and exporting pathways remains poorly understood. Mitochondrial dysfunction in retinal pigment epithelium (RPE) cells is an emerging contributor to the death of their neighboring photoreceptors in degenerative retinal diseases including age-related macular degeneration. In this study, we used targeted-metabolomics and 13C tracing to investigate how inhibition of mitochondrial respiration influences the intracellular and extracellular metabolome. We found inhibition of mitochondrial respiration strikingly influenced both the intracellular and extracellular metabolome in primary RPE cells. Intriguingly, the extracellular metabolic changes sensitively reflected the intracellular changes. These changes included substantially enhanced glucose consumption and lactate production; reduced release of pyruvate, citrate, and ketone bodies; and massive accumulation of multiple amino acids and nucleosides. In conclusion, these findings reveal a metabolic signature of nutrient consumption and release in mitochondrial dysfunction in RPE cells. Testing medium metabolites provides a sensitive and noninvasive method to assess mitochondrial function in nutrient utilization and transport.

Effect of selectively knocking down key metabolic genes in Müller glia on photoreceptor health.

The importance of Müller glia for retinal homeostasis suggests that they may have vulnerabilities that lead to retinal disease. Here, we studied the effect of selectively knocking down key metabolic genes in Müller glia on photoreceptor health. Immunostaining indicated that murine Müller glia expressed insulin receptor (IR), hexokinase 2 (HK2) and phosphoglycerate dehydrogenase (PHGDH) but very little pyruvate dehydrogenase E1 alpha 1 (PDH-E1α) and lactate dehydrogenase A (LDH-A). We crossed Müller glial cell-CreER (MC-CreER) mice with transgenic mice carrying a floxed IR, HK2, PDH-E1α, LDH-A, or PHGDH gene to study the effect of selectively knocking down key metabolic genes in Müller glia cells on retinal health. Selectively knocking down IR, HK2, or PHGDH led to photoreceptor degeneration and reduced electroretinographic responses. Supplementing exogenous l-serine prevented photoreceptor degeneration and improved retinal function in MC-PHGDH knockdown mice. We unexpectedly found that the levels of retinal serine and glycine were not reduced but, on the contrary, highly increased in MC-PHGDH knockdown mice. Moreover, dietary serine supplementation, while rescuing the retinal phenotypes caused by genetic deletion of PHGDH in Müller glial cells, restored retinal serine and glycine homeostasis probably through regulation of serine transport. No retinal abnormalities were observed in MC-CreER mice crossed with PDH-E1α- or LDH-A-floxed mice despite Cre expression. Our findings suggest that Müller glia do not complete glycolysis but use glucose to produce serine to support photoreceptors. Supplementation with exogenous serine is effective in preventing photoreceptor degeneration caused by PHGDH deficiency in Müller glia.

Treat-and-extend versus fixed bimonthly treatment regimens for treatment-naive neovascular age-related macular degeneration: real world data from the Fight Retinal Blindness registry.

PURPOSE: To compare the outcomes of two different antivascular endothelial growth factor treatment regimens for treatment-naive eyes with neovascular age-related macular degeneration in routine clinical care at 12 and 24 months in Spain. METHODS: Observational study using the Fight Retinal Blindness (FRB) outcomes registry platform. Eyes were treated with fixed bimonthly (FB) aflibercept group at one center and a treat-and-extend (TAE) regimen using either aflibercept or ranibizumab at the other center. RESULTS: We included 192 eyes. Of these, 160 eyes (83%) completed 12 months (86 TAE and 74 FB) and 79 (41%) completed 24 months (46 for TAE and 33 for FB) of follow-up. No statistically significant differences (p > 0.05) were found regarding mean visual acuity (VA, logMAR letters) at baseline (12 month cohort TAE 59.6 vs FB 57.9; 24 month cohort TAE 61.7 vs FB 62.6), final mean VA (12 month cohort TAE 61.1 vs FB 63.0; 24 month cohort TAE 64.8 vs FB 66.4), and median number of injections (12 months TAE 7 vs FB 7; 24 months TAE 11 vs FB 12). However, the distribution of injection frequencies for the TAE group was larger, with 35% of TAE eyes receiving ≤ 6 injections at 12 months compared with only 19% of FB eyes (p = 0.024). CONCLUSION: Similar VA results were observed with TAE and FB regimens, with no differences in the median number of injections. However, the TAE approach seemed to deliver a wider distribution of injection frequencies due to its individualized approach, which may help reduce the burden of injections in some eyes.

SURGICAL RETINAL EXPLANTS AS A SOURCE OF RETINAL PROGENITOR CELLS.

PURPOSE: To describe the novel observation of spontaneously migrating retinal cells from living donor surgical retinal explants that express progenitor cell markers in the absence of exogenous growth factors. METHODS: Surgical retinal explants were harvested from 5 consecutive patients undergoing 23 G pars plana vitrectomy for the management of rhegmatogenous detachment. During surgery, equatorial flap tears were trimmed with the vitreous cutter and aspirated. Excised tissue was then regurgitated into a syringe containing balanced salt solution and immediately transferred to tissue culture. Migrating cells subsequently underwent immunohistochemical staining and their characteristics were compared with those of a spontaneously immortalized Müller stem cell line. RESULTS: Spontaneously migrating cells were observed from samples taken from all 5 patients from Day 2 to 10 after transfer to culture. These cells were found to express embryonic cell markers, including paired box 6 (Pax6), sex-determining region Y-box 2 (Sox-2), nestin, cone-rod homeobox, and cyclin-dependent kinase inhibitor 1B (p27Kip1) as well as proteins consistent with early or retained differentiation down the Müller cell lineage, including glial fibrillary acidic protein and glutamine synthetase. CONCLUSION: After injury, the human equatorial retina is capable of spontaneously producing cells that demonstrate migration and that express progenitor cell markers. In addition, these cells express proteins consistent with Müller cell lineage. These initial observations support the assertion that the human retina may possess the potential for regeneration and that surgical retinal explants could also act as a ready source of retinal progenitor cells.

FIVE-YEAR INCIDENCE AND VISUAL ACUITY OUTCOMES FOR INTRAVITREAL THERAPY IN BILATERAL NEOVASCULAR AGE-RELATED MACULAR DEGENERATION: Fight Retinal Blindness! Project.

PURPOSE: To compare treatment intensity and mean visual acuity gains for first- and second-affected eyes with age-related macular degeneration nAMD over 5 years of treatment. The cumulative incidence of second-eye involvement was assessed. METHOD: We analyzed data from the Fight Retinal Blindness! project database, a prospectively designed registry of "real-world" outcomes from Australia, New Zealand, Switzerland, and Singapore. Patients with bilateral age-related macular degeneration with ≥5 years of follow-up on treatment were included. RESULTS: Six thousand five hundred and forty-two eyes being treated for age-related macular degeneration were tracked from 2005 to 2017. Thousand two hundred and sixty-one patients had bilateral age-related macular degeneration; of whom, 302 had 5 years of follow-up. Of these, 170 patients started treatment for each eye at least 2 months apart. The mean baseline visual acuity of second-affected eyes was significantly higher than that of first-eyes (20/50 + 2 vs. 20/80; P < 0.01). Second-affected eyes lost a mean of 5.8 (-9.1 to -2.6) logarithm of the minimum angle of resolution letters after 5 years of treatment, whereas the vision of the first-affected eyes remained stable (P = 0.01). Second-affected eyes received fewer injections than the first-affected eyes after the first year of treatment (6.2/year vs. 7.8/year; P < 0.01) and reactivated earlier (376 vs. 507 days; P = 0.04). The cumulative incidence of second eye involvement was 54% over 5 years. CONCLUSION: Second-affected eyes received fewer treatments and reactivated earlier. Care should be taken to avoid undertreating second-affected eyes.

ASSOCIATION BETWEEN ANATOMICAL AND CLINICAL OUTCOMES OF NEOVASCULAR AGE-RELATED MACULAR DEGENERATION TREATED WITH ANTIVASCULAR ENDOTHELIAL GROWTH FACTOR.

PURPOSE: Assess the relationship between subretinal fluid (SRFL), intraretinal fluid, and visual outcomes of neovascular age-related degeneration in routine clinical practice. METHODS: Treatment-naive eyes enrolled in the Fight Retinal Blindness! registry after January 2017 were identified. Lesion activity was graded at each visit as inactive, active not SRFL only (A-NSRFL only), or active SRFL only (A-SRFL only). Eyes were grouped based on initial activity as follows: 1) initially A-NSRFL only or 2) initially A-SRFL only, and their predominant activity status over 12 months was as follows: 1) mostly inactive, 2) mostly A-NSRFL only, or 3) mostly A-SRFL only. RESULTS: Seven hundred and three eyes were eligible for analysis. Initially A-NSRFL only had a similar adjusted mean 12-month visual acuity change to initially A-SRFL eyes (5.7 vs. 6.9 letters; P = 0.165), but their final visual acuity was worse (62.5 vs. 67.5 letters at 12 months; P = 0.003). The adjusted mean 12-month visual acuity change between the predominant activity groups was significantly different (P = 0.005), with mostly inactive (7.6 letters) and mostly A-SRFL only (7.5 letters) eyes gaining more than mostly A-NSRFL only eyes (3.6 letters). CONCLUSION: Eyes with SRFL only had similar outcomes at 1 year to eyes that were mostly inactive. Intraretinal fluid was associated with worse visual outcomes, highlighting the importance of distinguishing between intraretinal fluid and SRFL when managing neovascular age-related degeneration.

Neovascular age-related macular degeneration: A review of findings from the real-world Fight Retinal Blindness! registry.

The use of vascular endothelial growth factor (VEGF) inhibitors has revolutionised the treatment of neovascular age-related macular degeneration (nAMD) since the pivotal Phase III studies demonstrated their efficacy more than 10 years ago. The Fight Retinal Blindness! project was developed to track the treatment outcomes of patients with nAMD in real-world practice. Data from this registry have been used to answer several clinically relevant questions related to the treatment of nAMD including the effect of under-treatment, the comparative effectiveness of different anti-vascular endothelial growth factor agents, long-term treatment outcomes, identifying optimal treatment regimens and the rate and outcomes of rare adverse events. Observational studies are a valuable complement to the shortcomings of clinical trials and a combination of data from real-world settings and clinical trials are necessary to provide evidence on how to achieve the best outcomes for individual patients with nAMD.

Neovascular age-related macular degeneration at treatment intervals of 14 weeks or greater.

BACKGROUND: We assessed the proportion of eyes with neovascular age-related macular degeneration (nAMD) in routine clinical practice that reach ≥14 week treatment intervals and their outcomes. METHOD: We analysed data from the Fight Retinal Blindness! (FRB!) Project database, a prospectively designed registry of 'real-world' outcomes. Treatment-naive eyes starting vascular endothelial growth factor (VEGF) inhibitors for nAMD from 1st January 2006 were included. Eyes were defined to have reached the ≥14 week treatment interval if they received ≥2 consecutive injections at treatment intervals of ≥14 week but not exceeding 26 weeks. Outcomes were reported in a subgroup of eyes that had 12 months of follow-up from reaching this interval. RESULTS: Of the 3907 treatment-naïve eyes that started treatment during the identified periods on a treat-and-extend regimen and received at least 8 injections over the first 2 years, 402 (10%) eyes received at least 2 consecutive injections at an interval of ≥14 week during their follow-up. Fifty-two percent of these eyes maintained vision to 12 months, however only 40% stayed at this interval and 25% of the lesions reactivated. CONCLUSION: We found that only 10% of eyes with nAMD were extended beyond a 13-week injection interval and that over half had returned to a shorter interval by 12 months. Eyes that stayed at this extended treatment interval maintained stable vision. More data on the outcomes of eyes treated with intervals longer than 3 months are required to establish whether emerging VEGF inhibitors provide a more sustained effect than the currently available drugs.