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Supplemental Digital Content is Available in the Text.This study examined the risk of progression from complete retinal pigment epithelial and outer retinal atrophy to geographic atrophy. It also compared this risk with those associated with specific features that define nascent geographic atrophy.

IMPORTANCE: Age-related macular degeneration (AMD) is the leading cause of irreversible vision loss in old age. There is no proven intervention to prevent AMD and, apart from lifestyle, nutritional, and supplement advice, there is no intervention to delay its progression. OBJECTIVE: To determine the impact of long-term low-dose aspirin on the incidence and progression of AMD. DESIGN, SETTING AND PARTICIPANTS: The Aspirin in Reducing Events in the Elderly–AMD (ASPREE-AMD) study was an Australian-based substudy of the ASPREE trial, a multicenter, international, randomized, double-masked, placebo-clinical trial investigating the efficacy of low-dose aspirin in prolonging disability-free survival among older individuals. Retinal photography was conducted at baseline from March 2010 to January 2015, then 3 and 5 years after randomization. AMD status was determined using color retinal images and treatment records. Australian participants in ASPREE aged 70 years and older without dementia, independence-limiting physical disability, cardiovascular disease, or chronic illness limiting 5-year survival and with gradable retinal images at baseline were included. Data were analyzed from December 2022 to December 2023. INTERVENTIONS: Aspirin (100 mg daily, enteric coated) or placebo. MAIN OUTCOMES AND MEASURES: Incidence of AMD and progression from early/intermediate to late AMD. Outcomes were analyzed by modified intention-to-treat analysis. RESULTS: A total of 4993 participants were enrolled in this substudy. Baseline characteristics were similar between groups. At the time of sponsor-determined trial termination, retinal follow-up data were available for 3208 participants, 3171 of whom were analyzed for AMD incidence and progression, with a median (IQR) age of 73.5 (71.5-76.4) years and even sex distribution (1619 [51%] female). Median (IQR) follow-up time was 3.1 (3.0-3.5) years. Cumulative AMD incidence was 195 of 1004 (19.4%) in the aspirin group and 187 of 979 (19.1%) in the placebo group (relative risk [RR], 1.02; 95% CI, 0.85-1.22; P = .86). Cumulative progression from early/intermediate AMD to late AMD was observed in 14 of 615 (2.3%) participants in the aspirin group and 18 of 573 (3.1%) in the placebo group (RR, 0.72; 95% CI, 0.36-1.44; P = .36). CONCLUSIONS AND RELEVANCE: In this trial, low-dose aspirin administered for 3 years did not affect the incidence of AMD. The evidence was weaker for progression of AMD due to low number of progressed cases. Overall, these results do not support suggestion that low-dose daily aspirin prevents the development or progression of AMD. TRIAL REGISTRATION: anzctr.org Identifier: ACTRN12613000755730

Background: The validity of findings from epidemiological studies using self-report of ophthalmic conditions depends on several factors. We assessed the diagnostic accuracy of self-reported age-related macular degeneration (AMD) among older Australians enroled in a primary prevention clinical trial and compared diagnostic accuracy between demographic subgroups. Methods: At baseline (2010–2015), Australian sub-study participants of the ASPirin in Reducing Events in the Elderly (ASPREE) trial, underwent bilateral two-field, 45° non-mydriatic colour retinal photography. Beckman classification of any-stage AMD was used as the reference standard diagnosis. Participants were asked whether a doctor had ever diagnosed them with “macular degeneration” (the index test) via a paper-based questionnaire as part of the ASPREE Longitudinal Study of Older Persons (ALSOP) within the first year of enrolment. Results: In total, 4193 participants were included (aged 70–92 years, 50.8% female). Of those, 262 (6.3%) reported having AMD and 92 (2.2%) were unsure. Retinal grading detected 2592 (61.8%) with no AMD, 867 (20.7%) with early, 686 (16.4%) with intermediate and 48 (1.1%) with late AMD (n= 1601 with any-stage AMD, 38.2%). Self-reported AMD had 11.4% sensitivity (95% CI 9.9–13.1) and 96.9% specificity (95% CI 96.2–97.6) for any-stage AMD, with 69.8% and 63.9% positive and negative predictive values. Sensitivity was higher among participants with late-stage AMD (87.5%), older participants (26.8%), and those with poorer vision (41.0%). Conclusions: Although most participants with late-stage AMD were aware of having AMD, the majority with early and intermediate AMD were not. Therefore, findings from studies that rely on disease self-report should be interpreted with caution.

Objective: The fragility index (FI) of a meta-analysis evaluates the extent that the statistical significance can be changed by modifying the event status of individuals from included trials. Understanding the FI improves the interpretation of the results of meta-analyses and can help to inform changes to clinical practice. This review determined the fragility of ophthalmology-related meta-analyses. Methods: Meta-analyses of randomized controlled trials with binary outcomes published in a journal classified as ‘Ophthalmology’ according to the Journal Citation Report or an Ophthalmology-related Cochrane Review were included. An iterative process determined the FI of each meta-analysis. Multivariable linear regression modeling evaluated the relationship between the FI and potential predictive factors in statistically significant and non-significant meta-analyses. Results: 175 meta-analyses were included. The median FI was 6 (Q1–Q3: 3–12). This meant that moving 6 outcomes from one group to another would reverse the study’s findings. The FI was 1 for 18 (10.2%) of the included meta-analyses and was ≤5 for 75 (42.4%) of the included meta-analyses. The number of events (p< 0.001) and the p-value (p< 0.001) were the best predictors of the FI in both significant and non-significant meta-analyses. Conclusion: The statistical significance of meta-analyses in ophthalmology often hinges on the outcome of a few patients. The number of events and the p-value are the most important factors in determining the fragility of the evidence. The FI is an easily interpretable measure that can supplement the reader’s understanding of the strength of the evidence being presented. PROSPERO registration: CRD42022377589

Geographic atrophy is a leading cause of progressive, irreversible vision loss. The objectives of OAKS and DERBY were to assess the efficacy and safety of pegcetacoplan compared with sham treatment in patients with geographic atrophy.

This systematic review and meta-analysis investigated the impact of anti-vascular endothelial growth factor (VEGF) treatment in management of eyes with non-proliferative diabetic retinopathy (NPDR) without centre involving diabetic macular oedema (CI-DMO). We searched multiple databases for all randomised clinical trials (RCTs) that evaluated anti-VEGF treatment versus observation in eyes with NPDR without CI-DMO. Data was collected for six outcomes (best corrected visual acuity (BCVA) improvement, diabetic retinopathy severity score (DRSS), central subfield thickness, progression to vision threatening complications (VTCs), ocular adverse events and quality of life measures). Risk of bias was assessed using Cochrane risk-of-bias tool for randomised trials (RoB 2) and certainty of evidence was assessed using Grade of Recommendations, Assessment, Development and Evaluation (GRADE). We identified a total of 2 unique RCTs that compared aflibercept and sham to treat a total of 811 eyes. For BCVA change, there was a small, clinically insignificant benefit for aflibercept treatment at year 2 (MD 0.70, 95% CI 0.02–1.38, GRADE rating: MODERATE). DRSS demonstrated a statistically significant improvement with aflibercept use at year 2 (RR 3.76, 95% CI 2.75–5.13, GRADE rating: MODERATE). VTCs were significantly less in aflibercept arm at year 2 (RR 0.30, 95% CI 0.23–0.40, GRADE rating: MODERATE). In conclusion, aflibercept treatment versus observation in eyes with NPDR without CI-DMO can result in reduced risk of development of VTCs and regression of DRSS score over 2 years. Future trials are needed to increase the precision of the treatment effect and to provide data on quality-of-life metrics.

Relative ellipsoid zone reflectivity (rEZR) has been reported to be reduced in intermediate age-related macular degeneration (iAMD). However, longitudinal changes in rEZR remain unknown. This study investigated the natural history of rEZR in iAMD and its association with risk factors for disease progression, including the presence or extent of drusen volume, reticular pseudodrusen (RPD), and pigmentary abnormalities (PAs).

A study is conducted to identify and understand modifiable risk factors in age-related macular degeneration, which is a leading cause of irreversible blindness in Australia and other Western countries. Very little information on modifiable risk factors is consistent and well validated except that of smoking and hence a low-fat diet rich in vegetables containing lutein, zeaxanthin and antioxidants seems a reasonable recommendation along with further research to pinpoint the culprits.

To provide an image-based description of retinal features associated with risk for development of geographic atrophy (GA) in eyes with age-related macular degeneration (AMD), as visualized with multimodal imaging anchored by structural OCT.

To compare the performance of automatically quantified OCT imaging biomarkers and conventional risk factors manually graded on color fundus photographs for predicting progression to late age-related macular degeneration (AMD).

PurposeTo examine the added predictive value of microperimetric sensitivity and low luminance deficit (LLD; difference between photopic and low luminance visual acuity (VA)) to information from colour fundus photography (CFP) for progression to late age-related macular degeneration (AMD) in individuals with bilateral large drusen.Methods140 participants with bilateral large drusen underwent baseline microperimetry testing, VA measurements and CFP. They were then reviewed at 6-monthly intervals to 36 months, to determine late AMD progression. Microperimetry pointwise sensitivity SD (PSD), LLD and the presence of pigmentary abnormalities on CFPs were determined. Predictive models based on these parameters were developed and examined.ResultsBaseline microperimetry PSD and presence of pigmentary abnormalities were both significantly associated with time to develop late AMD (p≤0.004), but LLD was not (p=0.471). The area under the receiver operating characteristic curve (AUC) for discriminating between eyes that progressed to late AMD based on models using microperimetry PSD (AUC=0.68) and LLD (AUC=0.58) alone was significantly lower than that based on CFP grading for the presence of pigmentary abnormalities (AUC=0.80; both p<0.005). Addition of microperimetry and/or LLD information to a model that included CFP grading did not result in any improvement in its predictive performance (AUC=0.80 for all; all p≥0.66).ConclusionsWhile microperimetry, but not LLD, was significantly and independently associated with AMD progression at the population level, this study observed that both measures were suboptimal at predicting progression at the individual level when compared to conventional CFP grading and their addition to the latter did not improve predictive performance.

IMPORTANCE: Neovascular age-related macular degeneration (nAMD), the largest single cause of irreversible severe vision loss in high-income countries, can now be treated with vascular endothelial growth factor (VEGF) inhibitors, but to our knowledge, no data on lifetime outcomes are available. OBJECTIVE: To determine visual acuity (VA) outcomes of anti-VEGF treatment for nAMD in both eyes for patients’ remaining lifetime. DESIGN, SETTING, AND PARTICIPANTS: Multistate modeling using real-world cohort data of 3192 patients with nAMD (>67 000 visits) treated in routine eye clinics in Australia, New Zealand, and Switzerland. Data were analyzed between 2007 and 2015. EXPOSURES: Intravitreal anti-VEGF treatment at the treating physician’s discretion and prospective data collection in standardized registry. MAIN OUTCOMES AND MEASURES: Visual acuity in both eyes over the remaining lifetime. RESULTS: For the mean remaining lifetime of 11 years, an estimated 12% (n = 371; 95% CI, 345-400) of the sample retained driving VA and an estimated 15% (n = 463; 95% CI, 434-495) reading VA in at least 1 eye. At that time, an estimated 82% of the sample (n = 2629; 95% CI, 2590-2660) had dropped out. Younger age at baseline and more injections during the first year of treatment were associated with better long-term outcomes. CONCLUSIONS AND RELEVANCE: Anti-VEGF treatment was associated with preserved useful visual acuity in almost 20% of patients over their average remaining lifetime. More than 80% of patients will cease treatment over that time, having likely experienced a deterioration of vision beforehand. This is a remarkable outcome compared with outcomes without intervention, which lead to legal blindness within 3 years of disease onset in 80% of those affected. These findings underline the public health necessity of providing anti-VEGF treatment to persons in need.

To investigate the relationship between patient-reported outcome (PRO) questionnaire responses and time to late age-related macular degeneration (AMD; neovascular AMD [nAMD] or multimodal imaging [MMI]-defined atrophy) among individuals with bilateral large drusen, and the prognostic value of baseline PROs for 36-month AMD status.

Nascent geographic atrophy (nGA) describes features on OCT imaging previously observed to precede the development of atrophy. This study sought to prospectively evaluate the predictive ability of nGA for the conventional clinical endpoint of geographic atrophy (GA) as defined on color fundus photography (CFP).

To evaluate the secondary and exploratory outcomes of the Laser Intervention in Early Stages of Age-Related Macular Degeneration (LEAD) study, a 36-month trial of a subthreshold nanosecond laser (SNL) treatment for slowing the progression to late age-related macular degeneration (AMD) in its early stages.

Age-Related Macular Degeneration (AMD) is a highly prevalent form of retinal disease amongst Western communities over 50 years of age. A hallmark of AMD pathogenesis is the accumulation of drusen underneath the retinal pigment epithelium (RPE), a biological process also observable in vitro. The accumulation of drusen has been shown to predict the progression to advanced AMD, making accurate characterisation of drusen in vitromodels valuable in disease modelling and drug development. More recently, deposits above the RPE in the subretinal space, called reticular pseudodrusen (RPD) have been recognized as a sub-phenotype of AMD. While in vitroimaging techniques allow for the immunostaining of drusen-like deposits, quantification of these deposits often requires slow, low throughput manual counting of images. This further lends itself to issues including sampling biases, while ignoring critical data parameters including volume and precise localization. To overcome these issues, we developed a semi-automated pipeline for quantifying the presence of drusen-like deposits in vitro, using RPE cultures derived from patient-specific induced pluripotent stem cells (iPSCs). Using high-throughput confocal microscopy, together with three-dimensional reconstruction, we developed an imaging and analysis pipeline that quantifies the number of drusen-like deposits, and accurately and reproducibly provides the location and composition of these deposits. Extending its utility, this pipeline can determine whether the drusen-like deposits locate to the apical or basal surface of RPE cells. Here, we validate the utility of this pipeline in the quantification of drusen-like deposits in six iPSCs lines derived from patients with AMD, following their differentiation into RPE cells. This pipeline provides a valuable tool for the in vitromodelling of AMD and other retinal disease, and is amenable to mid and high throughput screenings.

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ajo.2007.12.005 Byline: Elaine W.-T. Chong (a), Andreas J. Kreis (a), Tien Y. Wong (a)(b), Julie A. Simpson (c)(d), Robyn H. Guymer (a) Abstract: To review systematically the evidence currently available on alcohol consumption and the risk of age-related macular degeneration (AMD). Author Affiliation: (a) Centre for Eye Research Australia, The University of Melbourne, Victoria, Australia (b) Singapore Eye Research Institute, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Republic of Singapore (c) Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, The University of Melbourne, Victoria, Australia (d) Cancer Epidemiology Centre, The Cancer Council of Victoria, Victoria, Australia. Article History: Accepted 5 December 2007

IMPORTANCE: To our knowledge, this is the first randomized clinical trial to compare visual outcomes and injection loads between ranibizumab and aflibercept using an identical treat-and-extend (TE) regimen for neovascular age-related macular degeneration (nAMD). OBJECTIVE: To report the results of the preplanned 12-month interim analysis of 2 predefined secondary efficacy end points of a randomized clinical trial. DESIGN, SETTING, AND PARTICIPANTS: The Comparison of Ranibizumab and Aflibercept for the Development of Geographic Atrophy in (Wet) AMD Patients (RIVAL) trial was conducted in 24 sites in Australia and included 281 treatment-naive eyes from 281 participants with active choroidal neovascularization secondary to nAMD and a visual acuity letter score of 23 or greater who were recruited between April 11, 2014, and October 31, 2015. A preplanned interim analysis was performed at month 12. Best-corrected visual acuity (BCVA) assessors and the central reading center, which determined treatment intervals, were masked to treatment assignments. INTERVENTIONS: Participants were randomized (1:1) to receive intravitreal injections of 0.5 mg of ranibizumab or 2.0 mg of aflibercept. After receiving 3 initial monthly injections, participants entered the TE phase. MAIN OUTCOMES AND MEASURES: Mean change in BCVA and the number of injections from baseline to month 12. RESULTS: Of 281 participants, 148 (52.7%) were women and the mean (SD) age was 77.7 (8.1) years. The baseline mean BCVA letter score (approximate Snellen equivalent) was 65.3 (20/50) in the ranibizumab arm and 65.1 (20/50) in the aflibercept arm. One hundred twenty-seven ranibizumab participants (90.1%) and 121 aflibercept participants (88.3%) completed month 12 with a mean (SD [Snellen equivalent]) BCVA letter score of 72.9 (15.5 [20/32]) and 70.5 (14.6 [20/40]), respectively. The mean change in BCVA letter scores from baseline to month 12 was 7.2 (95% CI, 5.5-8.9) for ranibizumab and 4.9 (95% CI, 3.1-6.6) for aflibercept (letter score difference, 2.3; 95% CI, −0.1 to 4.7; P = .06). The mean number of injections from baseline to month 12 was 9.7 in both the ranibizumab (SD, 2.8) and aflibercept (SD, 2.6) arms with a rate ratio of 1.00 (95% CI, 1.0-1.1; P = .86). CONCLUSIONS AND RELEVANCE: Our findings suggest that neither aflibercept nor ranibizumab for nAMD are superior to the other regarding the average visual acuity gains and number of injections during 1 year in a TE regimen. Further follow-up to 2 years may determine if advantages of one over the other can be identified. TRIAL REGISTRATION: Clinicaltrials.Gov identifier: NCT02130024

Although rod function is known to be severely impaired in eyes with reticular pseudodrusen (RPD), it remains unknown whether this impairment is associated with a total loss of rod function or merely a delay in rod recovery. The purpose of the study was to determine rod functional recovery profiles after prolonged dark adaptation (DA) in eyes with age-related macular degeneration (AMD) and RPD.

Objectives: To investigate the role of 2 specific alleles of the Stargardt disease gene (ABCA4) in the pathogenesis of age-related macular degeneration (AMD). Secondary objectives were to investigate differences in frequency of the G1961E allele in selected ethnic groups as well as to examine the segregation of both G1961E and D2177N alleles in 5 multiplex families with AMD. Methods: Five hundred forty-four patients with AMD and 689 controls were ascertained from 3 continents. Blood samples from 62 normal individuals of Somalian ancestry were also obtained. Participants were screened for the presence of these ABCA4 alleles with a combination of restriction digestion and single-strand conformation polymorphism analysis of polymerase chain reaction amplification products. Detected alleles were confirmed by DNA sequencing. The number of subjects exhibiting the G1961E or D2177N variants were compared between AMD and control groups using a 2-tailed Fisher exact test. Results: There was no significant difference (P [is greater than] .1) in the frequency of the G1961E and D2177N alleles in patients with AMD (2.2%) vs controls (1.0%). In contrast, there was a significant difference (P [is less than] .001) in the frequency of the G1961E alleles between normal individuals of Somali ancestry (11.3%) and normal individuals from other populations (0.4%). There was no evidence of cosegregation of these alleles and the AMD phenotype in the 5 multiplex families with AMD examined. These two ABCA4 alleles were slightly more frequent in patients with AMD with choroidal neovascularization (2.7%) than those without this complication (2.5%). Conclusions: Somali ancestry is more than 100 times more strongly associated with presence of the G1961E allele than the AMD phenotype. This study did not find any statistically significant evidence for involvement of the G1961E or D2177N alleles of the ABCA4 gene in AMD. Clinical Relevance: The ABCA4 gene is definitively involved in the pathogenesis of Stargardt disease and some cases of photoreceptor degeneration. However, it does not seem to be involved in a statistically significant fraction of AMD cases. Arch Ophthalmol. 2001;119:745-751

IMPORTANCE: Visual acuity (VA) outcomes differ considerably among patients with neovascular age-related macular degeneration (nAMD) treated with anti–vascular endothelial growth factor (VEGF) drugs. Identification of pharmacogenetic associations may help clinicians understand the mechanisms underlying this variability as well as pave the way for personalized treatment in nAMD. OBJECTIVE: To identify genetic factors associated with variability in the response to anti-VEGF therapy for patients with nAMD. DESIGN, SETTING, AND PARTICIPANTS: In this multicenter genome-wide association study, 678 patients with nAMD with genome-wide genotyping data were included in the discovery phase; 1380 additional patients with nAMD were genotyped for selected common variants in the replication phase. All participants received 3 monthly injections of bevacizumab or ranibizumab. Clinical data were evaluated for inclusion/exclusion criteria from October 2014 to October 2015, followed by data analysis from October 2015 to February 2016. For replication cohort genotyping, clinical data collection and analysis (including meta-analysis) was performed from March 2016 to April 2017. MAIN OUTCOMES AND MEASURES: Change in VA after the loading dose of 3 monthly anti-VEGF injections compared with baseline. RESULTS: Of the 2058 included patients, 1210 (58.8%) were women, and the mean (SD) age across all cohorts was 78 (7.4) years. Patients included in the discovery cohort and most of the patients in the replication cohorts were of European descent. The mean (SD) baseline VA was 51.3 (20.3) Early Treatment Diabetic Retinopathy Study (ETDRS) score letters, and the mean (SD) change in VA after the loading dose of 3 monthly injections was a gain of 5.1 (13.9) ETDRS score letters (ie, 1-line gain). Genome-wide single-variant analyses of common variants revealed 5 independent loci that reached a P value less than 10 × 10−5. After replication and meta-analysis of the lead variants, rs12138564 located in the CCT3 gene remained nominally associated with a better treatment outcome (ETDRS letter gain, 1.7; β, 0.034; SE, 0.008; P = 1.38 × 10−5). Genome-wide gene-based optimal unified sequence kernel association test of rare variants showed genome-wide significant associations for the C10orf88 (P = 4.22 × 10−7) and UNC93B1 (P = 6.09 × 10−7) genes, in both cases leading to a worse treatment outcome. Patients carrying rare variants in the C10orf88 and UNC93B1 genes lost a mean (SD) VA of 30.6 (17.4) ETDRS score letters (ie, loss of 6.09 lines) and 26.5 (13.8) ETDRS score letters (ie, loss of 5.29 lines), respectively, after 3 months of anti-VEGF treatment. CONCLUSIONS AND RELEVANCE: We propose that there is a limited contribution of common genetic variants to variability in nAMD treatment response. Our results suggest that rare protein-altering variants in the C10orf88 and UNC93B1 genes are associated with a worse response to anti-VEGF therapy in patients with nAMD, but these results require further validation in other cohorts.

To determine the natural history of asymptomatic, subretinal fluid (SRF) in intermediate age-related macular degeneration (iAMD) and highlight the entity of nonexudative detachment of the neurosensory retina (NEDNR).

Age-related macular degeneration (AMD) is a leading cause of irreversible, severe vision loss in Western countries. Recently, we identified a novel pathway involving P2X7 receptor scavenger function expressed on ocular immune cells as a risk factor for advanced AMD. In this study, we investigate the effect of loss of P2X7 receptor function on retinal structure and function during aging. P2X7-null and wild-type C57bl6J mice were investigated at 4, 12, and 18 months of age for macrophage phagocytosis activity, ocular histological changes, and retinal function. Phagocytosis activity of blood-borne macrophages decreased with age at 18 months in the wild-type mouse. Lack of P2X7 receptor function reduced phagocytosis at all ages compared to wild-type mice. At 12 months of age, P2X7-null mice had thickening of Bruchs membrane and retinal pigment epithelium dysfunction. By 18 months of age, P2X7-null mice displayed phenotypic characteristics consistent with early AMD, including Bruchs membrane thickening, retinal pigment epithelium cell loss, retinal functional deficits, and signs of subretinal inflammation. Our present study shows that loss of function of the P2X7 receptor in mice induces retinal changes representing characteristics of early AMD, providing a valuable model for investigating the role of scavenger receptor function and the immune system in the development of this age-related disease.

The Laser Intervention in Early Stages of Age-Related Macular Degeneration (LEAD) study is an investigation of the safety and efficacy of subthreshold nanosecond laser treatment to slow the progression of intermediate age-related macular degeneration (AMD). This report presents the novel study design and baseline characteristics.

We present a novel framework combining convolutional neural networks (CNN) and graph search methods (termed as CNN-GS) for the automatic segmentation of nine layer boundaries on retinal optical coherence tomography (OCT) images. CNN-GS first utilizes a CNN to extract features of specific retinal layer boundaries and train a corresponding classifier to delineate a pilot estimate of the eight layers. Next, a graph search method uses the probability maps created from the CNN to find the final boundaries. We validated our proposed method on 60 volumes (2915 B-scans) from 20 human eyes with non-exudative age-related macular degeneration (AMD), which attested to effectiveness of our proposed technique.

Age-related macular degeneration is an increasingly important public health issue due to ageing populations and increased longevity. Age-related macular degeneration affects individuals older than 55 years and threatens high-acuity central vision required for important tasks such as reading, driving, and recognising faces. Advances in retinal imaging have identified biomarkers of progression to late age-related macular degeneration. New treatments for neovascular age-related macular degeneration offer potentially longer-lasting effects, and progress is being made towards a treatment for atrophic late age-related macular degeneration. An effective intervention to slow progression in the earlier stages of disease, or to prevent late age-related macular degeneration development remains elusive, and our understanding of underlying mechanistic pathways continues to evolve.

To evaluate the safety and efficacy of repeat injections of the Brimonidine Drug Delivery System (Brimo DDS) Generation 2 (Gen 2) containing 400-μg brimonidine in patients with geographic atrophy (GA) secondary to age-related macular degeneration (AMD).

To compare the efficacy and safety of subthreshold macular laser to conventional focal laser photocoagulation for the treatment of vision loss secondary to diabetic macular edema (DME).

Supplemental digital content is available in the text.

There is poor correlation between visual acuity and the presence of fluid on optical coherence tomography, however new occurrence of fluid is more likely to lead to vision loss compared with absence or persistence of fluid. Factors other than fluid may also influence the visual outcome after antivascular endothelial growth factor treatment for neovascular age-related macular degeneration.

Advanced age-related macular degeneration (AMD) is the leading cause of blindness in the elderly, with limited therapeutic options. Here we report on a study of >12 million variants, including 163,714 directly genotyped, mostly rare, protein-altering variants. Analyzing 16,144 patients and 17,832 controls, we identify 52 independently associated common and rare variants (P < 5 × 10−8) distributed across 34 loci. Although wet and dry AMD subtypes exhibit predominantly shared genetics, we identify the first genetic association signal specific to wet AMD, near MMP9 (difference P value = 4.1 × 10−10). Very rare coding variants (frequency <0.1%) in CFH, CFI and TIMP3 suggest causal roles for these genes, as does a splice variant in SLC16A8. Our results support the hypothesis that rare coding variants can pinpoint causal genes within known genetic loci and illustrate that applying the approach systematically to detect new loci requires extremely large sample sizes.

IMPORTANCE: Topical phenylephrine hydrochloride is routinely administered with few safety precautions, but evidence regarding its systemic safety to date is controversial. As even short-term variations in 24-hour blood pressure (BP) and heart rate (HR) can adversely affect cardiovascular health, better evidence on phenylephrine’s effects on HR and BP is required. OBJECTIVE: To perform a meta-analysis of available evidence regarding cardiovascular adverse effects of topical phenylephrine. DATA SOURCES: PubMed, MEDLINE, and the Cochrane Database of Systematic Reviews and Clinical Trials were searched for relevant literature from January 1, 1970, to January 1, 2014, using a combination of the following search terms: topical, ocular, ophthalmic, phenylephrine, tropicamide, cardiovascular effect, side effect, blood pressure, heart rate, mydriatic, and eye drops. A total of 70 articles related to the topic were identified and all full texts were retrieved. STUDY SELECTION: Randomized clinical trials reporting change in BP and HR for adults were included in this review. All studies reporting results for neonates or infants, not reporting standard deviations, or not specifying the time of measurement or the concentration of phenylephrine used were excluded. DATA EXTRACTION AND SYNTHESIS: Data from randomized clinical trials that reported BP and/or HR as well as the time following administration of topical phenylephrine at which measurements were obtained by concentration of phenylephrine as a mean change and its standard deviation were extracted. Data were synthesized by concentration of phenylephrine and time of measurement following topical application using random-effects models with inverse variance weighting to account for heterogeneity across studies. MAIN OUTCOMES AND MEASURES: Difference in BP and HR after topical administration of phenylephrine. RESULTS: Eight RCTs with a total of 916 participants were included. Data were available for phenylephrine, 2.5%, at 20 to 30 minutes and 60 minutes or longer after administration, and neither BP nor HR changed at either time. Following application of phenylephrine, 10%, BP increased at 5 and 10 minutes (mean difference for both, +15 mm Hg; 95% CI, 11.94-18.54; P &lt; .001) but decreased at 20 to 30 minutes and 60 minutes or longer with no changes detected against baseline. A mean increase in HR by 4.48 beats/min (95% CI, 1.09-7.88; P = .01) was present at 20 to 30 minutes following application of phenylephrine, 10%, and HR decreased by 60 minutes or longer with no changes detected compared with baseline. CONCLUSIONS AND RELEVANCE: Phenylephrine, 2.5%, leads to no clinically relevant change in BP or HR, and the changes in BP and HR seen with phenylephrine, 10%, are short lived. Thus, phenylephrine, 2.5%, is safe to use in clinical routine.

To determine age-related macular degeneration (AMD) phenotypes associated with mutually exclusive homozygotic risk variants in rs1061170 (CFH) and rs11200638 (HTRA1).

IMPORTANCE: There is a need for more sensitive measures of disease in intermediate age-related macular degeneration (AMD) to evaluate novel interventions more effectively and expediently. OBJECTIVE: To determine if microperimetry and low luminance visual acuity can detect functional changes over a short duration of follow-up. DESIGN, SETTING, AND PARTICIPANTS: Prospective longitudinal examination of 49 participants with consecutive AMD and 10 healthy participants in a research clinic from May 1, 2012, to December 31, 2013. Forty-one participants had intermediate AMD, 8 had nonfoveal geographic atrophy due to AMD. Participants underwent microperimetry examinations in 1 eye during a 12-month period at 6-month intervals for participants with AMD and at baseline and 12 months for control participants; low luminance visual acuity was performed at baseline and at 12 months for all participants. Changes in pathological features of intermediate AMD eyes were determined using side-by-side comparisons of color fundus photographs from the initial and final visit as remaining stable, progressed, or improved. MAIN OUTCOMES AND MEASURES: Microperimetric sensitivity and low luminance visual acuity. RESULTS: A reduction in mean (SE) microperimetric pointwise sensitivity was identified at 12 months compared with the baseline for intermediate AMD eyes graded as stable (−0.31 dB [0.10 dB]; P = .003) or worsened (−0.42 dB [0.12 dB]; P &lt; .001) and an improvement in mean (SE) pointwise sensitivity was identified in eyes graded as improved (1.13 dB [0.23 dB]; P &lt; .001). A reduction in mean (SE) pointwise sensitivity was identified in eyes with nonfoveal geographic atrophy at both 6 months (−1.41 dB [0.22 dB]; P &lt; .001) and 12 months compared with the baseline (−2.56 dB [0.22 dB]; P &lt; .001) while a change in mean (SE) pointwise sensitivity was not identified over the 12-month period for control participants (−0.11 dB [0.11 dB]; P = .34). No changes in best-corrected visual acuity or low luminance visual acuity were identified in all groups over the 12-month period (P ≥ .07). CONCLUSIONS AND RELEVANCE: Microperimetry detected subtle changes in visual function over a 12-month period in eyes with intermediate AMD but visual acuity measures did not identify any such changes. These findings suggest that microperimetry is worth exploring as a method for assessing the efficacy of novel interventions for intermediate AMD potentially requiring a shorter duration of follow-up.

Certain allele types of the APOEgene seem to be associated with the presence/absence of fluid at baseline and after a loading dose regimen of anti-vascular endothelial growth factor. This could be useful in optimizing treatment protocols to improve visual outcomes.

To evaluate 2-year visual acuity outcome of a treat-and-extend protocol of anti–vascular endothelial growth factor treatment in age-related macular degeneration.