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Objective: To predict 2-year visual acuity (VA) responses to anti-VEGF therapy, using early morphologic and functional responses in patients with neovascular age-related macular degeneration (nAMD)., Design: Cohort within a randomized clinical trial., Participants: A total of 1185 participants with untreated active nAMD and best-corrected visual acuity (BCVA) 20/25 to 20/320 at baseline., Methods: Secondary analysis of data from participants randomized to either ranibizumab or bevacizumab and to 1 of 3 dosing regimens. Associations of 2-year BCVA responses with baseline morphologic and functional characteristics and their change from baseline at 3 months were assessed, using univariable and multivariable linear regression models for BCVA change and logistic regression models for ≥ 3-line BCVA gain from baseline. The performance of predictions for 2-year BCVA outcomes using these characteristics was assessed using R 2 for BCVA change and area under the receiver operating characteristic curve (AUC) for ≥ 3-line BCVA gain., Main Outcome Measures: Best-corrected visual acuity change and ≥ 3-line gain from baseline at year 2., Results: In multivariable analyses that included previously reported significant baseline predictors (baseline BCVA, baseline macular atrophy, baseline retinal pigment epithelium elevation [RPEE], and maximum width and early BCVA change from baseline at 3 months), new RPEE occurrence at 3 months was significantly associated with more BCVA gain at 2 years (10.2 letters vs. 3.5 letters for RPEE resolved, P < 0.001), and none of the other morphologic responses at 3 months were significantly associated with BCVA responses at 2 years. These significant predictors moderately predicted 2-year BCVA gain with an R 2  = 0.36. Baseline BCVA and ≥ 3-line BCVA gain at 3 months predicted 2-year ≥ 3-line gain with AUC 0.83 (95% confidence interval, 0.81-0.86)., Conclusions: Most structural responses on OCT at 3 months were not independently predictive of the 2-year BCVA responses, which were associated with baseline factors and the 3-month BCVA response to anti-VEGF therapy. A combination of baseline predictors, early BCVA, and morphologic responses at 3 months only moderately predicted the long-term BCVA responses. Future research is needed to better understand the factors contributing to the variation in long-term vision outcomes with anti-VEGF therapy., Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references., (Copyright © 2023 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Background: Thiazolidinediones, commonly used antidiabetic medications, have been associated with an increased risk of development of diabetic macular oedema and increased vascular endothelial cell permeability. Macular neovascularisation in age-related macular degeneration (AMD) and associated fluid leakage may be influenced by thiazolidinediones. This study aims to determine the association between thiazolidinedione usage and retinal morphological outcomes or visual acuity (VA) in patients treated with bevacizumab or ranibizumab for neovascular AMD (nAMD)., Methods: Secondary analysis of data from the Comparison of Age-related Macular Degeneration Treatments Trials. Participant self-reported diabetes status and thiazolidinedione usage at baseline. VA, intraretinal, subretinal and subretinal pigment epithelium fluid, and foveal thickness of retinal layers were evaluated at baseline and during 2-year follow-up. Comparisons of outcomes between thiazolidinedione usage groups were adjusted by macular neovascularisation lesion type in multivariable regression models., Results: Patients taking thiazolidinedione (n=30) had lower adjusted mean VA score at baseline (difference -6.2 letters; p=0.02), greater proportion with intraretinal fluid (IRF) at year 2 (75% vs 50%, adjusted OR 2.8; p=0.04), greater mean decrease in subretinal tissue complex thickness from baseline at year 1 (difference -75.1 um; p=0.02) and greater mean decrease in subretinal thickness at year 1 (difference -41.9 um; p=0.001) and year 2 (difference -43.3 um; p=0.001)., Conclusions: In this exploratory analysis, patients with diabetes taking thiazolidinediones and treated with bevacizumab or ranibizumab for nAMD had worse baseline mean VA, greater reductions in subretinal and subretinal tissue complex thickness from baseline, and greater proportions with IRF comparing to patients not taking thiazolidinediones., Trial Registration Number: ClinicalTrials.gov NCT00593450., Competing Interests: Competing interests: ED is a consultant to Novartis International AG. MGM serves on a data and safety monitoring committee for Genentech/Roche. GJ has a consultancy relationship with Alcon/Novartis, Genentech/Roche, Neurotech, EyePoint Pharmaceuticals and Adverum. G-SY is a consultant to Chengdu Kanghong Biotech, Ziemer Ophthalmic Systems AG and Synergy Research., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: To describe predominantly persistent intraretinal fluid (PP-IRF) and its association with visual acuity (VA) and retinal anatomic findings at long-term follow-up in eyes treated with pro re nata (PRN) ranibizumab or bevacizumab for neovascular age-related macular degeneration., Design: Cohort within a randomized clinical trial., Participants: Participants in the Comparison of Age-related Macular Degeneration Treatments Trials (CATT) assigned to PRN treatment., Methods: The presence of intraretinal fluid (IRF) on OCT scans was assessed at baseline and monthly follow-up visits by Duke OCT Reading Center. Predominantly persistent intraretinal fluid through week 12, year 1, and year 2 was defined as the presence of IRF at the baseline and in ≥ 80% of follow-up visits. Among eyes with baseline IRF, the mean VA scores (letters) and changes from the baseline were compared between eyes with and those without PP-IRF. Adjusted mean VA scores and changes from the baseline were also calculated using the linear regression analysis to account for baseline patient features identified as predictors of VA in previous CATT studies. Furthermore, outcomes were adjusted for concomitant predominantly persistent subretinal fluid., Main Outcome Measures: Predominantly persistent intraretinal fluid through week 12, year 1, and year 2; VA score and VA change; and scar development at year 2., Results: Among 363 eyes with baseline IRF, 108 (29.8%) had PP-IRF through year 1 and 95 (26.1%) had PP-IRF through year 2. When eyes with PP-IRF through year 1 were compared with those without PP-IRF, the mean 1-year VA score was 62.4 and 68.5, respectively (P = 0.002), and was 65.0 and 67.4, respectively (P = 0.13), after adjustment. Predominantly persistent intraretinal fluid through year 2 was associated with worse adjusted 1-year mean VA scores (64.8 vs. 69.2; P = 0.006) and change (4.3 vs. 8.1; P = 0.01) as well as worse adjusted 2-year mean VA scores (63.0 vs. 68.3; P = 0.004) and changes (2.4 vs. 7.1; P = 0.009). Predominantly persistent intraretinal fluid through year 2 was associated with a higher 2-year risk of scar development (adjusted hazard ratio = 1.49; P = 0.03)., Conclusions: Approximately one quarter of eyes had PP-IRF through year 2. Predominantly persistent intraretinal fluid through year 1 was associated with worse long-term VA, but the relationship disappeared after adjustment for baseline predictors of VA. Predominantly persistent intraretinal fluid through year 2 was independently associated with worse long-term VA and scar development., (Copyright © 2022 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Multi-kingdom community complexity and the chemically mediated dynamics between bacteria and insects have recently received increased attention in carrion research. However, the strength of these inter-kingdom interactions and the factors that regulate them are poorly studied. We used 75 piglet cadavers across three forest regions to survey the relationship between three actors (epinecrotic bacteria, volatile organic compounds (VOCs) and flies) during the first 4 days of decomposition and the factors that regulate this interdependence. The results showed a dynamic bacterial change during decomposition (temperature-time index) and across the forest management gradient, but not between regions. Similarly, VOC emission was dynamic across a temperature-time index and the forest management gradient but did not differ between regions. However, fly occurrence was dynamic across both space and time. The strong interdependence between the three actors was mainly regulated by the temperature-time index and the study regions, thereby revealing regulation at temporal and spatial scales. Additionally, the actor interdependence was stable across a gradient of forest management intensity. By combining different actors of decomposition, we have expanded our knowledge of the holistic mechanisms regulating carrion community dynamics and inter-kingdom interactions, an important precondition for better describing food web dynamics and entire ecosystem functions., (© 2022 The Authors.)

Objective: To describe predominantly persistent subretinal fluid (SRF) in eyes receiving ranibizumab or bevacizumab for neovascular age-related macular degeneration and to compare visual acuity (VA) to eyes with nonpersistent SRF., Design: Cohort within randomized clinical trial., Participants: Comparison of Age-related Macular Degeneration Treatments Trials patients assigned to pro re nata treatment., Methods: Graders evaluated monthly OCT scans for SRF. Predominantly persistent SRF through week 12 was defined as SRF at baseline and weeks 4, 8, and 12. Predominantly persistent SRF through 1 or 2 years was defined as SRF in 80% or more of visits by years 1 or 2, respectively. Linear regression models including baseline predictors of VA and predominantly persistent intraretinal fluid (IRF) were used to evaluate mean differences in vision outcomes., Primary Outcome Measures: Predominantly persistent SRF through year 1, adjusted VA score and VA change, and foveal SRF thickness., Results: Among 406 eyes with baseline SRF, SRF persisted in 108 eyes (26.6%) through week 12, in 94 eyes (23.2%) through year 1, and in 77 eyes (19.0%) through year 2. Adjusted VA means at year 1 were similar between eyes with predominantly persistent versus non persistent SRF by week 12 (68.1 vs. 70.2 letters; P = 0.18), year 1 (67.6 vs. 70.2 letters; P = 0.11), and year 2 (71.4 vs. 70.9 letters; P = 0.78). Adjusted changes in mean VA at year 1 were similar between eyes with predominantly persistent versus nonpersistent SRF by week 12 (6.3 vs. 7.6 letters; P = 0.38), year 1 (5.5 vs. 7.8 letters; P = 0.14), and year 2 (8.1 vs. 7.7 letters; P = 0.78). Among eyes with predominantly persistent SRF through year 1, foveal SRF was absent in 46 eyes (48.9%), thickness was 1 to 200 μm in 48 eyes (50.0%) and more than 200 μm in 1 eye (1.1%) at year 1., Conclusions: Eyes with predominantly persistent and nonpersistent SRF through week 12, year 1, or year 2 showed similar VA outcomes after adjustment for baseline covariates and persistent IRF. At the foveal center, predominantly persistent SRF was most commonly absent or present in small quantities., (Copyright © 2021 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: To determine associations of systemic medications with the incidence and growth of geographic atrophy (GA) in participants of the comparison of age-related macular degeneration treatments trials., Methods: Participants of comparison of age-related macular degeneration treatments trials with new untreated choroidal neovascularization in the study eye (one study eye per participant) were randomized to receive treatment with bevacizumab or ranibizumab. Participants were released from clinical trial treatment at 2 years and examined at approximately 5 years. Color fundus photographs and fluorescein angiograms taken at baseline, Years 1, 2, and 5 were assessed for the presence and size of GA by two masked graders. Participants were interviewed about systemic medication use at baseline. Systemic medications previously reported to be associated with age-related macular degeneration were evaluated for associations with GA incidence in study eye using univariable and multivariable Cox models and for association with the GA growth using linear mixed effects models., Results: In multivariable analysis of 1,011 study eyes without baseline GA, systemic medications, including cholinesterase inhibitors, angiotensin-converting enzyme inhibitors, calcium channel blockers, beta-blockers, diuretics, aspirin, steroids, statins, hormone replacement therapy, antacids, and drugs targeting G protein-coupled receptors, were not associated with GA incidence in the study eye (all adjusted hazard ratios ≤1.86, P ≥ 0.18). In multivariable analysis of 214 study eyes with longitudinal GA size measurements, calcium channel blockers were associated with a higher GA growth rate (0.40 vs. 0.30 mm/year, P = 0.02)., Conclusion: None of the systemic medications analyzed were associated with GA incidence. However, calcium channel blockers were associated with a higher growth rate of GA in the study eye.

Purpose: To identify precursors of macular atrophy (MA) and of fibrotic scar (FS) in eyes treated with anti-vascular endothelial growth factor through pixel-mapping analysis of baseline optical coherence tomography (OCT)., Methods: Design: Cross-sectional analysis., Setting: Multicenter clinical trial., Patient Population: 68 eyes from the Comparison of Age-Related Macular Degeneration Treatments Trials., Intervention: Treatment with anti-vascular endothelial growth factor agents., Main Outcome Measure: The percentage of MA or FS pixels with each OCT feature at baseline, and the odds ratio for baseline pixels with an OCT feature to develop MA or FS., Results: Retinal pigment epithelium atrophy and photoreceptor loss on OCT were highly predictive of MA at that location at years 2 and 5 (P < .0001), but accounted for only 22.5% of the ensuing atrophy at year 2 and less at year 5. Among pixels of MA at year 2, 78% were preceded by thick drusen, 54% by subretinal macular neovascularization (MNV), and 22.5% by no detectable OCT features. MNV, subretinal hyperreflective material, pigment epithelial detachment, intraretinal fluid, and sub-retinal pigment epithelium fluid were predictive of FS at that location (P values <.05). More than 75% of the pixels of FS at years 2 and 5 were preceded by pixels of baseline MNV., Conclusions: Most pixels of FS were preceded by components of neovascularization. Although one-quarter of MA was accounted for by pre-existing evidence of atrophy on OCT alone, the development of MA in areas of thick drusen, areas with and without subretinal MNV lesion, and areas without detectable OCT precursors argues that the development of MA is multifactorial and may follow, in part, a non-neovascular pathway., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: Chronic kidney disease (CKD) patients often develop cardiovascular disease (CVD) and retinopathy. The purpose of this study was to assess the association between progression of retinopathy and concurrent incidence of CVD events in participants with CKD., Design: We assessed 1051 out of 1936 participants in the Chronic Renal Insufficiency Cohort Study that were invited to have fundus photographs obtained at two timepoints separated by 3.5 years, on average., Methods: Using standard protocols, presence and severity of retinopathy (diabetic, hypertensive or other) and vessel diameter calibre were assessed at a retinal image reading centre by trained graders masked to study participants' information. Participants with a self-reported history of CVD were excluded. Incident CVD events were physician adjudicated using medical records and standardised criteria. Kidney function and proteinuria measurements along with CVD risk factors were obtained at study visits., Results: Worsening of retinopathy by two or more steps in the EDTRS retinopathy grading scale was observed in 9.8% of participants, and was associated with increased risk of incidence of any CVD in analysis adjusting for other CVD and CKD risk factors (OR 2.56, 95% CI 1.25 to 5.22, p<0.01). After imputation of missing data, these values were OR=1.66 (0.87 to 3.16), p=0.12., Conclusion: Progression of retinopathy is associated with higher incidence of CVD events, and retinal-vascular pathology may be indicative of macrovascular disease even after adjustment for kidney diseases and CVD risk factors. Assessment of retinal morphology may provide important information when assessing CVD in patients with CKD., Competing Interests: Competing interests: RRT is a consultant for Medtronic, ROX Medical, and receives royalties from UpToDate. ASG has received research funding from Novartis, GlaxoSmithKline and Sanofi. All other coauthors have no financial conflict of interest regarding the contents of this manuscript., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Importance: Retinal hypopigmentation and hyperpigmentation are precursors of geographic atrophy (GA). Incidence and progression to GA in eyes treated with anti-vascular endothelial growth factor for neovascular age-related macular degeneration (nAMD) have not been investigated., Objective: To determine the incidence and progression of non-GA (NGA) and associated risk factors., Design, Setting, and Participants: This study is a post hoc analysis of a cohort study within the Comparison of Age-Related Treatments Trials (CATT) clinical trial. Participants were recruited February 20, 2008, through December 9, 2009; released from protocol follow-up and treatment after 2 years; and recalled from March 14, 2014, through March 31, 2015. Data analyses were conducted from January 11, 2019, through November 27, 2019., Interventions: Participants were randomized to ranibizumab or bevacizumab for (1) 2 years of monthly or as-needed injections or (2) monthly injections for 1 year and as-needed injections the following year. Participants were treated according to best medical judgement thereafter., Main Outcomes and Measures: Incidence of nAMD-associated NGA (hypopigmentation and hyperpigmentation in color images) and progression; adjusted risk ratios (aRR) for baseline characteristics., Results: Among 1107 participants, risk of NGA was 35% (391 eyes), 59% (246 eyes), and 81% (122 eyes) at 1, 2, and 5 years, respectively. Risk factors for NGA included worse visual acuity (20/200-20/320: aRR, 1.74 [95% CI, 1.24-2.43], compared with ≤20/40; P = .006), larger neovascularization area (>4 disc areas: aRR, 1.31 [95% CI, 1.01-1.71], compared with ≤1 disc areas; P = .007), switched drug regimen (aRR, 1.28 [95% CI, 1.06-1.54], compared with as-needed injections; P = .02), and single-nucleotide variants Age-Related Maculopathy Susceptibility 2 (ARMS2) (TT variant: relative risk [RR], 1.53 [95% CI, 1.22-1.93]; P = .001) and HtrA Serine Peptidase 1 (HTRA1) (AG variant: RR, 1.23 [95% CI, 1.01-1.48]; AA variant: RR, 1.51 [95% CI, 1.20-1.91]; P = .002). Sub-retinal pigment epithelium thickness was protective (>275 μm: aRR, 0.59 [95% CI, 0.46-0.75], compared with ≤75 μm; P < .001). Among 389 eyes with NGA by 2 years and subsequent color images, risk of progression to GA was 29%, 43%, and 50% at 1, 3, and 4 years, respectively. Risk factors for progression to GA included worse visual acuity (20/200-20/320: aRR, 2.75 [95% CI, 1.54-4.93], compared with ≤20/40; P < .001), worse fellow-eye visual acuity (<20/40: aRR, 1.77 [95% CI, 1.12-2.79], compared with ≥20/40; P = .01), fellow-eye GA (aRR, 1.71 [95% CI, 1.06-2.75]; P = .03), and pseudodrusen in either eye (aRR, 1.65 [95% CI, 1.17-2.34]; P = .005). Subretinal fluid was associated with a decreased risk of progression (aRR, 0.42 [95% CI, 0.28-0.63]; P < .001)., Conclusions and Relevance: In this study, after 2 years of protocol-guided anti-vascular endothelial growth factor treatment for nAMD, more than half of the eyes in the study developed NGA in the location of nAMD. After 3 additional years of regular care, half of them progressed to GA., Trial Registration: ClinicalTrials.gov Identifier: NCT00593450.

Objective: To describe effects of ranibizumab and bevacizumab when administered monthly or as needed for 2 years and to describe the impact of switching to as-needed treatment after 1 year of monthly treatment., Design: Multicenter, randomized clinical trial., Participants: Patients (n = 1107) who were followed up during year 2 among 1185 patients with neovascular age-related macular degeneration who were enrolled in the clinical trial., Interventions: At enrollment, patients were assigned to 4 treatment groups defined by drug (ranibizumab or bevacizumab) and dosing regimen (monthly or as needed). At 1 year, patients initially assigned to monthly treatment were reassigned randomly to monthly or as-needed treatment, without changing the drug assignment., Main Outcome Measures: Mean change in visual acuity., Results: Among patients following the same regimen for 2 years, mean gain in visual acuity was similar for both drugs (bevacizumab-ranibizumab difference, -1.4 letters; 95% confidence interval [CI], -3.7 to 0.8; P = 0.21). Mean gain was greater for monthly than for as-needed treatment (difference, -2.4 letters; 95% CI, -4.8 to -0.1; P = 0.046). The proportion without fluid ranged from 13.9% in the bevacizumab-as-needed group to 45.5% in the ranibizumab monthly group (drug, P = 0.0003; regimen, P < 0.0001). Switching from monthly to as-needed treatment resulted in greater mean decrease in vision during year 2 (-2.2 letters; P = 0.03) and a lower proportion without fluid (-19%; P < 0.0001). Rates of death and arteriothrombotic events were similar for both drugs (P > 0.60). The proportion of patients with 1 or more systemic serious adverse events was higher with bevacizumab than ranibizumab (39.9% vs. 31.7%; adjusted risk ratio, 1.30; 95% CI, 1.07-1.57; P = 0.009). Most of the excess events have not been associated previously with systemic therapy targeting vascular endothelial growth factor (VEGF)., Conclusions: Ranibizumab and bevacizumab had similar effects on visual acuity over a 2-year period. Treatment as needed resulted in less gain in visual acuity, whether instituted at enrollment or after 1 year of monthly treatment. There were no differences between drugs in rates of death or arteriothrombotic events. The interpretation of the persistence of higher rates of serious adverse events with bevacizumab is uncertain because of the lack of specificity to conditions associated with inhibition of VEGF., Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references., (Copyright © 2020. Published by Elsevier Inc.)

Importance: Identifying the characteristics of eyes with neovascular age-related macular degeneration (nAMD) that maintain good vision without anti-vascular endothelial growth factor treatment for at least 3 years after management, as occurred in the Comparison of Age-Related Macular Degeneration Treatments Trials (CATT), may have prognostic importance and help in understanding the disease and its treatment., Objectives: To ascertain the characteristics of eyes in the CATT that retained good vision despite receiving no therapy for 3 years after release from the 2-year CATT treatment protocol., Design, Setting and Participants: This case-control study analyzed the baseline and follow-up characteristics of eyes with nAMD that were enrolled in the CATT from 43 US clinical centers between February 20, 2008, and December 9, 2009. After initial randomization to 1 of 4 treatment groups (ranibizumab monthly, bevacizumab monthly, ranibizumab as needed, or bevacizumab as needed), at year 1, participants in the monthly groups were rerandomized to continue monthly treatment or to switch to as-needed treatment using the same drug as originally assigned. At year 2, participants were released from the protocol to treatment at the discretion of their ophthalmologist. At year 5, participants were recalled for examination. This present analysis, conducted from December 1, 2018, to September 30, 2019, compared the eyes of 40 participants (referred to as the cessation of treatment with good visual acuity, or CTGVA, group) with the eyes of the remainder of the CATT Follow-up Study (referred to as the other group)., Main Outcomes and Measures: Visual acuity, morphologic characteristics, and number of treatments over 5 years., Results: Among 625 eyes with nAMD at baseline and a visual acuity measurement at year 5, 40 (6.4%; 95% CI, 4.7%-8.7%) were included in the analysis. These 40 participants, compared with the other group (n = 585), had a lower mean (SD) age of 74.7 (7.3) years (vs 77.7 [7.3] years; P = .01) and included 26 women (65.0%). Baseline characteristics were similar between eyes in the CTGVA and other groups, except for better visual acuity letter score in the study eye (68.8 vs 61.8; P = .001) and the fellow eye (78.4 vs 68.0; P = .01) as well as the presence of blocked fluorescence seen more often in participants in the CTGVA vs the other group (27.5% vs 13.8%; P = .02). Eyes in the CTGVA group with as-needed treatment received fewer mean (SD) injections in year 1 (5.8 [4.0] vs 8.1 [3.5]) and year 2 (7.7 [5.7] vs 13.8 [6.8]) than eyes in the other as-needed group. Mean (SD) visual acuity letter score at 5 years was 79.0 (5.5; Snellen 20/25) in the CTGVA group and 57.5 (24.2; Snellen 20/80) in the other group., Conclusions and Relevance: These findings suggest that a small proportion of eyes with nAMD can retain good visual acuity with no treatment for at least 3 years after the initial 2 years of treatment. Unique characteristics of eyes that could discontinue treatment while maintaining good visual acuity could not be identified at baseline, but data suggest that not all eyes with this disease may need treatment forever., Trial Registration: ClinicalTrials.gov Identifier: NCT00593450.

Importance: Recent reports suggest that cilioretinal arteries (CRAs) confer protection against developing advanced age-related macular degeneration (AMD)., Objective: To further characterize the association between the presence of a CRA and incidence of geographic atrophy (GA) or choroidal neovascularization (CNV)., Design: This cohort study constituted an ad hoc secondary analysis of data from the Comparison of Age-Related Macular Degeneration Treatments Trials (CATT) and was performed at 44 clinical centers in the United States among participants in CATT with CNV in the study eye and without advanced AMD in the fellow eye at baseline. The presence of a CRA was determined by 2 graders, masked to clinical data, using color fundus photographs, red-free fundus photographs, and fluorescein angiography. The proportion with CRAs at baseline between the study eye with CNV and fellow eye without CNV was first compared. The association of a CRA with incidence of CNV or GA at 5 years among fellow eyes and with incidence of GA among study (treated) eyes was then assessed. In addition, the association of CRAs with the Age-Related Eye Disease Study severity scale among the fellow eyes at baseline was assessed. Data were collected from February 1, 2008, through April 30, 2015, and analyzed from July 1, 2018, through April 30, 2019., Exposures: Presence of a CRA., Main Outcomes and Measures: The association between the presence of a CRA and incidence of CNV or GA at 5 years of follow-up., Results: A total of 350 patients (700 eyes) (230 [65.7% women; mean [SD] age, 77 [7.2] years) were included in the analysis. Cilioretinal arteries were present in 67 of 345 (19.4%) fellow eyes without baseline CNV and 73 of 349 (20.9%) study eyes with baseline CNV (P = .60). Cilioretinal arteries in fellow eyes were not associated with incidence of CNV at 5 years (125 of 278 [45.0%] among eyes without CRAs and 30 of 67 [44.8%] among eyes with CRAs; P = .99) or with incidence of GA at 5 years (110 of 278 [39.6%] among eyes without CRAs and 25 of 67 [37.3%] among eyes with CRAs; P = .89). Cilioretinal arteries in study eyes were not associated with incidence of GA at 5 years (105 of 276 [38.0%] study eyes without CRAs and 26 of 73 [35.6%] study eyes with CRAs; P = .72)., Conclusions and Relevance: The analysis did not find a protective association between CRAs and incidence of CNV or GA among CATT participants who had unilateral exudative AMD. Why these findings were different from those of previous publications is unclear but may be partially explained by the different techniques used to detect CRAs or by the baseline advanced disease in CATT participants., Trial Registration: ClinicalTrials.gov identifier: NCT00593450.

Purpose: Because patients often take iron supplements without medical indication, and iron can accumulate in vascular endothelial cells, the authors evaluated the association of oral iron supplementation with retinal/subretinal hemorrhage in patients with neovascular age-related macular degeneration., Methods: A post hoc secondary data analysis of comparison of age-related macular degeneration treatments trials was performed. Participants were interviewed for use of oral iron supplements. Trained readers evaluated retinal/subretinal hemorrhage in baseline fundus photographs. Adjusted odds ratios from multivariate logistic regression models assessed the association between iron use and baseline hemorrhage adjusted by age, sex, smoking, hypertension, anemia, and use of antiplatelet/anticoagulant drugs., Results: Among 1,165 participants, baseline retinal/subretinal hemorrhage was present in the study eye in 71% of 181 iron users and in 61% of 984 participants without iron use (adjusted odds ratio = 1.47, P = 0.04), and the association was dose dependent (adjusted linear trend P = 0.048). Iron use was associated with hemorrhage in participants with hypertension (adjusted odds ratio = 1.87, P = 0.006) but not without hypertension. The association of iron use with hemorrhage remained significant among hypertensive participants without anemia (adjusted odds ratio = 1.85, P = 0.02)., Conclusion: Among participants of comparison of age-related macular degeneration treatments trials, the use of oral iron supplements was associated with retinal/subretinal hemorrhage in a dose-response manner. Unindicated iron supplementation may be detrimental in patients with wet age-related macular degeneration.

Importance: Associations between retinopathy and kidney disease have been previously described. The association between the progression of retinopathy and concurrent progression of chronic kidney disease is unknown., Objective: To assess the association between progression of retinopathy and concurrent progression of chronic kidney disease (CKD) among persons with CKD enrolled in a prospective cohort study., Design, Setting, and Participants: A total of 1936 patients with chronic kidney disease enrolled in the multicenter, prospective Chronic Renal Insufficiency Cohort (CRIC) Study were invited to have 2 nonmydriatic fundus photography sessions separated by a mean (SD) of 3.5 (0.5) years. The study was conducted from May 12, 2006, to June 29, 2011. Data analysis was performed from March 16, 2016, to November 17, 2017., Main Outcomes and Measures: Fundus photographs obtained at baseline and then at a follow-up at 3.5 years were reviewed by masked graders for presence and severity of retinopathy, and vessel calibers were assessed using standard protocols. The associations of the changes in retinal features with progression of CKD (50% estimated glomerular filtration rate [eGFR] loss or incident end-stage renal disease, and differences in eGFR slope in the same time period) were assessed with univariable and multivariable logistic regression models., Results: Among 1583 CRIC participants who had baseline fundus photography, had additional follow-up in CRIC, and were at risk for retinopathy progression, 1025 patients (64.8%) had follow-up photography. The odds ratio (OR) for CKD progression associated with worsening of retinopathy in comparison with participants with stable retinopathy was 2.24 (95% CI, 1.28-3.91; P = .005) in univariable analysis among participants with baseline and follow-up photography. In the multivariable analysis, the OR was 1.62 (95% CI, 0.77-3.39; P = .20). The multiple imputation analysis provided similar results., Conclusions and Relevance: Progression of retinopathy appears to be associated with progression of CKD on univariable analysis but not on multivariable analysis suggesting that similar risk factors may be affecting the progression of both retinal and chronic kidney disease.

Purpose: To describe changes in visual acuity (VA) and macular morphologic features at 5 years in eyes with nonfibrotic scar (NFS) identified at 1 year in the Comparison of Age-Related Macular Degeneration Treatments Trials (CATT)., Design: Prospective cohort study within a randomized clinical trial., Participants: Participants in CATT., Methods: Participants assigned to ranibizumab or bevacizumab and to 1 of 3 dosing regimens were released from the clinical trial protocol after 2 years and recalled at 5 years. Nonfibrotic scar was identified on color images at year 1 as flat, small, well-circumscribed areas of pigmentation with varying degrees of central hypopigmentation without exposure of underlying choroidal vessels at the site of baseline choroidal neovascularization. Follow-up images were assessed for changes in and around NFS., Main Outcome Measures: Pigmentation changes, VA, development of fibrotic scar (FS), nongeographic atrophy (NGA), geographic atrophy (GA), retinal fluid on OCT, and fluorescein leakage., Results: Among 474 eyes with images obtained at 1, 2, and 5 years, 39 (8.2%) showed NFS at 1 year with a mean VA of 80 letters (Snellen equivalent, 20/25). Among these eyes, FS developed in 5% at 2 years and 28% at 5 years. Nongeographic atrophy was observed in 34%, 47%, and 65% of eyes at 1, 2, and 5 years, respectively. Geographic atrophy developed in 5% of eyes at 2 years and 21% at 5 years. Among eyes with NFS, FS, or no scar at 1 year, mean VA at 5 years was 73 letters (20/32), 48 letters (20/100), and 62 letters (20/63), respectively. At 5 years, NFS eyes demonstrated less GA, less intraretinal fluid, more subretinal fluid, and less subretinal pigment epithelium fluid (all P < 0.01). Among NFS eyes, mean thickness of the retina, subretinal tissue complex, and total retina did not change across years 1 to 5 (P > 0.50). The proportion of eyes with fluid on OCT also did not change (P = 0.36). Subretinal hyperreflective material disappeared by 5 years in 40% of eyes with NFS., Conclusions: These results indicate that, on average, eyes with NFS after anti-VEGF treatment have good VA not only at 1 and 2 years, but also through 5 years., (Copyright © 2018 American Academy of Ophthalmology. All rights reserved.)

Purpose: Macular atrophy and scar increase in prevalence during treatment for neovascular age-related macular degeneration and are associated with poor visual acuity. We sought to identify the distribution of spectral-domain OCT (SD-OCT)-determined features and subretinal lesion thicknesses at sites of macular scar or atrophy after 2 years of treatment in the Comparison of Age-Related Macular Degeneration Treatments Trials (CATT)., Design: Cross-sectional analysis., Participants: CATT participants with SD-OCT, color photographic (CP) and fluorescein angiogram (FA; CP/FA) images at year 2., Methods: Sixty-eight study eyes at year 2 in CATT were selected based on image quality and CP/FA-determined predominant presence of the following: geographic atrophy (GA, n = 25), non-GA (NGA, n = 44), fibrotic scar (FS, n = 26), or non-FS (NFS, n = 7). The CP/FA components were delineated by CP/FA readers; SD-OCT morphologic features and thicknesses were delineated by OCT readers. Using custom software and graphic user interfaces, images were registered, overlaying features and components per pixel; differences were analyzed across groups., Main Outcome Measures: OCT features, CP/FA components, and retinal and subretinal lesion thicknesses at each pixel of regional overlays., Results: SD-OCT assessment of registered areas of pathology revealed the following: (1) retinal pigment epithelium atrophy (with or without residual lesion material) covered 75% of pixels designated as GA, 22% of NGA, 24% of NFS, and 46% of FS (P < 0.001). (2) Photoreceptor layer thinning covered 85% of GA, 42% of NGA, 33% of NFS, and 59% of FS (P < 0.001). (3) Subretinal lesion features covered 31% of GA, 42% of NGA, 85% of NFS, and 92% of FS (P < 0.001). Mean thickness of the subretinal lesion complex (measured in microns ± standard deviation) differed among GA (48±25 μm), NGA (61±35 μm), NFS (83±17 μm), and FS (151±74 μm) (P < 0.001). In eyes with GA, the thickness was greater in areas with residual lesion (51.4±27 μm) than in those without (27.2±9 μm)., Conclusions: Retinal pigment epithelium atrophy and photoreceptor layer thinning are common not only in areas of macular atrophy but also in areas of FS. Photoreceptor loss extends beyond the areas of clinically apparent atrophy and FS. Subretinal lesion components were common in areas of scar, but they were also present in nearly one-third or more of areas of macular atrophy., (Copyright © 2018 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Throughout the years, DNA barcoding has gained in importance in forensic entomology as it leads to fast and reliable species determination. High-quality results, however, can only be achieved with a comprehensive DNA barcode reference database at hand. In collaboration with the Bavarian State Criminal Police Office, we have initiated at the Bavarian State Collection of Zoology the establishment of a reference library containing arthropods of potential forensic relevance to be used for DNA barcoding applications. CO1-5P' DNA barcode sequences of hundreds of arthropods were obtained via DNA extraction, PCR and Sanger Sequencing, leading to the establishment of a database containing 502 high-quality sequences which provide coverage for 88 arthropod species. Furthermore, we demonstrate an application example of this library using it as a backbone to a high throughput sequencing analysis of arthropod bulk samples collected from human corpses, which enabled the identification of 31 different arthropod Barcode Index Numbers., (© 2018 American Academy of Forensic Sciences.)

Purpose: To evaluate associations of morphologic features with 5-year visual acuity (VA) in the Comparison of Age-related Macular Degeneration Treatments Trials (CATT)., Design: Cohort study within a randomized clinical trial., Participants: Participants in CATT., Methods: Eyes with age-related macular degeneration-associated choroidal neovascularization (CNV) and VA between 20/25 and 20/320 were eligible. Treatment was assigned randomly to ranibizumab or bevacizumab and to 3 dosing regimens for 2 years and was at the ophthalmologists' discretion thereafter., Main Outcome Measures: Visual acuity, thickness and morphologic features on OCT, and lesion size and foveal composition on fundus photography (FP) and fluorescein angiography (FA)., Results: Visual acuity and image gradings were available for 523 of 914 participants (57%) alive at 5 years. At 5 years, 60% of eyes had intraretinal fluid (IRF), 38% had subretinal fluid (SRF), 36% had subretinal pigment epithelium (RPE) fluid, and 66% had subretinal hyper-reflective material (SHRM). Mean (standard deviation) foveal center thickness was 148 μm (99) for retina, 5 μm (21) for SRF, 125 μm (107) for subretinal tissue complex, 11 μm (33) for SHRM, and 103 μm (95) for RPE + RPE elevation. The SHRM, thinner retina, greater CNV lesion area, and foveal center pathology (all P < 0.001) and IRF (P < 0.05) were independently associated with worse VA. Adjusted mean VA letters were 62 for no pathology in the foveal center; 61 for CNV, fluid, or hemorrhage; 65 for non-geographic atrophy (GA); 64 for nonfibrotic scar; 53 for GA; and 56 for fibrotic scar. Incidence or worsening of 8 pathologic features (foveal GA, foveal scar, foveal CNV, SHRM, foveal IRF, retinal thinning, CNV lesion area, and GA area) between years 2 and 5 was independently associated with greater loss of VA from years 2 to 5 and VA loss from baseline to year 5., Conclusions: Associations between VA and morphologic features previously identified through year 1 were maintained or strengthened at year 5. New foveal scar, CNV, intraretinal fluid, SHRM and retinal thinning, development or worsening of foveal GA, and increased lesion size are important contributors to the VA decline from years 2 to 5. A significant need to develop therapies to address these adverse pathologic features remains., (Copyright © 2018 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: To describe risk factors for scar formation and changes to fibrotic scar through 5 years in the Comparison of Age-related Macular Degeneration Treatments Trials (CATT)., Design: Multicenter, prospective cohort study., Participants: A total of 1061 subjects in CATT., Methods: Color photographic and fluorescein angiographic images from baseline and 1, 2, and 5 years were evaluated. Incidence of scar formation was estimated with Kaplan-Meier curves. Risk factors were assessed with Cox regression models., Main Outcome Measures: Scar formation, fibrotic scar area, and macular atrophy associated with fibrotic scar ("atrophy")., Results: Cumulative proportion of eyes with scar was 32%, 46%, and 56% at years 1, 2, and 5, respectively. Baseline factors associated with increased risk (adjusted hazards ratio [aHR] and 95% confidence interval [CI]) were classic choroidal neovascularization (CNV) (aHR, 4.49; 95% CI, 3.34-6.04) versus occult, hemorrhage >1 disc area (DA) (aHR, 2.28; 95% CI, 1.49-3.47) versus no hemorrhage, retinal thickness >212 μm (aHR, 2.58; 95% CI, 1.69-3.94) versus <120 μm, subretinal tissue complex thickness >275 μm (aHR, 2.64; 95% CI, 1.81-3.84) versus ≤75 μm, subretinal fluid thickness >25 μm (aHR, 1.31; 95% CI, 0.97-1.75) versus no fluid, visual acuity (VA) in fellow eye 20/20 (aHR, 1.72; 95% CI, 1.25-2.36) versus 20/50 or worse, retinal pigment epithelium elevation absence (aHR, 1.71; 95% CI, 1.21-2.41), and subretinal hyperreflective material (aHR, 1.72; 95% CI, 1.25-2.36). Among 68 eyes that developed fibrotic scar at year 1, VA decreased by a mean of additional 13 letters between years 1 and 5. Mean scar area was 1.2, 1.2, and 1.9 DA at 1, 2, and 5 years, respectively. Atrophy was present in 18%, 24%, and 54% of these eyes at years 1, 2, and 5, respectively; the mean areas were 1.6, 2.0, and 3.1 DA, respectively. Atrophy replaced fibrotic scar in 8 eyes at year 5. There was no significant correlation between scar growth and atrophy growth. The rate of growth for both was similar between the clinical trial and observation periods., Conclusions: Several morphologic features, including classic CNV and large hemorrhage, are associated with scar formation. Rate of new scar formation declined after 2 years. Most fibrotic scars and accompanying macular atrophy expanded over time, reducing VA., (Copyright © 2018 American Academy of Ophthalmology. All rights reserved.)

Purpose: To determine baseline predictors of visual acuity (VA) outcomes at 5 years after initiating treatment with ranibizumab or bevacizumab for neovascular age-related macular degeneration (AMD)., Design: Secondary analysis of data from a cohort study., Participants: Patients enrolled in the Comparison of AMD Treatments Trials (CATT) who completed a 5-year follow-up visit., Methods: Participants were randomly assigned to ranibizumab or bevacizumab and to 1 of 3 dosing regimens. After two years, patients were released from the clinical trial protocol, and were recalled for examination at 5 years. Trained readers evaluated baseline lesion features, fluid and thickness. Baseline predictors were determined using univariate and multivariate regression analysis., Main Outcome Measures: VA score and change from baseline, ≥3-line gain, and VA 20/200 or worse at 5 years., Results: Among 647 patients with VA measured at 5 years, mean VA score in the study eye was 58.9 letters (≈20/63), mean decrease from baseline was 3.3 letters, 17.6% eyes gained ≥3 lines, and 19.9% had VA of 20/200 or worse. In multivariate analysis, worse baseline VA was associated with worse VA, more VA gain, higher percentage with ≥3-line gain, and higher percentage with 20/200 or worse at 5 years (all p<0.001). Larger baseline CNV lesion area was associated with worse VA, greater VA loss, and higher percentage with 20/200 or worse at 5 years (all p<0.05). Absence of baseline subretinal fluid was associated with worse VA (p=0.03) and more VA loss (p=0.03). Female gender, bevacizumab treatment in the first 2 years, and absence of RPE elevation were associated with higher percentage with ≥3-line gain. Cigarette smoking was associated with a higher percentage with 20/200 or worse. None of the 21 SNPs evaluated were associated with VA outcomes., Conclusions: Five years after initiating treatment with ranibizumab or bevacizumab in CATT participants, worse baseline VA, larger baseline CNV lesion area, and presence of baseline RPE elevation remained independently associated with worse VA at 5 years. In addition, male gender, cigarette smoking, absence of subretinal fluid and treatment with ranibizumab in the first 2 years were independently associated with worse vision outcomes at 5 years.

Importance: Previous studies investigating the association of single-nucleotide polymorphisms (SNPs) that confer increased risk of age-related macular degeneration (AMD) with pseudodrusen have yielded conflicting results and have not evaluated other AMD SNPs or pseudodrusen subtypes., Objective: To determine the association of SNPs in the complement factor H (CFH), age-related maculopathy susceptibility 2 (ARMS2), HtrA serine peptidase 1 (HTRA1), complement C2 (C2), complement C3 (C3), lipase C (LIPC), and complement factor B (CFB) genes with the presence of pseudodrusen and pseudodrusen subtypes (ie, dot, reticular, and confluent)., Design, Setting, and Participants: In this post hoc analysis of cross-sectional data from US participants in the Comparison of AMD Treatments Trials, genotyping was performed in 835 participants with TaqMan assays for the SNPs rs1061170 (Y402H variant in CFH), rs800292 (I62V variant in CFH), rs10490924 (A69S variant in ARMS2), rs11200638 (HTRA1), rs547154 (C2), rs2230199 (R102G variant in C3), rs10468017 (LIPC), and rs4151667 (L9H variant in CFB)., Main Outcomes and Measures: Presence and subtype of baseline pseudodrusen in either eye determined using color fundus photography, red-free images, and fluorescein angiograms., Results: Among 835 participants enrolled for genotyping, 755 (90.4%) were evaluated for pseudodrusen. Of these, 471 (62.4%) were female and 750 (99.3%) were white, and the mean (SD) age was 78.3 (7.5) years. A total of 213 of 755 participants (28.2%) had pseudodrusen (107 [14.2%] had dot pseudodrusen, 180 [23.8%] had reticular pseudodrusen, and 102 [13.5%] had confluent pseudodrusen). After adjusting for age, sex, and smoking status, the ARMS2 risk allele T was associated with higher risk of pseudodrusen (odds ratio [OR], 1.93; 95% CI, 1.19-3.12) for TT vs GG (P = .04). A similar association was found for HTRA1 (OR, 2.04; 95% CI, 1.26-3.31) for AA vs GG (P = .03). The CFH Y402H risk allele C was associated with lower risk of pseudodrusen (OR, 0.61; 95% CI, 0.38-0.97) for CC vs TT but was not statistically significant after correcting for multiple comparison (P = .20). CFH Y402H, ARMS2, HTRA1, and C3 were significantly associated with reticular pseudodrusen., Conclusions and Relevance: Among patients with neovascular AMD, the AMD risk alleles ARMS2 and HTRA1 were associated with an increased risk of pseudodrusen and the risk allele CFH Y402H was associated with lower risk of pseudodrusen, supporting findings from previous studies. Understanding the role of these SNPs in the development of pseudodrusen might improve our understanding of the pathogenesis of AMD and help develop future therapies.

Patients with chronic kidney diseases (CKDs) are at risk for further loss of kidney function and death, which occur despite reasonable blood pressure treatment. To determine whether arterial stiffness influences CKD progression and death, independent of blood pressure, we conducted a prospective cohort study of CKD patients enrolled in the CRIC study (Chronic Renal Insufficiency Cohort). Using carotid-femoral pulse wave velocity (PWV), we examined the relationship between PWV and end-stage kidney disease (ESRD), ESRD or halving of estimated glomerular filtration rate, or death from any cause. The 2795 participants we enrolled had a mean age of 60 years, 56.4% were men, 47.3% had diabetes mellitus, and the average estimated glomerular filtration rate at entry was 44.4 mL/min per 1.73 m 2 During follow-up, there were 504 ESRD events, 628 ESRD or halving of estimated glomerular filtration rate events, and 394 deaths. Patients with the highest tertile of PWV (>10.3 m/s) were at higher risk for ESRD (hazard ratio [95% confidence interval], 1.37 [1.05-1.80]), ESRD or 50% decline in estimated glomerular filtration rate (hazard ratio [95% confidence interval], 1.25 [0.98-1.58]), or death (hazard ratio [95% confidence interval], 1.72 [1.24-2.38]). PWV is a significant predictor of CKD progression and death in people with impaired kidney function. Incorporation of PWV measurements may help define better the risks for these important health outcomes in patients with CKDs. Interventions that reduce aortic stiffness deserve study in people with CKD., (© 2018 American Heart Association, Inc.)

Purpose: To develop methods to make precise comparisons of specific retinal features between and within spectral-domain (SD) OCT images, color fundus photography (CFP) images, and fluorescein angiography (FA) images in eyes treated with anti-vascular endothelial growth factor (VEGF) agents for neovascular age-related macular degeneration (nAMD)., Design: Retrospective study., Participants: Patients with good study-eye images at the 104-week visit in the Comparison of Age-Related Macular Degeneration Treatments Trials., Methods: Graders reviewed CFP and FA images and delineated areas of fibrotic or nonfibrotic scar and geographic atrophy (GA) or non-GA. Other graders reviewed SD-OCT images and delineated retinal and subretinal lesion characteristics. Using newly developed custom software and graphic user interfaces, the presence and thickness of each feature at each pixel on the en face view was determined., Main Outcome Measures: Spectral-domain OCT findings versus CFP and FA lesion components from regional overlays., Results: Per-eye distribution and thickness of SD-OCT features within CFP- and FA-established areas of scar and atrophy can be determined precisely, can be displayed in multiple formats, and can be extracted into pixel-specific data sets. These methods enable statistical analysis of imaging results within eyes and across eyes of different patients. For example, photoreceptor loss, subretinal lesion material, and thicknesses of photoreceptor layer and subretinal material across those SD-OCT features can be related precisely to CFP and FA regions of scar or atrophy., Conclusions: Methods to integrate qualitative and quantitative retinal and subretinal changes to coincide with photographic and angiographic designations of the nAMD lesion areas and sequelae are integral for accurate assessments of posttreatment retinal morphologic features. These may lead to better understanding of disease progression and improved treatment strategies., (Copyright © 2017 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Background and Aims: Coronary artery calcification (CAC) is common among patients with chronic kidney disease (CKD) and predicts the risk for cardiovascular disease (CVD). We examined the associations of novel risk factors with CAC progression among patients with CKD., Methods: Among 1123 CKD patients in the Chronic Renal Insufficiency Cohort (CRIC) Study, CAC was measured in Agatston units at baseline and a follow-up visit using electron beam computed tomography or multidetector computed tomography., Results: Over an average 3.3-year follow-up, 109 (25.1%) participants without CAC at baseline had incident CAC and 124 (18.0%) participants with CAC at baseline had CAC progression, defined as an annual increase of ≥100 Agatston units. After adjustment for established atherosclerotic risk factors, several novel risk factors were associated with changes in CAC over follow-up. Changes in square root transformed CAC score associated with 1 SD greater level of risk factors were -0.20 (95% confidence interval, -0.31 to -0.10; p < 0.001) for estimated glomerular filtration rate, 0.14 (0.02-0.25; p = 0.02) for 24-h urine albumin, 0.25 (0.15-0.34; p < 0.001) for cystatin C, -0.17 (-0.27 to -0.07; p < 0.001) for serum calcium, 0.14 (0.03-0.24; p = 0.009) for serum phosphate, 0.24 (0.14-0.33; p < 0.001) for fibroblast growth factor-23, 0.13 (0.04-0.23; p = 0.007) for total parathyroid hormone, 0.17 (0.07-0.27; p < 0.001) for interleukin-6, and 0.12 (0.02-0.22; p = 0.02) for tumor necrosis factor-α., Conclusions: Reduced kidney function, calcium and phosphate metabolism disorders, and inflammation, independent of established CVD risk factors, may progress CAC among CKD patients., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Purpose: To compare baseline characteristics, visual acuity (VA) and morphological outcomes between eyes with baseline hard exudates (HE) and all other eyes among patients with neovascular age-related macular degeneration (NVAMD) treated with anti-vascular endothelial growth factors (anti-VEGF)., Design: Prospective cohort study within the Comparison of Age-Related Macular Degeneration Treatments Trials (CATT)., Participants: Patients with NVAMD., Methods: Readers evaluated baseline and follow-up morphology on digital color images, fluorescein angiography (FA), and optical coherence tomography (OCT) in eyes with NVAMD that were randomly assigned to treatment with either ranibizumab or bevacizumab. Ophthalmologists identified HE on color images in the study eye., Main Outcome Measures: VA; scar; geographic atrophy; retinal thickness, fluid; and number of anti-VEGF injections., Results: HE was present in 128 of 1185 (11%) study eyes at baseline, 77% within 1 disc diameter of the foveal center. Patients with study eye HE were more likely female (81% vs 60%; p<0.001) and non-smokers (53% vs 42%; p=0.004). Both groups had similar proportions of hypercholesterolemia and hypertriglyceridemia. At baseline, eyes with HE had worse VA (mean 57 vs 61 letters; p=0.003), larger total lesion size (3.3 vs 2.4 DA; p <0.001), greater total foveal thickness (522µm vs 452µm; p<0.001), more retinal angiomatous proliferation (18% vs 10%; p=0.009) and sub-RPE fluid (65% vs 47%; p<0.001). At 1 year, VA was similar in both groups; more eyes with baseline HE had no fluid (45% vs 29%; p<0.001) and greater reduction in total foveal thickness (-266µm vs -158u; p<0.001). VA at year 2 was similar but retinas of eyes with baseline HE were thinner (267µm vs 299µm; p=0.03) and fewer eyes had sub-retinal fluid (23% vs 36%; p=0.008). HE was present in 19% of eyes at 1 year and 5% of eyes at 2 years. LIPC promoter SNP rs10468017 was not associated with NVAMD HE., Conclusion: Eyes with HE have larger CNV lesions and more RAP. Their initially thicker retina rapidly becomes thinner on anti-VEGF treatment. HE is not significantly associated with hyperlipidemia. HE at baseline does not significantly influence VA, scar and GA outcomes in eyes with NVAMD treated with anti-VEGF. Few eyes have HE at year 2.

Purpose: To estimate the incidence, size, and growth rate of geographic atrophy (GA) during 5 years of follow-up among participants in the Comparison of Age-Related Macular Degeneration Treatments Trials (CATT)., Design: Cohort within a clinical trial., Participants: Participants included in CATT., Methods: A total of 1185 CATT participants were randomly assigned to ranibizumab or bevacizumab treatment and to 3 treatment regimens. Participants were released from protocol treatment at 2 years and examined at approximately 5 years (N = 647). Two masked graders assessed the presence and size of GA in digital color photographs (CPs) and fluorescein angiograms (FAs) taken at baseline and years 1, 2, and 5. Cox proportional hazard models were used to identify risk factors for incidence of GA. Annual change in the square root of the total area of GA was the measure of growth. Multivariate linear mixed models including baseline demographic, treatment, and ocular characteristics on CP/FA and optical coherence tomography (OCT) as candidate risk factors were used to estimate adjusted growth rates, standard errors (SEs), and 95% confidence intervals (CIs)., Main Outcome Measures: Geographic atrophy incidence and growth rate., Results: Among the 1011 participants who did not have GA at baseline and had follow-up images gradable for GA, the cumulative incidence was 12% at 1 year, 17% at 2 years, and 38% at 5 years. At baseline, older age, hypercholesterolemia, worse visual acuity, larger choroidal neovascularization (CNV) area, retinal angiomatous proliferation (RAP) lesion, GA in the fellow eye, and intraretinal fluid were associated with a higher risk of incident GA. Thicker subretinal tissue complex and presence of subretinal fluid were associated with less GA development. The overall GA growth rate was 0.33 mm/year (SE, 0.02 mm/year). Eyes treated with ranibizumab in the first 2 years of the clinical trial had a higher growth rate than eyes treated with bevacizumab (adjusted growth rate, 0.38 vs. 0.28 mm/year; P = 0.009). Geographic atrophy in the fellow eye, hemorrhage, and absence of sub-retinal pigment epithelium fluid at baseline were associated with a higher growth rate., Conclusions: Development of GA is common 5 years after initiating therapy. Several risk factors identified at 2 years of follow-up persist at 5 years of follow-up., (Copyright © 2016 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: To describe outcomes 5 years after initiating treatment with bevacizumab or ranibizumab for neovascular age-related macular degeneration (AMD)., Design: Cohort study., Participants: Patients enrolled in the Comparison of AMD Treatments Trials., Methods: Patients were assigned randomly to ranibizumab or bevacizumab and to 1 of 3 dosing regimens. After 2 years, patients were released from the clinical trial protocol. At 5 years, patients were recalled for examination., Main Outcome Measures: Visual acuity (VA) and morphologic retinal features., Results: Visual acuity was obtained for 647 of 914 (71%) living patients with average follow-up of 5.5 years. The mean number of examinations for AMD care after the clinical trial ended was 25.3, and the mean number of treatments was 15.4. Most patients (60%) were treated 1 time or more with a drug other than their assigned drug. At the 5-year visit, 50% of eyes had VA of 20/40 or better and 20% had VA of 20/200 or worse. Mean change in VA was -3 letters from baseline and -11 letters from 2 years. Among 467 eyes with fluorescein angiography, mean total lesion area was 12.9 mm(2), a mean of 4.8 mm(2) larger than at 2 years. Geographic atrophy was present in 213 of 515 (41%) gradable eyes and was subfoveal in 85 eyes (17%). Among 555 eyes with spectral-domain optical coherence tomography, 83% had fluid (61% intraretinal, 38% subretinal, and 36% sub-retinal pigment epithelium). Mean foveal total thickness was 278 μm, a decrease of 182 μm from baseline and 20 μm from 2 years. The retina was abnormally thin (<120 μm) in 36% of eyes. Between 2 and 5 years, the group originally assigned to ranibizumab for 2 years lost more VA than the bevacizumab group (-4 letters; P = 0.008). Otherwise, there were no statistically significant differences in VA or morphologic outcomes between drug or regimen groups., Conclusions: Vision gains during the first 2 years were not maintained at 5 years. However, 50% of eyes had VA of 20/40 or better, confirming anti-vascular endothelial growth factor therapy as a major long-term therapeutic advance for neovascular AMD., (Copyright © 2016 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: To evaluate the association between pseudodrusen and incidence of late age-related macular degeneration (AMD) in fellow eyes of patients with unilateral neovascular AMD (nAMD)., Design: Cohort study within the Comparison of AMD Treatments Trials (CATT)., Participants: Patients with neither nAMD nor geographic atrophy (GA) in the fellow eye at baseline., Methods: Presence and type (dot, reticular, or confluent) of baseline pseudodrusen were assessed using digital color fundus photography (CFP) viewed under full color, green channel, and blue channel; red-free images; and fluorescein angiography (FA). Incidence of nAMD was based on monthly clinical examination and reading center evaluation of images at years 1 and 2. Incidence of GA was based on reading center evaluation of CFP and FA images at years 1 and 2. Associations of baseline pseudodrusen with incident nAMD and GA were summarized with adjusted risk ratios (aRRs) and their 95% confidence intervals (CIs) from multivariate Cox models, with adjustment of covariates identified through backward stepwise selection., Main Outcome Measures: Incident nAMD and GA., Results: Among 620 fellow eyes, 176 (28.4%) had baseline pseudodrusen (55% dot, 82% reticular, 35% confluent). Within 2 years, nAMD occurred in 54 eyes (30.7%) with pseudodrusen and in 72 eyes (16.2%) without pseudodrusen (aRR, 2.05; 95% CI, 1.43-2.93); GA occurred in 27 eyes (15.3%) with pseudodrusen and in 37 eyes (8.3%) without pseudodrusen (aRR, 1.89; 95% CI, 1.13-3.17); late AMD occurred in 73 eyes (41.5%) with pseudodrusen and in 101 eyes (22.8%) without pseudodrusen (aRR, 2.07; 95% CI, 1.51-2.83). Dot pseudodrusen were associated independently with nAMD (aRR, 2.53; 95% CI, 1.60-4.00), whereas confluent pseudodrusen were associated independently with GA (aRR, 4.35; 95% CI, 1.69-11.2). Eyes with pseudodrusen had increased incidence of late AMD regardless of whether the Age-Related Eye Diseases Study (AREDS) severity score was 2 (28.7% vs. 10.3%), 3 (34.9% vs. 13.7%), or 4 (50.5% vs. 32.0%)., Conclusions: In fellow eyes of CATT participants, pseudodrusen were associated independently with a higher incidence of both nAMD and GA. Dot pseudodrusen were associated with nAMD, whereas confluent pseudodrusen were associated with GA. Pseudodrusen should be considered along with the AREDS severity score for predicting late AMD., (Copyright © 2016 American Academy of Ophthalmology. All rights reserved.)

Purpose: To describe the association between morphologic features on fundus photography (FP), fluorescein angiography (FA), and optical coherence tomography (OCT) and visual acuity (VA) in the second year of the Comparison of Age-related Macular Degeneration Treatments Trials (CATT)., Design: Prospective cohort study within a randomized clinical trial., Participants: Participants in the CATT., Methods: Study eye eligibility required angiographic and OCT evidence of choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD) and VA between 20/25 and 20/320. Treatment was assigned randomly to ranibizumab or bevacizumab with 3 different dosing regimens over a 2-year period., Main Outcome Measures: Fluid type, location, and thickness; retina and subretinal tissue complex thickness on OCT; size and lesion composition on FP and FA; and VA., Results: Among 1185 CATT participants, 993 (84%) had fluid on OCT at baseline and completed 2 years of follow-up. At 2 years, intraretinal fluid (IRF), subretinal fluid (SRF), sub-retinal pigment epithelium (RPE) fluid, and subretinal tissue complex thickness decreased in all treatment groups. Ranibizumab monthly was best able to resolve each type of fluid. Eyes with SRF in the foveal center on OCT had better mean VA than eyes with no SRF (72.8 vs. 66.6 letters; P = 0.006). Eyes with IRF in the foveal center had worse mean VA than eyes without IRF (59.9 vs. 70.9 letters; P < 0.0001). Eyes with retinal thickness <120 μm had worse VA compared with eyes with retinal thickness 120 to 212 and >212 μm (59.4 vs. 71.3 vs. 70.3 letters; P < 0.0001). At 2 years, the mean VA (letters) of eyes varied substantially by the type of subfoveal pathology on FP and FA: 70.6 for no pathology; 74.1 for fluid only; 73.3 for CNV or pigment epithelial (RPE) detachment; 68.4 for nongeographic atrophy; and 62.9 for geographic atrophy, hemorrhage, RPE tear, or scar (P < 0.0001)., Conclusions: The associations between VA and morphologic features identified through year 1 were maintained or strengthened during year 2. Eyes with foveal IRF, abnormally thin retina, greater thickness of the subretinal tissue complex on OCT, and subfoveal geographic atrophy or scar on FP/FA had the worst VA. Subretinal fluid was associated with better VA., (Copyright © 2016 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: To describe morphologic and visual outcomes in eyes with angiographic cystoid macular edema (CME) treated with ranibizumab or bevacizumab for neovascular age-related macular degeneration (nAMD)., Design: Prospective cohort study within a randomized clinical trial., Participants: A total of 1185 CATT study subjects., Methods: Baseline fluorescein angiography (FA) images of all CATT study eyes were evaluated for CME. Grading of other characteristics on optical coherence tomography (OCT) and photographic images at baseline and during 2-year follow-up was completed by readers at the CATT Reading Centers. Three groups were created on the basis of baseline CME and intraretinal fluid (IRF) status: (1) CME, (2) IRF without CME, (3) neither CME nor IRF., Main Outcome Measures: Visual acuity (VA) and total central retinal thickness (CRT) on OCT at baseline, year 1, and year 2., Results: Among 1131 participants with images of sufficient quality for determining CME and IRF at baseline, 92 (8.1%) had CME, 766 (67.7%) had IRF without CME, and 273 (24.1%) had neither. At baseline, eyes with CME had worse mean VA (letters) than eyes with IRF without CME and eyes with neither CME nor IRF (52 vs. 60 vs. 66 letters, P < 0.001); higher mean total CRT (μm) on OCT (514 vs. 472 vs. 404, P < 0.001); and greater hemorrhage, retinal angiomatous proliferation (RAP) lesions, and classic choroidal neovascularization (CNV). All groups showed improvement in VA at follow-up; however, the CME group started and ended with the worst VA among the 3 groups. Central retinal thickness, although higher at baseline for the CME group, was similar at 1 and 2 years follow-up for all groups. More eyes with CME (65.3%) developed scarring during 2 years of follow-up compared with eyes with IRF without CME (43.8%) and eyes with neither CME nor IRF (32.5%; P < 0.001)., Conclusions: In CATT, eyes with CME had worse baseline and follow-up VA, although all groups showed similar rates of improvement in VA during 2 years of follow-up. Cystoid macular edema seems to be a marker for poorer visual outcomes in nAMD because of underlying baseline retinal dysfunction and subsequent scarring., (Copyright © 2016 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: To compare baseline characteristics, visual acuity (VA), and morphologic outcomes between eyes with retinal angiomatous proliferation (RAP) and all other eyes among patients with neovascular age-related macular degeneration (NVAMD) treated with anti-vascular endothelial growth factor (VEGF) drugs., Design: Prospective cohort study within the Comparison of Age-Related Macular Degeneration Treatments Trials (CATT)., Participants: Patients with NVAMD., Methods: Reading center staff evaluated digital color fundus photographs, fluorescein angiography (FA) images, and optical coherence tomography (OCT) scans of eyes with NVAMD treated with either ranibizumab or bevacizumab over a 2-year period. Retinal angiomatous proliferation was identified by the intense intra-retinal leakage of fluorescein in combination with other associated features., Main Outcome Measures: Visual acuity; fluorescein leakage; scar; geographic atrophy (GA) on FA; retinal thickness, fluid, and subretinal hyperreflective material (SHRM) on OCT; and the number of intravitreal anti-VEGF injections at 1 and 2 years., Results: Retinal angiomatous proliferation was present in 126 of 1183 (10.7%) study eyes at baseline. Mean VA improvement from baseline was greater (10.6 vs. 6.9 letters; P = 0.01) at 1 year, but similar at 2 years (7.8 vs. 6.2 letters; P = 0.34). At 1 year, eyes with RAP were more likely to have no fluid (46% vs. 26%; P < 0.001) on OCT, no leakage on FA (61% vs. 50%; P = 0.03), and greater reduction in foveal thickness (-240 μm vs. -161 μm; P < 0.001). They were more likely to demonstrate GA (24% vs. 15%; P = 0.01) and less likely to have scarring (17% vs. 36%; P < 0.001) or SHRM (36% vs. 48%; P = 0.01). These results were similar at 2 years. The mean change in lesion size at 1 year differed (-0.27 DA vs. 0.27 DA; P = 0.02), but was similar at 2 years (0.49 DA vs. 0.79 DA; P = 0.26). Among eyes treated PRN, eyes with RAP received a lower mean number of injections in year 1 (6.1 vs. 7.4; P = 0.003) and year 2 (5.4 vs. 6.6; P = 0.025)., Conclusions: At both 1 and 2 years after initiation of anti-VEGF treatment in CATT, eyes with RAP were less likely to have fluid, FA leakage, scar, and SHRM and more likely to have GA than eyes without RAP. Mean improvement in VA was similar at 2 years., (Copyright © 2016 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: To evaluate the association between use of antiplatelet or anticoagulant drugs and retinal or subretinal hemorrhage in participants with neovascular age-related macular degeneration (AMD) in the Comparison of AMD Treatments Trials (CATT)., Design: Cohort study within CATT., Participants: Participants in CATT with untreated active neovascular AMD (n = 1185)., Methods: Participants were interviewed for use of antiplatelet or anticoagulant drugs. Trained readers evaluated photographs for the presence and size of retinal or subretinal hemorrhage at baseline and years 1 and 2. Associations between use of antiplatelet or anticoagulant drugs and hemorrhage were evaluated among all participants and by baseline hypertension status using multivariate logistic regression models., Main Outcome Measures: Odds ratio for association with antiplatelet or anticoagulant use., Results: Among 1165 participants with gradable photographs, 724 (62.1%) had retinal or subretinal hemorrhage at baseline; 84.4% of hemorrhages were 1 disc area (DA) or less, 8.1% were 1 to 2 DA, and 7.5% were more than 2 DA. At baseline, 608 participants (52.2%) used antiplatelet or anticoagulant drugs, including 514 participants (44.1%) using antiplatelets only, 77 (6.6%) using anticoagulants only, and 17 (1.5%) using both. Hemorrhage was present in 64.5% of antiplatelet or anticoagulant users and in 59.6% of nonusers (P = 0.09; adjusted odds ratio [OR], 1.18; 95% confidence interval, 0.91-1.51; P = 0.21). Neither presence nor size of baseline hemorrhage was associated with the type, dose, or duration of antiplatelet or anticoagulant use. Forty-four of 1078 participants (4.08%) had retinal or subretinal hemorrhage detected on 1- or 2-year photographs; these hemorrhages were not associated with antiplatelet or anticoagulant use at baseline (P = 0.28) or during follow-up (P = 0.64). Among participants with hypertension (n = 807), antiplatelet or anticoagulant use was associated with a higher rate of hemorrhage at baseline (66.8% vs. 56.4%; adjusted OR, 1.48; P = 0.01), but not size of retinal or subretinal hemorrhage (P = 0.41)., Conclusions: Most retinal or subretinal hemorrhages in eyes enrolled in CATT were less than 1 DA. Among all CATT participants, antiplatelet or anticoagulant use was not associated significantly with hemorrhage, but it was associated significantly with hemorrhage in participants with hypertension., (Copyright © 2016 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: To evaluate the association of baseline characteristics and early visual acuity (VA) response with visual outcomes at years 1 or 2 in the Comparison of Age-Related Macular Degeneration (AMD) Treatments Trials (CATT)., Design: Secondary analysis of CATT., Participants: The 1185 CATT participants with baseline VA of 20/25 to 20/320., Methods: Participants were assigned to ranibizumab or bevacizumab and to 1 of 3 dosing regimens. Associations of baseline characteristics and early VA response (week 4 or 12) with VA response at years 1 or 2 were assessed by R(2) from linear regression analyses. Patients who had a poor initial response (VA 20/40 or worse with persistent fluid and without ≥1-line VA gain) were defined as candidates for changing treatment., Main Outcome Measures: Visual acuity change from baseline., Results: Statistically significant (P < 0.05) baseline predictors for less VA gain at year 2 were older age, VA of 20/40 or better, larger choroidal neovascularization area, presence of geographic atrophy, total foveal thickness ≤325 μm or ≥425 μm, and elevation of retinal pigment epithelium. Among 176 eyes gaining ≥3 lines at week 12, 78% had a ≥3-line gain at year 2, whereas among 113 eyes losing ≥1 line at week 12, 27% improved to a ≥1-line gain at year 2. Visual acuity response at week 12 was more predictive of VA response at year 2 (R(2) = 0.30) than VA response at week 4 (R(2) = 0.17) and baseline predictors (R(2) = 0.13; P < 0.0001). Among 126 candidates for changing treatment drug at week 12, mean VA improved by 2.8 letters (P = 0.050), mean total retinal thickness decreased 53 μm (P < 0.0001), and fluid resolved in 33% (P < 0.0001) between week 12 and year 1 with continued use of the same drug and regimen. Similar improvements were observed among 83 candidates for changing drugs at week 24., Conclusions: Visual acuity response at week 12 is more predictive of 2-year vision outcomes than either several baseline characteristics or week 4 response. Eyes with poor initial response may benefit from continued treatment without switching to another drug., (Copyright © 2015 American Academy of Ophthalmology. All rights reserved.)

Patients with chronic kidney disease (CKD) experience other diseases such as cardiovascular disease (CVD) and retinopathy. The purpose of this study was to assess whether retinopathy predicts future CVD events in a subgroup of the participants of the Chronic Renal Insufficiency Cohort (CRIC) study. In this ancillary investigation, 2,605 participants of the CRIC study were invited to participate, and nonmydriatic fundus photographs were obtained in 1,936 subjects. Using standard protocols, presence and severity of retinopathy (diabetic, hypertensive, or other) and vessel diameter caliber were assessed at a central photograph reading center by trained graders masked to study participant's information. Patients with a self-reported history of cardiovascular disease were excluded. Incident CVD events were adjudicated using medical records. Kidney function measurements, traditional and nontraditional risk factors, for CVD were obtained. Presence and severity of retinopathy were associated with increased risk of development of any CVD in this population of CKD patients, and these associations persisted after adjustment for traditional risk factors for CVD. We also found a direct relation between increased venular diameter and risk of development of CVD; however, the relation was not statistically significant after adjustment for traditional risk factors. In conclusion, the presence of retinopathy was associated with future CVD events, suggesting that retinovascular pathology may be indicative of macrovascular disease even after adjustment for renal dysfunction and traditional CVD risk factors. Assessment of retinal morphology may be valuable in assessing risk of CVD in patients with CKD, both clinically and in research settings., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Purpose: To evaluate the association of subretinal hyperreflective material (SHRM) with visual acuity (VA), geographic atrophy (GA), and scar in the Comparison of Age-Related Macular Degeneration Treatments Trials (CATT)., Design: Prospective cohort study within a randomized clinical trial., Participants: The 1185 CATT participants., Methods: Masked readers graded scar and GA on fundus photography and fluorescein angiography and graded SHRM on time-domain and spectral-domain (SD) optical coherence tomography (OCT) throughout 104 weeks. Measurements of SHRM height and width in the fovea, within the center 1 mm(2), or outside the center 1mm(2) were obtained on SD OCT images at 56 (n = 76) and 104 (n = 66) weeks., Main Outcome Measures: Presence of SHRM, as well as location and size, and associations with VA, scar, and GA., Results: Among CATT participants, the percentage with SHRM at enrollment was 77%, decreasing to 68% at 4 weeks after treatment and to 54% at 104 weeks. At 104 weeks, scar was present more often in eyes with persistent SHRM than in eyes with SHRM that resolved (64% vs. 31%; P < 0.0001). Among eyes with detailed evaluation of SHRM at weeks 56 (n = 76) and 104 (n = 66), mean VA letter score was 73.5 (standard error [SE], 2.8), 73.1 (SE, 3.4), 65.3 (SE, 3.5), and 63.9 (SE, 3.7) when SHRM was absent, present outside the central 1 mm(2), present within the central 1 mm(2) but not the foveal center, or present at the foveal center (P = 0.02), respectively. When SHRM was present, the median maximum height under the fovea, within the central 1 mm(2) including the fovea and anywhere within the scan, was 86 μm, 120 μm, and 122 μm, respectively. Visual acuity was decreased with greater SHRM height and width (P < 0.05)., Conclusions: In eyes with neovascular age-related macular degeneration (AMD), SHRM is common and often persists after anti-vascular endothelial growth factor treatment. At 2 years, eyes with scar were more likely to have SHRM than other eyes. Greater SHRM dimensions were associated with worse VA. In eyes with neovascular AMD, SHRM is an important morphologic biomarker., (Copyright © 2015 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Objective: To assess the association of the vitreomacular interface with outcomes of eyes treated with anti-vascular endothelial growth factor drugs for neovascular age-related macular degeneration (AMD)., Design: Prospective cohort study within a multicenter, randomized clinical trial., Participants: Patients enrolled in the Comparison of AMD Treatments Trials (CATT)., Methods: Treatment was assigned randomly as either ranibizumab or bevacizumab and as 3 different regimens for dosing over a 2-year period. Masked readers at a reading center assessed optical coherence tomography (OCT) scans at baseline and follow-up for vitreomacular traction (VMT) and vitreomacular adhesion (VMA), fluid, and central thickness. Visual acuity (VA) was measured by masked, certified examiners., Main Outcome Measures: Anatomic features and VA at baseline and 1 and 2 years and number of treatments., Results: At baseline, 143 patient eyes (12.8%) had VMT or VMA. Compared with those with neither (n = 972), patients with VMT or VMA were younger (mean ± standard error, 75.5 ± 0.6 vs. 79.7 ± 0.24 years; P < 0.0001) and more likely to be male (52.4% vs. 36.2%; P = 0.0003), to be cigarette smokers (68.5% vs. 55.3%; P = 0.003), and to have subretinal fluid on OCT (86.7% vs. 81.0%; P = 0.047). Vitreomacular interface status was not associated with VA at baseline or follow-up. Among eyes treated as needed (n = 598) and followed up for 2 years (n = 516), the mean number of injections was 15.4 ± 0.9 for eyes having VMT at baseline or during follow-up (n = 60), 13.8 ± 0.7 for eyes with VMA at baseline or follow-up (n = 79), and 12.9 ± 0.4 (P = 0.02) for eyes without VMT or VMA (n = 377). In addition, the mean number of injections in eyes treated as needed increased from 13.0 ± 0.3 when VMT was not observed to 13.6 ± 1.3 when observed once and to 17 ± 1.2 when observed more than once during follow-up. At 2 years, geographic atrophy developed in a lower percentage of eyes with VMT or VMA at baseline (11.7%) than with neither condition (22.5%; P = 0.005)., Conclusions: In eyes in the CATT, VMT and VMA were infrequent. At baseline and follow-up, VMT or VMA were not associated with VA. Eyes with VMT or VMA treated as needed required on average 2 more injections over 2 years., (Copyright © 2015 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: To evaluate the growth of geographic atrophy (GA) during anti-vascular endothelial growth factor (VEGF) therapy., Design: Cohort within a clinical trial., Participants: Patients included in the Comparison of Age-related Macular Degeneration Treatments Trials (CATT)., Methods: Participants were randomly assigned to injections of ranibizumab or bevacizumab and to a 2-year dosing regimen of monthly or pro re nata (PRN) or to monthly for 1 year and PRN the following year. Digital color photographs and fluorescein angiograms at baseline and 1 and 2 years were evaluated for GA, and the total area of GA was measured by 2 graders masked to treatment; differences were adjudicated. Multivariate linear mixed models of the annual change in the square root of the area included baseline demographic, treatment, and ocular characteristics on imaging as candidate risk factors., Main Outcome Measures: Geographic atrophy growth rate., Results: Among 1185 participants, 86 (7.3%) had GA at baseline, 120 (10.1%) developed GA during year 1, and 36 (3.0%) developed GA during year 2. Among 194 eyes evaluable for growth, the rate was 0.43 mm/yr (standard error [SE], ±0.03 mm/year). In multivariate analysis, the growth rate was 0.37 mm/year in eyes receiving bevacizumab and 0.49 mm/year in eyes receiving ranibizumab (difference, 0.11 mm/yr; 95% confidence interval [CI], 0.01-0.22; P = 0.03). Growth rate did not differ between eyes treated monthly and PRN (P = 0.85). Eyes with subfoveal choroidal neovascularization (CNV) lesions had a lower growth rate than eyes with nonsubfoveal CNV lesions (difference, 0.12; 95% CI, 0.01-0.22; P = 0.03). Eyes with GA farther from the fovea had higher growth rates by 0.14 (95% CI, 0.01-27) mm/year for every millimeter farther from the fovea. The growth rate was 0.58 mm/year for eyes with predominantly classic lesions, 0.41 mm/year for eyes with minimally classic lesions, and 0.30 mm/year for eyes with occult only lesions (P < 0.01). The growth rate in eyes having a fellow eye with GA was higher by 0.13 mm/year (95% CI, 0.01-0.24; P = 0.03) than in eyes without GA in the fellow eye. Eyes with epiretinal membrane had a higher growth rate than eyes without epiretinal membrane (difference, 0.16; 95% CI, 0.03-0.30; P = 0.02)., Conclusions: Geographic atrophy growth depends on several ocular factors. Ranibizumab may accelerate GA growth., (Copyright © 2015 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Objective: To compare baseline characteristics, treatment frequency, visual acuity (VA), and morphologic outcomes of eyes with >50% of the lesion composed of blood (B50 group) versus all other eyes (Other group) enrolled in the Comparison of Age-Related Macular Degeneration Treatments Trials (CATT)., Design: Prospective cohort study within a multicenter randomized clinical trial., Participants: CATT patients with neovascular age-related macular degeneration (AMD)., Methods: Treatment for the study eye was assigned randomly to either ranibizumab or bevacizumab and to 3 different dosing regimens over a 2-year period. Reading center graders evaluated baseline and follow-up morphology in color fundus photographs, fluorescein angiography (FA), and optical coherence tomography (OCT). Masked examiners tested VA., Main Outcome Measures: Morphologic features and VA at 1 and 2 years., Results: The B50 group consisted of 84 of 1185 (7.1%) patients enrolled in CATT. Baseline lesion characteristics differed between groups. In the B50 group, choroidal neovascularization size was smaller (0.73 vs 1.83 disc areas [DA]; P < 0.001), total lesion size was greater (4.55 vs 2.31 DA; P <0.001), total retinal thickness was greater (524 vs 455 μm; P = 0.02), and mean VA was worse (56.0 vs 60.9 letters; P = 0.002). Increases in mean VA were similar in the B50 and Other groups at 1 year (+9.3 vs +7.2 letters; P = 0.22) and at 2 years (9.0 vs 6.1 letters; P = 0.17). Eyes treated PRN received a similar number of injections in the 2 groups (12.2 vs 13.4; P = 0.27). Mean lesion size in the B50 group decreased by 1.2 DA at both 1 and 2 years (primarily owing to resolution of hemorrhage) and increased in the Other group by 0.33 DA at 1 year and 0.91 DA at 2 years (P < 0.001). Leakage on FA and fluid on OCT were similar between groups at 1 and 2 years., Conclusions: In CATT, the B50 group had a visual prognosis similar to the Other group. Lesion size decreased markedly through 2 years. Eyes like those enrolled in CATT with neovascular AMD lesions composed of >50% blood can be managed similarly to those with less or no blood., (Copyright © 2015 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: To determine the relationship between delayed patchy choroidal filling and morphologic and functional outcomes among eyes treated with ranibizumab or bevacizumab., Design: Cohort study., Methods: Comparison of Age-related Macular Degeneration Treatment Trials participants were assigned randomly to ranibizumab or bevacizumab on a monthly or as-needed schedule. Presence of delayed patchy choroidal filling and morphologic and functional outcomes were evaluated among eyes with gradable fluorescein angiography at baseline (n = 973) and at 1 year (n = 860) eyes., Results: Delayed filling was present in 75 (7.7%) of 973 eyes at baseline. Eyes with incident delayed filling at 1 year (23 [2.9%] of 798) showed a mean decrease of 1.7 letters in visual acuity, whereas eyes without incident delayed filling had a mean improvement of 8.1 letters (difference [Δ], -9.8; 95% confidence interval [CI] , -15.8 to -3.9; P < .01). Eyes with incident delayed filling had a larger increase in mean total lesion area of choroidal neovascularization (3.00 mm(2)) than eyes without incident delayed filling (0.56 mm(2); Δ , 2.4; 95% CI, 0.4 to 4.4; P = .02). The proportion with incident delayed filling at 1 year was similar among eyes treated with ranibizumab (10 [2.4%] of 413) or bevacizumab (13 [3.3%] of 385; P = .53) and among eyes treated monthly (12 [3.1%] of 388) or as needed (11 [2.7%] of 410; P = .83)., Conclusions: Delayed patchy choroidal filling was uncommon at baseline. Although only a small percentage of eyes demonstrated delayed filling during the first year of anti-vascular endothelial growth factor treatment, these eyes had worse visual acuity and a larger increase in total lesion area of choroidal neovascularization., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Importance: Although anti-vascular endothelial growth factor treatment of neovascular age-related macular degeneration (AMD) results in improved vision overall, loss of substantial vision can occur. Understanding the processes that lead to loss of vision may lead to preventive strategies., Objective: To determine the incidence, characteristics, causes, and baseline predictors of sustained visual acuity loss after 2 years of treatment with ranibizumab or bevacizumab for neovascular AMD., Design, Setting, and Participants: A cohort study within a randomized clinical trial of participants in the Comparison of Age-Related Macular Degeneration Treatments Trials (CATT)., Interventions: Participants were randomly assigned to treatment with ranibizumab or bevacizumab and to 2 years of monthly or as needed injections or monthly injections for 1 year and as needed injections the following year., Main Outcomes and Measures: Sustained visual acuity loss, defined as loss of 15 or more letters from baseline at weeks 88 and 104., Results: Among 1030 participants, 61 eyes (5.9%) developed sustained visual acuity loss in 2 years. Within this group, visual acuity decreased gradually over time, with a mean decrease of 2, 19, and 33 letters from baseline at 4 weeks, 1 year, and 2 years, respectively. At 2 years, eyes with sustained visual acuity loss had more scarring (60.0% vs 41.4%, P = .007), more geographic atrophy (GA) (31.6% vs 20.7%, P = .004), larger lesions (16 vs 8 mm2, P < .001), and higher proportions of intraretinal fluid (82.5% vs 51.0%, P < .001), subretinal hyperreflective material (84.5% vs 44.2%, P < .001), retinal thinning (43.3% vs 23.0%, P < .001), and thickening (20.0% vs 12.1%, P < .001). Likely causes of sustained visual acuity loss included foveal scarring (44.3%), pigmentary abnormalities (27.9%), and foveal GA (11.5%). Baseline factors independently associated with a higher incidence of sustained visual acuity loss were the presence of nonfoveal GA (odds ratio [OR],  2.86; 95% CI, 1.35-6.08; P = .006), larger area of choroidal neovascularization (OR for a >4-disc area vs ≤1-disc area, 3.91; 95% CI, 1.70-9.03; P = .007), and bevacizumab treatment (OR,  1.83; 95% CI, 1.07-3.14; P = .03)., Conclusions and Relevance: Sustained visual acuity loss was relatively rare in CATT. The development of foveal scar, pigmentary abnormalities, or GA contributed to most of the sustained visual acuity loss. Risk was 3% higher among eyes treated with bevacizumab. Treatment that targeted the prevention of scarring or GA may improve vision outcomes., Trial Registration: clinicaltrials.gov Identifier: NCT00593450.

Background: Retinopathy is associated with increased mortality risk in general populations. We evaluated the joint effect of retinopathy and chronic kidney disease (CKD) on mortality in a representative sample of U.S. adults., Study Design: Prospective cohort study., Setting & Participants: 7,640 adults from NHANES (National Health and Nutrition Examination Survey) 1988-1994 with mortality linkage through December 31, 2006., Predictors: CKD, defined as low estimated glomerular filtration rate (<60 mL/min/1.73 m2) or albuminuria (urine protein-creatinine ratio ≥30 mg/g), and retinopathy, defined as the presence of microaneurysms, hemorrhages, exudates, microvascular abnormalities, or other evidence of diabetic retinopathy by fundus photograph., Outcomes: All-cause and cardiovascular mortality., Measurements: Multivariable-adjusted Cox proportional hazards., Results: Overall, 4.6% of participants had retinopathy and 15% had CKD. Mean age was 56 years, 53% were women, and 81% were non-Hispanic whites. The prevalence of retinopathy in patients with CKD was 11%. We identified 2,634 deaths during 14.5 years' follow-up. In multivariable analyses, compared with individuals with neither CKD nor retinopathy, HRs for all-cause mortality were 1.02 (95% CI, 0.75-1.38), 1.52 (95% CI, 1.35-1.72), and 2.39 (95% CI, 1.77-3.22) for individuals with retinopathy only, those with CKD only, and those with both CKD and retinopathy, respectively. Corresponding HRs for cardiovascular mortality were 0.96 (95% CI, 0.50-1.84), 1.72 (95% CI, 1.47-2.00), and 2.96 (95% CI, 2.11-4.15), respectively. There was a significant synergistic interaction between retinopathy and CKD on all-cause mortality (P=0.04)., Limitations: The presence of retinopathy was evaluated only once. Small sample size of some of the subpopulations studied., Conclusions: In the presence of CKD, retinopathy is a strong predictor of mortality in this adult population., (Copyright © 2014 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background and Objectives: Retinal abnormalities may be associated with changes in the renal vasculature. This study assessed the association between retinopathy and progression of kidney disease in participants of the Chronic Renal Insufficiency Cohort (CRIC) study., Design, Setting, Participants, & Measurements: This was a prospective study in which patients with CKD enrolled in CRIC had nonmydriatic fundus photographs of both eyes. All CRIC participants in six clinical sites in which fundus cameras were deployed were offered participation. Photographs were reviewed at a reading center. The presence and severity of retinopathy and vessel calibers were assessed using standard protocols by graders masked to clinical information. The associations of retinal features with changes in eGFR and the need for RRT (ESRD) were assessed., Results: Retinal images and renal progression outcomes were obtained from 1852 of the 2605 participants (71.1%) approached. During follow-up (median 2.3 years), 152 participants (8.2%) developed ESRD. Presence and severity of retinopathy at baseline were strongly associated with the risk of subsequent progression to ESRD and reductions in eGFR in unadjusted analyses. For example, participants with retinopathy were 4.4 times (95% confidence interval [95% CI], 3.12 to 6.31) more likely to develop ESRD than those without retinopathy (P<0.001). However, this association was not statistically significant after adjustment for initial eGFR and 24-hour proteinuria. Venular and arteriolar diameter calibers were not associated with ESRD or eGFR decline. The results showed a nonlinear relationship between mean ratio of arteriole/vein calibers and the risk of progression to ESRD; participants within the fourth arteriole/vein ratio quartile were 3.11 times (95% CI, 1.51 to 6.40) more likely to develop ESRD than those in the first quartile (P<0.001)., Conclusions: The presence and severity of retinopathy were not associated with ESRD and decline in eGFR after taking into account established risk factors., (Copyright © 2014 by the American Society of Nephrology.)

Objective: To describe risk factors for scar in eyes treated with ranibizumab or bevacizumab for neovascular age-related macular degeneration (AMD)., Design: Prospective cohort study within a randomized clinical trial., Participants: Patients with no scar on color fundus photography (CFP) or fluorescein angiography (FA) at enrollment in the Comparison of Age-related Macular Degeneration Treatments Trials (CATT)., Methods: Eyes were assigned to ranibizumab or bevacizumab treatment and to 1 of 3 dosing regimens for 2 years. Masked readers assessed CFP and FA. Baseline demographic characteristics, visual acuity, morphologic features on photography and optical coherence tomography (OCT), and genotypes associated with AMD risk were evaluated as risk factors using adjusted hazard ratios (aHRs) and associated 95% confidence intervals (CIs). Scars were classified as fibrotic with well-demarcated elevated mounds of yellowish white tissue or nonfibrotic with discrete flat areas of hyperpigmentation with varying amounts of central depigmentation., Main Outcome Measures: Scar formation., Results: Scar developed in 480 of 1059 eyes (45.3%) by 2 years. Baseline characteristics associated with greater risk of scarring were predominantly classic choroidal neovascularization (CNV) (aHR, 3.1; CI, 2.4-3.9) versus occult CNV, blocked fluorescence (aHR, 1.4; CI, 1.1-1.8), foveal retinal thickness >212 μm (aHR, 2.4; CI, 1.7-3.6) versus <120 μm, foveal subretinal tissue complex thickness >275 μm (aHR, 2.4; CI, 1.7-3.6) versus ≤75 μm, foveal subretinal fluid (aHR, 1.5; CI, 1.1-2.0) versus no subretinal fluid, and subretinal hyperreflective material (SHRM) (aHR, 1.7; CI, 1.3-2.3) versus no SHRM. Eyes with elevation of the retinal pigment epithelium had lower risk (aHR, 0.6; CI, 0.5-0.8) versus no elevation. Drug, dosing regimen, and genotype had no statistically significant association with scarring. Fibrotic scars developed in 24.7% of eyes, and nonfibrotic scars developed in 20.6% of eyes. Baseline risk factors for the scar types were similar except that eyes with larger lesion size or visual acuity <20/40 were more likely to develop fibrotic scars., Conclusions: Approximately half of eyes enrolled in CATT developed scar by 2 years. Eyes with classic neovascularization, a thicker retina, and more fluid or material under the foveal center of the retina are more likely to develop scar., (Copyright © 2014 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

An elevated level of fibroblast growth factor-23 (FGF-23) is the earliest abnormality of mineral metabolism in CKD. High FGF-23 levels promote left ventricular hypertrophy but not coronary artery calcification. We used survival analysis to determine whether elevated FGF-23 is associated with greater risk of adjudicated congestive heart failure (CHF) and atherosclerotic events (myocardial infarction, stroke, and peripheral vascular disease) in a prospective cohort of 3860 participants with CKD stages 2-4 (baseline estimated GFR [eGFR], 44±15 ml/min per 1.73 m(2)). During a median follow-up of 3.7 years, 360 participants were hospitalized for CHF (27 events/1000 person-years) and 287 had an atherosclerotic event (22 events/1000 person-years). After adjustment for demographic characteristics, kidney function, traditional cardiovascular risk factors, and medications, higher FGF-23 was independently associated with graded risk of CHF (hazard ratio [HR], 1.45 per doubling [95% confidence interval (CI), 1.28 to 1.65]; HR for highest versus lowest quartile, 2.98 [95% CI, 1.97 to 4.52]) and atherosclerotic events (HR per doubling, 1.24 [95% CI, 1.09 to 1.40]; HR for highest versus lowest quartile, 1.76 [95% CI, 1.20 to 2.59]). Elevated FGF-23 was associated more strongly with CHF than with atherosclerotic events (P=0.02), and uniformly was associated with greater risk of CHF events across subgroups stratified by eGFR, proteinuria, prior heart disease, diabetes, BP control, anemia, sodium intake, income, fat-free mass, left ventricular mass index, and ejection fraction. Thus, higher FGF-23 is independently associated with greater risk of cardiovascular events, particularly CHF, in patients with CKD stages 2-4.

Purpose: To describe risk factors for geographic atrophy (GA) in the Comparison of Age-related Macular Degeneration Treatments Trials (CATT)., Design: Cohort within a randomized clinical trial., Participants: We analyzed 1024 CATT patients with no GA visible on color fundus photographs (CFPs) and/or fluorescein angiograms (FAs) at enrollment., Methods: Eyes were assigned to ranibizumab (0.5 mg) or bevacizumab (1.25 mg) treatment and to a 2-year monthly or pro re nata (PRN) injection regimen, or monthly injections for 1 year and PRN for 1 year. Demographic, genetic, and baseline ocular characteristics and lesion features of CFP/FA and optical coherence tomography (OCT) were evaluated as risk factors for GA through 2 years of follow-up. Time-dependent Cox proportional hazard models were used to estimate adjusted hazard ratios (aHRs)., Main Outcome Measures: Development of GA., Results: By 2 years, GA developed in 187 of 1024 patients (18.3%). Baseline risk factors for GA development included baseline visual acuity (VA) ≤20/200 (aHR, 2.65; 95% confidence interval [CI], 1.43-4.93), retinal angiomatous proliferation (RAP; aHR, 1.69; 95% CI, 1.16-2.47), GA in the fellow eye (aHR, 2.07; 95% CI, 1.40-3.08), and intraretinal fluid at the foveal center (aHR, 2.10; 95% CI, 1.34-3.31). Baseline factors associated with lower risk for GA development included blocked fluorescence (aHR, 0.49; 95% CI, 0.29-0.82), OCT measurements of subretinal fluid thickness of >25 μ (aHR, 0.52; 95% CI, 0.35-0.78), subretinal tissue complex thickness of >275 compared with ≤75 μ (aHR, 0.31; 95% CI, 0.19-0.50), and vitreomacular attachment (aHR, 0.55; 95% CI, 0.31-0.97). Ranibizumab compared with bevacizumab had a higher risk (aHR, 1.43; 95% CI, 1.06-1.93), and monthly dosing had a higher risk (aHR, 1.59; 95% CI, 1.17-2.16) than PRN dosing. There were no strong associations between development of GA and the presence of risk alleles for CFH, ARMS 2, HTRA1, C3, or TLR3., Conclusions: Approximately one fifth of CATT patients developed GA within 2 years of treatment. Independent baseline risk factors included poor VA, RAP, foveal intraretinal fluid, monthly dosing, and treatment with ranibizumab. Anti-vascular endothelial growth factor therapy may have a role in the development of GA., (Copyright © 2014 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Objective: To assess the influence of drug; dosing regimen; and traditional, nontraditional, and genetic risk factors on the incidence of choroidal neovascularization (CNV) in the fellow eye of patients treated for CNV with ranibizumab or bevacizumab., Design: Cohort study of patients enrolled in a multicenter, randomized clinical trial., Participants: Patients with no CNV in the fellow eye at the time of enrollment in the Comparison of Age-Related Macular Degeneration Treatments Trials (CATT)., Methods: Eligibility criteria for the clinical trial required that study eyes have evidence on fluorescein angiography and optical coherence tomography of CNV secondary to age-related macular degeneration (AMD) and visual acuity between 20/25 and 20/320. Treatment for the study eye was assigned randomly to either ranibizumab or bevacizumab and to 3 different regimens for dosing over a 2-year period. The genotypes for 4 single nucleotide polymorphisms (SNPs) associated with risk of AMD were determined. Only patients without CNV in the fellow eye at baseline were considered at risk. The CATT ophthalmologists examined patients every 4 weeks through 2 years and recorded treatment for CNV in the fellow eye., Main Outcome Measures: Development of CNV in the fellow eye., Results: Among 1185 CATT participants, 727 (61%) had no CNV in the fellow eye at enrollment. At 2 years, CNV had developed in 75 (20.6%) of 365 patients treated with ranibizumab and in 60 (16.6%) of 362 patients treated with bevacizumab (absolute difference, 4.0%; 95% confidence interval [CI], -1.7% to 9.6%; P = 0.17). The risk ratio for pro re nata dosing relative to monthly dosing was 1.1 (95% CI, 0.8-1.6). Greater elevation of the retinal pigment epithelium and fluid in the foveal center of the study eye were associated with increased incidence of CNV in the fellow eye. Incidence was not associated with genotype on rs1061170 (CFH), rs10490924 (ARMS2), rs11200638 (HTRA1), and rs2230199 (C3; P>0.35)., Conclusions: Through 2 years, there was no statistically significant difference between ranibizumab and bevacizumab in incidence of CNV in the fellow eye. Genotype on 4 SNPs previously found to be associated with AMD did not affect the risk of CNV in the fellow eye among CATT patients., Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references., (Copyright © 2013 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)