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Sharon D Solomon,1 Victoria Kyerematen,2 Madiha Qutab,3 Adam S Wenick,1 Jiangxia Wang,4 Barbara S Hawkins1,4 1Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; 2Bloomfield Court Hospital, National Health Services, London, UK; 3Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; 4Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USACorrespondence: Sharon D Solomon Email ssolomon1@jhmi.eduPurpose: To report findings when dilated fundus examination (DFE) is omitted from follow-up of patients receiving anti-VEGF injections for neovascular age-related macular degeneration (NVAMD).Design: Randomized pilot study.Participants: NVAMD patients with two or more injections of anti-VEGF within prior six months who were expected to require treatment for at least eight more months.Methods and Interventions: Participants were assigned to either retinal imaging and DFE or retinal imaging without a DFE except at 16 weeks and 32 weeks and at study completion.Outcomes: Primary safety outcomes were change in usual-corrected visual acuity (UCVA) and central subfield thickness (CST). Primary efficacy outcomes included time spent in clinic and patient satisfaction with clinic visits.Results: The 66 participants had mean baseline UCVA of 20/50 in the study eye. Median change in UCVA from baseline to each clinic visit in each arm was “no change”. Mean change in CST was less than 15 microns from baseline to any follow-up clinic visit. Time spent in the clinic at follow-up visits averaged 20 minutes less for participants in the Imaging Only group than those in the Full Exam group. More participants in the Imaging Only group were satisfied with the time spent in clinic and with the clinic visits overall than participants in the Full Exam group: means of 71 vs 91 minutes, respectively, per clinic visit.Conclusion: Based on findings from this randomized pilot study, follow-up retina clinic visits for established patients who have NVAMD and are under treatment with intravitreous injection of anti-VEGF agents could be streamlined by implementing longer intervals between DFE and by relying on imaging alone to make most decisions regarding the need for retreatment, thereby reducing the time spent by patients in clinic and increasing their satisfaction with care received, without excess adverse events.Trial Registration: NCT02251366.Keywords: neovascular age-related macular degeneration, anti-VEGF injection, time in clinic

Category: Ankle; Trauma Introduction/Purpose: Existing literature has established that obese patients have nearly double the risk of sustaining an ankle fracture when compared to a non-obese population. However, few studies have investigated obesity’s effect on fracture complications and patient reported outcomes (PROs) when patients are stratified by fracture type. Furthermore, as the average body mass index (BMI) of our population steadily rises, it becomes prudent to investigate variations in complications rates and patient reported outcomes in various stages of obesity. The aim of this study is to identify trends in complication rates and patient reported outcome scores among patients of different BMI before and after dividing by fracture complexity. Methods: We retrospectively assessed clinical and surgical data from 595 patients who underwent ankle fracture surgery at a single institution between 2017 and 2021 for surgical related complications. All patients had a minimum of 18 months follow up (mean-42.2 [18.2-71.4] months). PROMIS Physical Health and Visual Analog Scale pain scores surveys were available only for patients receiving surgery after November 2019. We aggregated survey data for timepoints between three months and two years post-operatively to assess only patients with meaningful clinical data in regard to their recovery. Patients were divided based on BMI and fracture type. BMI subgroups were classified as: Non-obese (18.5-24.9 kg/m 2 , n=88), Overweight/Obese I (25-34.9 kg/m 2 , n=314), Obese II/III (≥35 kg/m 2 , n=192). Fracture subgroups were divided into two groups: Simple (Unimalleolar types) and complex (Bimalleolar and Trimalleolar variants). Data analysis was performed using Chi-Square and T-Tests with statistical significance set at an alpha (α) of ≤ 0.05. Results: We observed a whole cohort complication rate of (15.3%, n=91/594). Complication rates when stratified by BMI were: Non-obese (12.3%, n=9), Overweight/Obese class I (19.4%, n=61), Obese class II/III (10.3%, n=20). Complication rates for Overweight/Obese I patients were significantly higher when compared to Non-obese patients (p=0.044, OR=2.11). However, there was no significant difference when comparing Non-obese to Class II/III (p=0.972). We observed no significant differences in complications when performing a sub analysis on specific fracture types, regardless of BMI group. Pain scores were significantly higher in both Overweight/Obese I and Obese II/III groups when compared to Non-Obese patients (p= < 0.001, p=0.015). Physical health scores were significantly lower only in the Obese II/III group when compared to Non-Obese patients (p=0.011). Conclusion: Our results indicate that patients who are Overweight/Obese I have a significantly higher risk of complication when compared to patients of normal BMI. Surprisingly, our cohort demonstrated nearly equivalent risk between Obese II/III and Non- obese patient groups. Patient reported outcome data shows different trends with worse pain scores and lower physical health outcomes in the Obese II/III group. These findings add to the growing debate surrounding obesity’s effect on ankle fracture complication rates as well as patient reported outcomes and suggest that increased BMI cannot be viewed purely as a one-to-one relationship with negative outcomes.

Objective: To review the current sickle cell disease (SCD) literature to assess how "retinopathy" has been defined and to identify ocular outcomes that have been measured and described., Design: A systematic scoping review of SCD literature was completed regarding ocular manifestations of SCD and vision outcomes across all medical specialties., Subjects: Participants with SCD and control patients were included in our data extraction., Methods: We reviewed English-language literature from 2000 to 2021 for eligible studies by searching PubMed, Google Scholar, Embase, and the Cochrane library using terms to encompass SCD and ocular findings., Main Outcome Measures: Data collection included study information, patient characteristics, vision-related findings (inclusion criteria and/or study outcomes), and retinopathy characteristics (definition, when, how and by whom diagnosed)., Results: We identified 4006 unique citations and 111 were included in the analysis. Ophthalmologists were senior authors of about half (59/111; 53.2%) of the articles; most articles were published between 2016 and 2021 (71/111; 70.0%). The studies had been conducted primarily in North America (54/111; 48.6%) or Europe (23/111; 20.7%); designs were cross-sectional (51/111; 45.9%), prospective cohort (28/111; 25.2%), retrospective cohort (27/111; 24.3%), and case-control (4/111; 3.6%). Among studies reporting any retinopathy, it was commonly defined as a combination of nonproliferative sickle cell retinopathy and proliferative sickle cell retinopathy (PSR; 52/87; 59.8%), infrequently as PSR only (6/87; 6.9%), or not defined at all (23/87; 26.4%). The Goldberg classification was used to grade retinopathy in almost half of the studies (41/87; 47.1%). Investigators reporting diagnostic methods used clinical fundus examination (56/111; 50.4%), OCT (24/111; 21.6%), fluorescein angiography (20/111; 18.0%), ultrawidefield fundus photographs (15/111; 13.5%), and OCT angiography (10/111; 9.0%), or did not report methods (28/111; 25.2%)., Conclusions: There are inconsistencies in documentation of methods and outcomes in studies of SCD ophthalmic findings. Particularly concerning is the lack of documentation of ophthalmic examination methods, qualifications of examiners, and clarity and specificity of sickle cell retinopathy definitions. With the increase in SCD treatment research and novel systemic therapies available, it is important to adopt clear and consistent descriptions and rigorous data collection and reporting of ophthalmic outcomes in SCD studies., Financial Disclosure(s): The authors have no proprietary or commercial interest in any materials discussed in this article., (Copyright © 2023 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Background: Diabetic retinopathy is a common complication of diabetes and a leading cause of visual impairment and blindness. Research has established the importance of blood glucose control to prevent development and progression of the ocular complications of diabetes. Concurrent blood pressure control has been advocated for this purpose, but individual studies have reported varying conclusions regarding the effects of this intervention., Objectives: To summarize the existing evidence regarding the effect of interventions to control blood pressure levels among diabetics on incidence and progression of diabetic retinopathy, preservation of visual acuity, adverse events, quality of life, and costs., Search Methods: We searched several electronic databases, including CENTRAL, and trial registries. We last searched the electronic databases on 3 September 2021. We also reviewed the reference lists of review articles and trial reports selected for inclusion., Selection Criteria: We included randomized controlled trials (RCTs) in which either type 1 or type 2 diabetic participants, with or without hypertension, were assigned randomly to more intense versus less intense blood pressure control; to blood pressure control versus usual care or no intervention on blood pressure (placebo); or to one class of antihypertensive medication versus another or placebo., Data Collection and Analysis: Pairs of review authors independently reviewed the titles and abstracts of records identified by the electronic and manual searches and the full-text reports of any records identified as potentially relevant. The included trials were independently assessed for risk of bias with respect to outcomes reported in this review., Main Results: We included 29 RCTs conducted in North America, Europe, Australia, Asia, Africa, and the Middle East that had enrolled a total of 4620 type 1 and 22,565 type 2 diabetic participants (sample sizes from 16 to 4477 participants). In all 7 RCTs for normotensive type 1 diabetic participants, 8 of 12 RCTs with normotensive type 2 diabetic participants, and 5 of 10 RCTs with hypertensive type 2 diabetic participants, one group was assigned to one or more antihypertensive agents and the control group to placebo. In the remaining 4 RCTs for normotensive participants with type 2 diabetes and 5 RCTs for hypertensive type 2 diabetic participants, methods of intense blood pressure control were compared to usual care. Eight trials were sponsored entirely and 10 trials partially by pharmaceutical companies; nine studies received support from other sources; and two studies did not report funding source. Study designs, populations, interventions, lengths of follow-up (range less than one year to nine years), and blood pressure targets varied among the included trials. For primary review outcomes after five years of treatment and follow-up, one of the seven trials for type 1 diabetics reported incidence of retinopathy and one trial reported progression of retinopathy; one trial reported a combined outcome of incidence and progression (as defined by study authors). Among normotensive type 2 diabetics, four of 12 trials reported incidence of diabetic retinopathy and two trials reported progression of retinopathy; two trials reported combined incidence and progression. Among hypertensive type 2 diabetics, six of the 10 trials reported incidence of diabetic retinopathy and two trials reported progression of retinopathy; five of the 10 trials reported combined incidence and progression. The evidence supports an overall benefit of more intensive blood pressure intervention for five-year incidence of diabetic retinopathy (11 studies; 4940 participants; risk ratio (RR) 0.82, 95% confidence interval (CI) 0.73 to 0.92; I 2 = 15%; moderate certainty evidence) and the combined outcome of incidence and progression (8 studies; 6212 participants; RR 0.78, 95% CI 0.68 to 0.89; I 2 = 42%; low certainty evidence). The available evidence did not support a benefit regarding five-year progression of diabetic retinopathy (5 studies; 5144 participants; RR 0.94, 95% CI 0.78 to 1.12; I 2 = 57%; moderate certainty evidence), incidence of proliferative diabetic retinopathy, clinically significant macular edema, or vitreous hemorrhage (9 studies; 8237 participants; RR 0.92, 95% CI 0.82 to 1.04; I 2 = 31%; low certainty evidence), or loss of 3 or more lines on a visual acuity chart with a logMAR scale (2 studies; 2326 participants; RR 1.15, 95% CI 0.63 to 2.08; I 2 = 90%; very low certainty evidence). Hypertensive type 2 diabetic participants realized more benefit from intense blood pressure control for three of the four outcomes concerning incidence and progression of diabetic retinopathy. The adverse event reported most often (13 of 29 trials) was death, yielding an estimated RR 0.87 (95% CI 0.76 to 1.00; 13 studies; 13,979 participants; I 2 = 0%; moderate certainty evidence). Hypotension was reported in two trials, with an RR of 2.04 (95% CI 1.63 to 2.55; 2 studies; 3323 participants; I 2 = 37%; low certainty evidence), indicating an excess of hypotensive events among participants assigned to more intervention on blood pressure., Authors' Conclusions: Hypertension is a well-known risk factor for several chronic conditions for which lowering blood pressure has proven to be beneficial. The available evidence supports a modest beneficial effect of intervention to reduce blood pressure with respect to preventing diabetic retinopathy for up to five years, particularly for hypertensive type 2 diabetics. However, there was a paucity of evidence to support such intervention to slow progression of diabetic retinopathy or to affect other outcomes considered in this review among normotensive diabetics. This weakens any conclusion regarding an overall benefit of intervening on blood pressure in diabetic patients without hypertension for the sole purpose of preventing diabetic retinopathy or avoiding the need for treatment for advanced stages of diabetic retinopathy., (Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Purpose: To summarize key findings from a Cochrane systematic review of the effectiveness and safety of topical pharmacologic interventions compared with active control or placebo for epidemic keratoconjunctivitis (EKC)., Design: Systematic review., Methods: We included randomized controlled trials that compared antiseptic agents, virustatic agents, or immune-modulating topical therapies with placebo or an active control. We adhered to Cochrane methods for trial selection, data extraction, risk of bias evaluation, and data synthesis., Results: Ten randomized controlled trials with 892 participants with acute or chronic EKC were included. Eight trials compared interventions with artificial tears or saline (n = 4) or with steroids (n = 4); two 3-arm trials contributed data to both comparisons. Estimates suggested that compared with tears, after povidone-iodine (PVP-I) alone (2 studies, 409 participants) more participants with acute EKC had resolution of symptoms (risk ratio [RR] 1.15 [95% confidence interval {CI} 1.07-1.24]) and signs (RR 3.19 [95% CI 2.29-4.45]) within 10 days. In 2 trials comparing treatments with steroid alone or steroid with levofloxacin, fewer eyes treated with PVP-I or polyvinyl alcohol iodine (PVA-I) plus steroid developed subepithelial infiltrates within 21 days (RR 0.08 [95% CI 0.01-0.55]; 69 eyes). No treatment was shown to improve resolution of infiltrates., Conclusions: Low- to very low-level certainty of evidence suggested that PVP-I or PVA-I with steroid may confer some benefit in acute EKC, but imprecision from small sample sizes, the potential risk of bias from inadequate reporting or trial design, and variability in participant selection, outcome measurement, and reporting limit the amount and quality of evidence., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Viruses cause about 80% of all cases of acute conjunctivitis. Human adenoviruses are believed to account for 65% to 90% of cases of viral conjunctivitis, or 20% to 75% of all causes of infectious keratoconjunctivitis worldwide. Epidemic keratoconjunctivitis (EKC) is a highly contagious subset of adenoviral conjunctivitis that has been associated with large outbreaks at military installations and at medical facilities. It is accompanied by severe conjunctival inflammation, watery discharge, and light sensitivity, and can lead to chronic complications such as corneal and conjunctival scarring with discomfort and poor quality of vision. Due to a lack of consensus on the efficacy of any pharmacotherapy to alter the clinical course of EKC, no standard of care exists, therefore many clinicians offer only supportive care., Objectives: To assess the efficacy and safety of topical pharmacological therapies versus placebo, an active control, or no treatment for adults with EKC., Search Methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL, which contains the Cochrane Eyes and Vision Trials Register; 2021, Issue 4); Ovid MEDLINE; Ovid Embase; Latin American and Caribbean Health Sciences database (LILACS); ClinicalTrials.gov; and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP), with no restrictions on language or year of publication. The date of the last search was 27 April 2021., Selection Criteria: We included randomized controlled trials in which antiseptic agents, virustatic agents, or topical immune-modulating therapy was compared with placebo, an active control, or no treatment., Data Collection and Analysis: We used standard Cochrane methodology., Main Results: We identified 10 studies conducted in Asia, Europe, the Middle East, and North Africa with a total of 892 participants who were treated for 7 days to 6 months and followed for 7 days up to 1.5 years. Study characteristics and risk of bias In most studies participants were predominantly men (range: 44% to 90%), with an age range from 9 to 82 years. Three studies reported information on trial registration, but we found no published study protocol. The majority of trials had small sample sizes, ranging from 18 to 90 participants enrolled per study; the only exception was a trial that enrolled 350 participants. We judged most studies to be at high or unclear risk of bias across risk of bias domains. Findings We included 10 studies of 892 EKC participants and estimated combined intervention effects in analyses stratified by steroid-containing control treatment or artificial tears. Six trials contributed to the comparisons of topical interventions (povidone-iodine [PVP-I], trifluridine, ganciclovir, dexamethasone plus neomycin) with artificial tears (or saline). Very low certainty evidence from two trials comparing trifluridine or ganciclovir with artificial tears showed inconsistent effects on shortening the mean duration of cardinal symptoms or signs of EKC. Low certainty evidence based on two studies (409 participants) indicated that participants treated with PVP-I alone more often experienced resolution of symptoms (risk ratio (RR) 1.15, 95% confidence interval (CI) 1.07 to 1.24) and signs (RR 3.19, 95% CI 2.29 to 4.45) during the first week of treatment compared with those treated with artificial tears. Very low certainty evidence from two studies (77 participants) suggested that PVP-I or ganciclovir prevented the development of subepithelial infiltrates (SEI) when compared with artificial tears within 30 days of treatment (RR 0.24, 95% CI 0.10 to 0.56). Four studies compared topical interventions (tacrolimus, cyclosporin A [CsA], trifluridine, PVP-I + dexamethasone) with topical steroids, and one trial compared fluorometholone (FML) plus polyvinyl alcohol iodine (PVA-I) with FML plus levofloxacin. Evidence from one trial showed that more eyes receiving PVP-I 1.0% plus dexamethasone 0.1% had symptoms resolved by day seven compared with those receiving dexamethasone alone (RR 9.00, 95% CI 1.23 to 66.05; 52 eyes). In two trials, fewer eyes treated with PVP-I or PVA-I plus steroid developed SEI within 15 days of treatment compared with steroid alone or steroid plus levofloxacin (RR 0.08, 95% CI 0.01 to 0.55; 69 eyes). One study found that CsA was no more effective than steroid for resolving SEI within four weeks of treatment (RR 0.84, 95% CI 0.67 to 1.06; N = 88). The evidence from trials comparing topical interventions with steroids was overall of very low level certainty. Adverse effects Antiviral or antimicrobial agents plus steroid did not differ from artificial tears in terms of ocular discomfort upon instillation (RR 9.23, 95% CI 0.61 to 140.67; N = 19). CsA and tacrolimus eye drops were associated with more cases of severe ocular discomfort, and sometimes intolerance, when compared with steroids (RR 4.64, 95% CI 1.15 to 18.71; 2 studies; N = 141). Compared with steroids, tacrolimus did not increase the risk of elevated intraocular pressure (RR 0.07, 95% CI 0 to 1.13; 1 study; N = 80), while trifluridine conferred no additional risk compared to tear substitute (RR 5.50, 95% CI 0.31 to 96.49; 1 study; N = 97). Overall, bacterial superinfection was rare (one in 23 CsA users) and not associated with use of the intervention steroid (RR 3.63, 95% CI 0.15 to 84.98; N = 51). The evidence for all estimates was of low or very low certainty., Authors' Conclusions: The evidence for the seven specified outcomes was of low or very low certainty due to imprecision and high risk of bias. The evidence that antiviral agents shorten the duration of symptoms or signs when compared with artificial tears was inconclusive. Low certainty evidence suggests that PVP-I alone resolves signs and symptoms by seven days relative to artificial tears. PVP-I or PVA-I, alone or with steroid, is associated with lower risks of SEI development than artificial tears or steroid (very low certainty evidence). The currently available evidence is insufficient to determine whether any of the evaluated interventions confers an advantage over steroids or artificial tears with respect to virus eradication or its spread to initially uninvolved fellow eyes. Future updates of this review should provide evidence of high-level certainty from trials with larger sample sizes, enrollment of participants with similar durations of signs and symptoms, and validated methods to assess short- and long-term outcomes., (Copyright © 2022 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Purpose: The purpose of this study was to summarize key findings from a systematic review of the effectiveness and safety of transepithelial corneal crosslinking (CXL) compared with epithelium-off CXL for progressive keratoconus., Design: Cochrane systematic review., Methods: We included in our review only randomized controlled trials (RCTs) in which transepithelial and epithelium-off CXL had been compared among participants with progressive keratoconus. The primary outcome was keratoconus stabilization based on post-operative maximum keratometry (Kmax). We adhered to Cochrane methods for trial selection, data extraction, risk of bias evaluation, and data synthesis., Results: Thirteen RCTs with 567 participants (661 eyes) were included; 11 studies compared non-iontophoresis-assisted transepithelial with epithelium-off CXL. Keratoconus stabilization was described as an outcome in 2 studies. The estimated difference in Kmax means (ie, the "mean difference," MD) from meta-analysis of 177 eyes in 5 RCTs indicated that there were no differences between intervention groups in Kmax at 12 months or later (MD: 0.99 diopter [D]; 95% confidence interval: -0.11 to 2.09). Meta-analysis of keratometry and visual acuity outcomes at 12 months or longer after surgery from 2 studies that had compared transepithelial CXL using iontophoresis provided no conclusive evidence of an advantage over epithelium-off CXL., Conclusions: Lack of precision due to small sample sizes, indeterminate risk of bias due to inadequate reporting, and inconsistency in how outcomes were measured and reported among studies make it difficult to state with confidence whether transepithelial CXL confers an advantage over epithelium-off CXL for patients with progressive keratoconus with respect to stabilization of keratoconus, visual acuity, or patient-reported outcomes based on available data., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Cataract surgery is one of the most common surgical procedures performed worldwide. Achieving appropriate intraoperative mydriasis is one of the critical factors associated with the safety and performance of the surgery. Inadequate pupillary dilation or constriction of the pupil during cataract surgery can impair the surgeon's field of view and make it difficult to maneuver instruments., Objectives: To evaluate the relative effectiveness of achieving pupillary dilation during phacoemulsification for cataract extraction using three methods of pupillary dilation: topical mydriatics, intracameral mydriatics, or depot delivery systems. We also planned to document and compare the risk of intraoperative and postoperative complications following phacoemulsification for cataract extraction, as well as the cost-effectiveness of these methods for pupillary dilation., Search Methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), which contains the Cochrane Eyes and Vision Trials Register) (2021, Issue 1); Ovid MEDLINE; Embase.com; PubMed; Latin American and Caribbean Health Sciences Literature Database (LILACS); ClinicalTrials.gov; and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP). We did not use any date or language restrictions in the electronic search for trials. We last searched the electronic databases on 22 January 2021., Selection Criteria: We included only randomized controlled trial (RCTs) in which participants underwent phacoemulsification for cataract extraction., Data Collection and Analysis: We followed standard Cochrane methodology., Main Results: We included a total of 14 RCTs (1670 eyes of 1652 participants) in this review. Of the 14 trials, 7 compared topical versus intracameral mydriatics, 6 compared topical mydriatics versus depot delivery systems, and 1 compared all three methods. We were unable to calculate overall estimates of comparative effectiveness for most outcomes due to statistical heterogeneity among the estimates from individual studies or because outcome data were available from only a single study. Furthermore, the certainty of evidence for most outcomes was low or very low, due primarily to imprecision and risk of bias. Comparison 1: topical mydriatics versus intracameral mydriatics Four RCTs (739 participants, 757 eyes) of the 8 RCTs that had compared these two methods reported mean pupillary diameters at the time surgeons had performed capsulorhexis; all favored topical mydriatics, but heterogeneity was high (I 2 = 95%). After omitting 1 RCT that used a paired-eyes design, evidence from three RCTs (721 participants and eyes) suggests that mean pupil diameter at the time of capsulorhexis may be greater with topical mydriatics than with intracameral mydriatics, but the evidence is of low certainty (mean difference 1.06 mm, 95% confidence interval (CI) 0.81 mm to 1.31 mm; I 2 = 49%). Four RCTs (224 participants, 242 eyes) reported mean pupillary diameter at the beginning of cataract surgery; the effect estimates from all trials favored topical mydriatics, with very low-certainty evidence. Five RCTs (799 participants, 817 eyes) reported mean pupillary diameter at the end of cataract surgery. Data for this outcome from the largest RCT (549 participants and eyes) provided evidence of a small difference in favor of intracameral mydriasis. On the other hand, 2 small RCTs (78 participants, 96 eyes) favored topical mydriatics, and the remaining 2 RCTs (172 participants) found no meaningful difference between the two methods, with very low-certainty evidence. Five RCTs (799 participants, 817 eyes) reported total intraoperative surgical time. The largest RCT (549 participants and eyes) reported decreased total intraoperative time with intracameral mydriatics, whereas 1 RCT (18 participants, 36 eyes) favored topical mydriatics, and the remaining 3 RCTs (232 participants) found no difference between the two methods, with very low-certainty evidence. Comparison 2: topical mydriatics versus depot delivery systems Of the 7 RCTs that compared these two methods, none reported mean pupillary diameter at the time surgeons performed capsulorhexis. Six RCTs (434 participants) reported mean pupillary diameter at the beginning of cataract surgery. After omitting 1 RCT suspected to be responsible for high heterogeneity (I 2 = 80%), meta-analysis of the other 5 RCTs (324 participants and eyes) found no evidence of a meaningful difference between the two methods, with very low-certainty evidence. Three RCTs (210 participants) reported mean pupillary diameter at the end of cataract surgery, with high heterogeneity among effect estimates for this outcome. Estimates of mean differences and confidence intervals from these three RCTs were consistent with no difference between the two methods. A fourth RCT reported only means for this outcome, with low-certainty evidence. Two small RCTs (118 participants) reported total intraoperative time. Surgical times were lower when depot delivery was used, but the confidence interval estimated from one trial was consistent with no difference, and only mean times were reported from the other trial, with very low-certainty evidence. Comparison 3: Intracameral mydriatics versus depot delivery systems Only one RCT (60 participants) compared intracameral mydriatics versus depot delivery system. Mean pupillary diameter at the time the surgeon performed capsulorhexis, phacoemulsification time, and cost outcomes were not reported. Mean pupil diameter at the beginning and end of cataract surgery favored the depot delivery system, with very low-certainty evidence. Adverse events Evidence from one RCT (555 participants and eyes) comparing topical mydriatics versus intracameral mydriatics suggests that ocular discomfort may be greater with topical mydriatics than with intracameral mydriatics at one week (risk ratio (RR) 10.57, 95% CI 1.37 to 81.34) and one month (RR 2.51, 95% CI 1.36 to 4.65) after cataract surgery, with moderate-certainty evidence at both time points. Another RCT (30 participants) reported iris-related complications in 11 participants in the intracameral mydriatics group versus no complications in the depot delivery system group, with very low-certainty evidence. Cardiovascular related adverse events were rarely mentioned., Authors' Conclusions: Data from 14 completed RCTs were inadequate to establish the superiority of any of three methods to achieve mydriasis for cataract surgery, based on pupillary dilation at different times during the surgery or on time required for surgery. Only one trial had a sample size adequate to yield a robust effect estimate. Larger, well-designed trials are needed to provide robust estimates for the comparison of mydriasis approaches for beneficial and adverse effects., (Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

The molecular dynamics (MD) simulation technique is among the most broadly used computational methods to investigate atomistic phenomena in a variety of chemical and biological systems. One of the most common (and most uncertain) parametrization steps in MD simulations of soft materials is the assignment of partial charges to atoms. Here, we apply uncertainty quantification and sensitivity analysis calculations to assess the uncertainty associated with partial charge assignment in the context of MD simulations of an organic solvent. Our results indicate that the effect of partial charge variance on bulk properties, such as solubility parameters, diffusivity, dipole moment, and density, measured from MD simulations is significant; however, measured properties are observed to be less sensitive to partial charges of less accessible (or buried) atoms. Diffusivity, for example, exhibits a global sensitivity of up to 22 × 10 -5 cm 2 /s per electron charge on some acetonitrile atoms. We then demonstrate that machine learning techniques, such as Gaussian process regression (GPR), can be effective and rapid tools for uncertainty quantification of MD simulations. We show that the formulation and application of an efficient GPR surrogate model for the prediction of responses effectively reduces the computational time of additional sample points from hours to milliseconds. This study provides a much-needed context for the effect that partial charge uncertainty has on MD-derived material properties to illustrate the benefit of considering partial charges as distributions rather than point-values. To aid in this treatment, this work then demonstrates methods for rapid characterization of resulting sensitivity in MD simulations.

Background: Keratoconus is the most common corneal dystrophy. It can cause loss of uncorrected and best-corrected visual acuity through ectasia (thinning) of the central or paracentral cornea, irregular corneal scarring, or corneal perforation. Disease onset usually occurs in the second to fourth decade of life, periods of peak educational attainment or career development. The condition is lifelong and sight-threatening. Corneal collagen crosslinking (CXL) using ultraviolet A (UVA) light applied to the cornea is the only treatment that has been shown to slow progression of disease. The original, more widely known technique involves application of UVA light to de-epithelialized cornea, to which a photosensitizer (riboflavin) is added topically throughout the irradiation process. Transepithelial CXL is a recently advocated alternative to the standard CXL procedure, in that the epithelium is kept intact during CXL. Retention of the epithelium offers the putative advantages of faster healing, less patient discomfort, faster visual rehabilitation, and less risk of corneal haze., Objectives: To assess the short- and long-term effectiveness and safety of transepithelial CXL compared with epithelium-off CXL for progressive keratoconus., Search Methods: To identify potentially eligible studies, we searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Trials Register) (2020, Issue 1); Ovid MEDLINE; Embase.com; PubMed; Latin American and Caribbean Health Sciences Literature database (LILACS); ClinicalTrials.gov; and World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP). We did not impose any date or language restrictions. We last searched the electronic databases on 15 January 2020., Selection Criteria: We included randomized controlled trials (RCTs) in which transepithelial CXL had been compared with epithelium-off CXL in participants with progressive keratoconus., Data Collection and Analysis: We used standard Cochrane methodology., Main Results: We included 13 studies with 723 eyes of 578 participants enrolled; 13 to 119 participants were enrolled per study. Seven studies were conducted in Europe, three in the Middle East, and one each in India, Russia, and Turkey. Seven studies were parallel-group RCTs, one study was an RCT with a paired-eyes design, and five studies were RCTs in which both eyes of some or all participants were assigned to the same intervention. Eleven studies compared transepithelial CXL with epithelium-off CXL in participants with progressive keratoconus. There was no evidence of an important difference between intervention groups in maximum keratometry (denoted 'maximum K' or 'Kmax'; also known as steepest keratometry measurement) at 12 months or later (mean difference (MD) 0.99 diopters (D), 95% CI -0.11 to 2.09; 5 studies; 177 eyes; I 2 = 41%; very low certainty evidence). Few studies described other outcomes of interest. The evidence is very uncertain that epithelium-off CXL may have a small (data from two studies were not pooled due to considerable heterogeneity (I 2 = 92%)) or no effect on stabilization of progressive keratoconus compared with transepithelial CXL; comparison of the estimated proportions of eyes with decreases or increases of 2 or more diopters in maximum K at 12 months from one study with 61 eyes was RR 0.32 (95% CI 0.09 to 1.12) and RR (non-event) 0.86 (95% CI 0.74 to 1.00), respectively (very low certainty). We did not estimate an overall effect on corrected-distance visual acuity (CDVA) because substantial heterogeneity was detected (I 2 = 70%). No study evaluated CDVA gain or loss of 10 or more letters on a logarithm of the minimum angle of resolution (logMAR) chart. Transepithelial CXL may result in little to no difference in CDVA at 12 months or beyond. Four studies reported that either no adverse events or no serious adverse events had been observed. Another study noted no change in endothelial cell count after either procedure. Moderate certainty evidence from 4 studies (221 eyes) found that epithelium-off CXL resulted in a slight increase in corneal haze or scarring when compared to transepithelial CXL (RR (non-event) 1.07, 95% CI 1.01 to 1.14). Three studies, one of which had three arms, compared outcomes among participants assigned to transepithelial CXL using iontophoresis versus those assigned to epithelium-off CXL. No conclusive evidence was found for either keratometry or visual acuity outcomes at 12 months or later after surgery. Low certainty evidence suggests that transepithelial CXL using iontophoresis results in no difference in logMAR CDVA (MD 0.00 letter, 95% CI -0.04 to 0.04; 2 studies; 51 eyes). Only one study examined gain or loss of 10 or more logMAR letters. In terms of adverse events, one case of subepithelial infiltrate was reported after transepithelial CXL with iontophoresis, whereas two cases of faint corneal scars and four cases of permanent haze were observed after epithelium-off CXL. Vogt's striae were found in one eye after each intervention. The certainty of the evidence was low or very low for the outcomes in this comparison due to imprecision of estimates for all outcomes and risk of bias in the studies from which data have been reported., Authors' Conclusions: Because of lack of precision, frequent indeterminate risk of bias due to inadequate reporting, and inconsistency in outcomes measured and reported among studies in this systematic review, it remains unknown whether transepithelial CXL, or any other approach, may confer an advantage over epithelium-off CXL for patients with progressive keratoconus with respect to further progression of keratoconus, visual acuity outcomes, and patient-reported outcomes (PROs). Arrest of the progression of keratoconus should be the primary outcome of interest in future trials of CXL, particularly when comparing the effectiveness of different approaches to CXL. Furthermore, methods of assessing and defining progressive keratoconus should be standardized. Trials with longer follow-up are required in order to assure that outcomes are measured after corneal wound-healing and stabilization of keratoconus. In addition, perioperative, intraoperative, and postoperative care should be standardized to permit meaningful comparisons of CXL methods. Methods to increase penetration of riboflavin through intact epithelium as well as delivery of increased dose of UVA may be needed to improve outcomes. PROs should be measured and reported. The visual significance of adverse outcomes, such as corneal haze, should be assessed and correlated with other outcomes, including PROs., (Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Importance: Patient care and clinical practice guidelines should be informed by evidence from reliable systematic reviews. The reliability of systematic reviews related to forthcoming guidelines for retina and vitreous conditions is unknown., Objectives: To summarize the reliability of systematic reviews on interventions for 7 retina and vitreous conditions, describe characteristics of reliable and unreliable systematic reviews, and examine the primary area in which they appeared to be lacking., Design, Setting, and Participants: A cross-sectional study of systematic reviews was conducted. Systematic reviews of interventions for retina- and vitreous-related conditions in a database maintained by the Cochrane Eyes and Vision United States Satellite were identified. Databases that the reviewers searched, whether any date or language restrictions were applied, and bibliographic information, such as year and journal of publication, were documented. The initial search was conducted in March 2007, and the final update was performed in July 2018. The conditions of interest were age-related macular degeneration; diabetic retinopathy; idiopathic epiretinal membrane and vitreomacular traction; idiopathic macular hole; posterior vitreous detachment, retinal breaks, and lattice degeneration; retinal and ophthalmic artery occlusions; and retinal vein occlusions. The reliability of each review was evaluated using prespecified criteria. Data were extracted by 2 research assistants working independently, with disagreements resolved through discussion or by 1 research assistant with verification by a senior team member., Main Outcomes and Measures: Proportion of reviews that meet all of the following criteria: (1) defined eligibility criteria for study selection, (2) described conducting a comprehensive literature search, (3) reported assessing risk of bias in included studies, (4) described using appropriate methods for any meta-analysis performed, and (5) provided conclusions consistent with review findings., Results: A total of 327 systematic reviews that addressed retina and vitreous conditions were identified; of these, 131 reviews (40.1%) were classified as reliable and 196 reviews (59.9%) were classified as not reliable. At least 1 reliable review was found for each of the 7 retina and vitreous conditions. The most common reason that a review was classified as not reliable was lack of evidence that a comprehensive literature search for relevant studies had been conducted (149 of 196 reviews [76.0%])., Conclusion and Relevance: The findings of this study suggest that most systematic reviews that addressed interventions for retina and vitreous conditions were not reliable. Systematic review teams and guideline developers should work with information professionals who can help navigate sophisticated and varied syntaxes required to search different resources.

Importance: For findings from clinical trials to be actionable, outcomes measured in trials must be fully defined and, when appropriate, defined consistently across trials. Otherwise, it is difficult to compare findings between trials, combine results in meta-analyses, or leverage findings collectively to inform health care decision-making., Objective: To identify and characterize outcomes specified in ClinicalTrials.gov records for publicly funded clinical trials for 3 high-burden, high-prevalence eye conditions., Design, Setting, and Participants: ClinicalTrials.gov, a registry of publicly and privately supported clinical studies, was searched on January 31, 2019, for records of clinical trials for age-related macular degeneration (AMD), dry eye, or refractive error. The search was limited to trials funded by the National Eye Institute but did not impose a date restriction. Five elements of a well-specified outcome were extracted from each outcome stated in each record, including the domain, method of measurement, metric, method of aggregation, and time points., Main Outcomes and Measures: Number of outcome domains specified for trials for AMD, dry eye, and refractive error and the number of trial records specifying each unique domain., Results: A total of 49 unique outcome domains specified across 39 records of trials were identified. The median (interquartile range) number of records specifying each unique outcome domain was 1 (1-3), 1.5 (1-2), and 1 (1-1) for AMD, dry eye, and refractive error, respectively. Even when the same domains were registered across multiple trials, the time point, specific metric, and method of aggregation were specified in multiple ways., Conclusions and Relevance: There were too many outcomes with too little overlap in the sample of trials that were examined. Differences in how outcomes are measured across trials make it difficult to compare results, even for well-established domains, such as visual acuity. To reduce this waste in eye and vision research, the time is ripe for agreeing on what outcomes to measure.

Background: Age-related macular degeneration (AMD) is the most common cause of uncorrectable severe vision loss in people aged 55 years and older in the developed world. Choroidal neovascularization (CNV) secondary to AMD accounts for most cases of AMD-related severe vision loss. Intravitreous injection of anti-vascular endothelial growth factor (anti-VEGF) agents aims to block the growth of abnormal blood vessels in the eye to prevent vision loss and, in some instances, to improve vision., Objectives: • To investigate ocular and systemic effects of, and quality of life associated with, intravitreous injection of three anti-VEGF agents (pegaptanib, ranibizumab, and bevacizumab) versus no anti-VEGF treatment for patients with neovascular AMD• To compare the relative effects of one of these anti-VEGF agents versus another when administered in comparable dosages and regimens SEARCH METHODS: To identify eligible studies for this review, we searched the Cochrane Central Register of Controlled Trials (CENTRAL), which contains the Cochrane Eyes and Vision Trials Register (searched January 31, 2018); MEDLINE Ovid (1946 to January 31, 2018); Embase Ovid (1947 to January 31, 2018); the Latin American and Caribbean Health Sciences Literature Database (LILACS) (1982 to January 31, 2018); the International Standard Randomized Controlled Trials Number (ISRCTN) Registry (www.isrctn.com/editAdvancedSearch - searched January 31, 2018); ClinicalTrials.gov (www.clinicaltrials.gov - searched November 28, 2018); and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en - searched January 31, 2018). We did not impose any date or language restrictions in electronic searches for trials., Selection Criteria: We included randomized controlled trials (RCTs) that evaluated pegaptanib, ranibizumab, or bevacizumab versus each other or versus a control treatment (e.g. sham treatment, photodynamic therapy), in which participants were followed for at least one year., Data Collection and Analysis: Two review authors independently screened records, extracted data, and assessed risks of bias. We contacted trial authors for additional data. We compared outcomes using risk ratios (RRs) or mean differences (MDs). We used the standard methodological procedures expected by Cochrane., Main Results: We included 16 RCTs that had enrolled a total of 6347 participants with neovascular AMD (the number of participants per trial ranged from 23 to 1208) and identified one potentially relevant ongoing trial. Six trials compared anti-VEGF treatment (pegaptanib, ranibizumab, or bevacizumab) versus control, and 10 trials compared bevacizumab versus ranibizumab. Pharmaceutical companies conducted or sponsored four trials but funded none of the studies that evaluated bevacizumab. Researchers conducted these trials at various centers across five continents (North and South America, Europe, Asia, and Australia). The overall certainty of the evidence was moderate to high, and most trials had an overall low risk of bias. All but one trial had been registered prospectively.When compared with those who received control treatment, more participants who received intravitreous injection of any of the three anti-VEGF agents had gained 15 letters or more of visual acuity (risk ratio [RR] 4.19, 95% confidence interval [CI] 2.32 to 7.55; moderate-certainty evidence), had lost fewer than 15 letters of visual acuity (RR 1.40, 95% CI 1.27 to 1.55; high-certainty evidence), and showed mean improvement in visual acuity (mean difference 6.7 letters, 95% CI 4.4 to 9.0 in one pegaptanib trial; mean difference 17.8 letters, 95% CI 16.0 to 19.7 in three ranibizumab trials; moderate-certainty evidence) after one year of follow-up. Participants treated with anti-VEGF agents showed improvement in morphologic outcomes (e.g. size of CNV, central retinal thickness) compared with participants not treated with anti-VEGF agents (moderate-certainty evidence). No trial directly compared pegaptanib versus another anti-VEGF agent and followed participants for one year; however, when compared with control treatments, ranibizumab and bevacizumab each yielded larger improvements in visual acuity outcomes than pegaptanib.Visual acuity outcomes after bevacizumab and ranibizumab were similar when the same RCTs compared the same regimens with respect to gain of 15 or more letters of visual acuity (RR 0.95, 95% CI 0.81 to 1.12; high-certainty evidence) and loss of fewer than 15 letters of visual acuity (RR 1.00, 95% CI 0.98 to 1.02; high-certainty evidence); results showed similar mean improvement in visual acuity (mean difference [MD] -0.5 letters, 95% CI -1.5 to 0.5; high-certainty evidence) after one year of follow-up, despite the substantially lower cost of bevacizumab compared with ranibizumab. Reduction in central retinal thickness was less among bevacizumab-treated participants than among ranibizumab-treated participants after one year (MD -11.6 μm, 95% CI -21.6 to -1.7; high-certainty evidence); however, this difference is within the range of measurement error, and we did not interpret it to be clinically meaningful.Ocular inflammation and increased intraocular pressure (IOP) after intravitreal injection were the most frequently reported serious ocular adverse events. Researchers reported endophthalmitis in less than 1% of anti-VEGF-treated participants and in no cases among control groups. The occurrence of serious systemic adverse events was comparable across anti-VEGF-treated groups and control groups; however, the numbers of events and trial participants may have been insufficient to show a meaningful difference between groups (evidence of low- to moderate-certainty). Investigators rarely measured and reported data on visual function, quality of life, or economic outcomes., Authors' Conclusions: Results of this review show the effectiveness of anti-VEGF agents (pegaptanib, ranibizumab, and bevacizumab) in terms of maintaining visual acuity; studies show that ranibizumab and bevacizumab improved visual acuity in some eyes that received these agents and were equally effective. Available information on the adverse effects of each medication does not suggest a higher incidence of potentially vision-threatening complications with intravitreous injection of anti-VEGF agents compared with control interventions; however, clinical trial sample sizes were not sufficient to estimate differences in rare safety outcomes. Future Cochrane Reviews should incorporate research evaluating variable dosing regimens of anti-VEGF agents, effects of long-term use, use of combination therapies (e.g. anti-VEGF treatment plus photodynamic therapy), and other methods of delivering these agents.

Importance: Identifying and prioritizing unanswered clinical questions may help to best allocate limited resources for research associated with the treatment of age-related macular degeneration (AMD)., Objective: To identify and prioritize clinical questions and outcomes for research associated with the treatment of AMD through engagement with professional and patient stakeholders., Design, Setting, and Participants: Multiple cross-sectional survey questions were used in a modified Delphi process for panel members of US and international organizations, the American Academy of Ophthalmology (AAO) Retina/Vitreous Panel (n=7), health care professionals from the American Society of Retinal Specialists (ASRS) (n=90), Atlantic Coast Retina Conference (ACRC) and Macula 2017 meeting (n=34); and patients from MD (Macular Degeneration) Support (n=46). Data were collected from January 20, 2015, to January 9, 2017., Main Outcomes and Measures: The prioritizing of clinical questions and patient-important outcomes for AMD., Results: Seventy clinical questions were derived from the AAO Preferred Practice Patterns for AMD and suggestions by the AAO Retina/Vitreous Panel. The AAO Retina/Vitreous Panel assessed all 70 clinical questions and rated 17 of 70 questions (24%) as highly important. Health care professionals assessed the 17 highly important clinical questions and rated 12 of 17 questions (71%) as high priority for research to answer; 9 of 12 high-priority clinical questions were associated with aspects of anti-vascular endothelial growth factor agents. Patients assessed the 17 highly important clinical questions and rated all as high priority. Additionally, patients identified 6 of 33 outcomes (18%) as most important to them (choroidal neovascularization, development of advanced AMD, retinal hemorrhage, gain of vision, slowing vision loss, and serious ocular events)., Conclusions and Relevance: Input from 4 stakeholder groups suggests good agreement on which 12 priority clinical questions can be used to underpin research related to the treatment of AMD. The 6 most important outcomes identified by patients were balanced between intended effects of AMD treatment (eg, slowing vision loss) and adverse events. Consideration of these patient-important outcomes may help to guide clinical care and future areas of research.

Importance: Trustworthy clinical practice guidelines require reliable systematic reviews of the evidence to support recommendations. Since 2016, the American Academy of Ophthalmology (AAO) has partnered with Cochrane Eyes and Vision US Satellite to update their guidelines, the Preferred Practice Patterns (PPP)., Objective: To describe experiences and findings related to identifying reliable systematic reviews that support topics likely to be addressed in the 2016 update of the 2011 AAO PPP guidelines on cataract in the adult eye., Design, Setting, and Participants: Cross-sectional study. Systematic reviews on the management of cataract were searched for in an established database. Each relevant systematic review was mapped to 1 or more of the 24 management categories listed under the Management section of the table of contents of the 2011 AAO PPP guidelines. Data were extracted to determine the reliability of each systematic review using prespecified criteria, and the reliable systematic reviews were examined to find whether they were referenced in the 2016 AAO PPP guidelines. For comparison, we assessed whether the reliable systematic reviews published before February 2010 the last search date of the 2011 AAO PPP guidelines were referenced in the 2011 AAO PPP guidelines. Cochrane Eyes and Vision US Satellite did not provide systematic reviews to the AAO during the development of the 2011 AAO PPP guidelines., Main Outcomes and Measures: Systematic review reliability was defined by reporting eligibility criteria, performing a comprehensive literature search, assessing methodologic quality of included studies, using appropriate methods for meta-analysis, and basing conclusions on review findings., Results: From 99 systematic reviews on management of cataract, 46 (46%) were classified as reliable. No evidence that a comprehensive search had been conducted was the most common reason a review was classified as unreliable. All 46 reliable systematic reviews were cited in the 2016 AAO PPP guidelines, and 8 of 15 available reliable reviews (53%) were cited in the 2011 PPP guidelines., Conclusions and Relevance: The partnership between Cochrane Eyes and Vision US Satellite and the AAO provides the AAO access to an evidence base of relevant and reliable systematic reviews, thereby supporting robust and efficient clinical practice guidelines development to improve the quality of eye care.

Background: Cataract formation or acceleration can occur after intraocular surgery, especially following vitrectomy, a surgical technique for removing the vitreous that is used in the treatment of many disorders that affect the posterior segment of the eye. The underlying problem that led to vitrectomy may limit the benefit from removal of the cataractous lens., Objectives: To evaluate the effectiveness and safety of surgery versus no surgery for postvitrectomy cataract with respect to visual acuity, quality of life, and other outcomes., Search Methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Trials Register) (2017, Issue 5), MEDLINE Ovid (1946 to 17 May 2017), Embase.com (1947 to 17 May 2017), PubMed (1946 to 17 May 2017), Latin American and Caribbean Health Sciences Literature database (LILACS) (January 1982 to 17 May 2017), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com); last searched May 2013, ClinicalTrials.gov (www.clinicaltrials.gov); searched 17 May 2017, and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en); searched 17 May 2017. We did not use any date or language restrictions in the electronic searches for trials., Selection Criteria: We planned to include randomized controlled trials (RCTs) and quasi-RCTs that had compared surgery versus no surgery to remove the lens from eyes of adults in which cataracts had developed following vitrectomy., Data Collection and Analysis: Two review authors independently screened the search results according to the standard methodological procedures expected by Cochrane., Main Results: We found no RCTs or quasi-RCTs that had compared surgery versus no surgery to remove the lens from eyes of adults in which cataracts had developed following vitrectomy., Authors' Conclusions: There is no evidence from RCTs or quasi-RCTs on which to base clinical recommendations for surgery for postvitrectomy cataract. There is a clear need for RCTs to address this evidence gap. Such trials should stratify participants by their age, the retinal disorder leading to vitrectomy, and the status of the underlying disease process in the contralateral eye. Outcomes assessed in such trials may include changes (both gains and losses) of visual acuity, quality of life, and adverse events such as posterior capsular rupture and retinal detachment. Both short-term (six-month) and long-term (one- or two-year) outcomes should be examined.

Purpose: To summarize key findings from a systematic review of the effectiveness and risks of conjunctival autograft (CAG) compared with amniotic membrane transplant (AMT) for pterygium., Design: Cochrane systematic review., Methods: We included only randomized controlled trials (RCTs) in which CAG and AMT had been compared for primary or recurrent pterygia. The primary outcome was recurrence of pterygium ≥1 mm onto the cornea by 3 and 6 months post surgery. We adhered to Cochrane methods for trial selection, data extraction, risk of bias evaluation, and data synthesis., Results: Twenty RCTs with 1866 participants (1947 eyes) were included. Pterygium recurrence 6 months after surgery ranged from 3.3% to 16.7% in the CAG group and 6.4% to 42.3% in the AMT group based on data from 1021 eyes in 10 RCTs. Estimated risk ratios from meta-analysis indicated that CAG-treated eyes had a 47% lower risk of recurrence 6 months after surgery compared with the AMT group (RR, 0.53, 95% confidence interval [CI], 0.33-0.85). For 96 eyes with recurrent pterygium, the risk of recurrence 6 months after CAG was reduced by 55% compared with AMT (risk ratio [RR], 0.45, 95% CI, 0.21-0.99). Three-month recurrence rates were similar for CAG and AMT based on data from 538 eyes (6 RCTs)., Conclusions: CAG was more effective than AMT to prevent pterygium recurrence by 6 months post surgery, especially in recurrent pterygia. CAG-treated eyes had half the recurrence rates of AMT-treated eyes. Future RCTs should assess changes in patient-reported outcomes (symptoms, cosmesis) and visual acuity, and evaluate effects of surgical variations., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Purpose: To determine changes in quality of life measures when choroidal neovascularization (CNV) developed in the second eye of patients with initially unilateral neovascular age-related macular degeneration (AMD)., Methods: We analyzed responses to the 39-item National Eye Institute Visual Function Questionnaire (NEI-VFQ), 36-item Short Form Health Survey (SF-36), and Hospital Anxiety and Depression Scale (HADS) at baseline, and prior to and following second eye CNV diagnosis in 92 participants enrolled in two Submacular Surgery Trials. Paired t-tests for sample sizes over 30 and Wilcoxon signed-rank tests for sample sizes <30 were performed to compare scores., Results: CNV development resulted in statistically and clinically significant changes in responses to 20 of 39 NEI-VFQ items, indicating visual function decline during a mean interval of 25 months. Little difference was noted between baseline scores and prior to CNV diagnosis, which averaged 8.9 months duration. Subscales demonstrated a statistically significant decline in general vision, near activities, distance activities, social functioning, role difficulties, dependency, and driving. There were minimal changes in the HADS and SF-36 scales., Conclusion: CNV development in the second eye had a dramatic effect on visual functioning based on patient responses to the NEI-VFQ questionnaire. Our investigation is believed to be the first study using data collected prospectively to demonstrate vision-related quality of life changes that resulted from development of CNV in AMD patients.

The rate of new chemical development in commerce combined with a paucity of toxicity data for legacy chemicals presents a unique challenge for human health risk assessment. There is a clear need to develop new technologies and incorporate novel data streams to more efficiently inform derivation of toxicity values. One avenue of exploitation lies in the field of transcriptomics and the application of gene expression analysis to characterize biological responses to chemical exposures. In this context, gene set enrichment analysis (GSEA) was employed to evaluate tissue-specific, dose-response gene expression data generated following exposure to multiple chemicals for various durations. Patterns of transcriptional enrichment were evident across time and with increasing dose, and coordinated enrichment plausibly linked to the etiology of the biological responses was observed. GSEA was able to capture both transient and sustained transcriptional enrichment events facilitating differentiation between adaptive versus longer term molecular responses. When combined with benchmark dose (BMD) modeling of gene expression data from key drivers of biological enrichment, GSEA facilitated characterization of dose ranges required for enrichment of biologically relevant molecular signaling pathways, and promoted comparison of the activation dose ranges required for individual pathways. Median transcriptional BMD values were calculated for the most sensitive enriched pathway as well as the overall median BMD value for key gene members of significantly enriched pathways, and both were observed to be good estimates of the most sensitive apical endpoint BMD value. Together, these efforts support the application of GSEA to qualitative and quantitative human health risk assessment., (Published by Oxford University Press on behalf of the Society of Toxicology 2017. This work is written by US Government employees and is in the public domain in the US.)

Topic: To summarize the relative effects of bevacizumab (Avastin; Genentech, Inc, South San Francisco, CA) and ranibizumab (Lucentis; Genentech, Inc.), using findings from a Cochrane Eyes and Vision Group systematic review., Clinical Relevance: Neovascular age-related macular degeneration (NVAMD) is the most common cause of uncorrectable vision loss among the elderly in developed countries. Bevacizumab and ranibizumab are the most frequently used anti-vascular endothelial growth factor (VEGF) agents injected intravitreally to treat NVAMD., Methods: For this systematic review, we included only randomized controlled trials in which the 2 anti-VEGF agents had been compared directly. The primary outcome was 1-year gain in best-corrected visual acuity (BCVA) of ≥15 letters. We followed Cochrane methods for trial selection, data extraction, and data analyses. Relative effects of bevacizumab versus ranibizumab are presented as estimated risk ratios (RRs) and mean differences (MDs) with 95% confidence intervals (CIs)., Results: We identified 6 eligible randomized controlled trials with 2809 participants. The proportion of eyes that gained ≥15 letters of BCVA by 1 year was similar for the 2 agents when the same regimens were compared (RR, 0.90; 95% CI, 0.73-1.11). The mean change in BCVA from baseline also was similar (MD, -0.5 letter; 95% CI, -1.6 to +0.6). Other BCVA and quality of life outcomes were similar for the 2 agents. One-year treatment cost with ranibizumab was 5.1 and 25.5 times the cost for bevacizumab in the 2 largest trials. Ocular adverse events were uncommon (<1%), and rates were similar for the 2 agents., Conclusions: We found no important difference in effectiveness or safety between bevacizumab and ranibizumab for NVAMD treatment, but there was a large cost difference., (Copyright © 2016 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Background: Systematic reviews of interventions provide a summary of the evidence available on intervention effectiveness and harm. Cochrane systematic reviews (CSRs) have been published electronically in the Cochrane Database of Systematic Reviews (CDSR) since 1994, and co-publication (publication of a Cochrane review in another journal) has been allowed since that time, as long as the co-publishing journal has agreed to the arrangement. Although standards for co-publication were established in 2008, the frequency of co-publication and adherence to the standards have remained largely unexamined. Our objective was to examine the frequency of co-publication of Cochrane Eyes and Vision Group (CEVG) reviews, adherence to the co-publication policy, the relative numbers of citations of the two modes of publishing, and differences in times cited in CSRs with and without a co-publication., Methods: We identified all CEVG reviews published by May 30, 2014 in The Cochrane Library. Using keywords from the title, author names, and "Cochrane Eyes and Vision Group", we searched Google Scholar, Web of Science, Scopus, and PubMed databases to identify possible co-publications. We also emailed contact authors of all identified CEVG reviews to ask them whether they had published their CSR elsewhere. We compared each co-publication to the corresponding CEVG review for adherence to the Cochrane Policy Manual (dated June 10, 2014). We recorded the number of times each CEVG review and each co-publication had been cited by others according to Google Scholar, Web of Science, and Scopus, as of June 11, 2014., Results: We identified 117 CEVG reviews;19 had been co-published in 22 articles. Adherence to Cochrane policy on co-publication was moderate, with all authors complying with at least one of four requirements we addressed. Co-publications were cited more often than the corresponding CEVG reviews; CEVG reviews with at least one co-publication were cited approximately twice as often as CEVG reviews without a co-publication. The number of citations varied considerably depending on whether the CEVG review had a co-publication or not., Conclusions: The findings support encouraging co-publication while maintaining the primacy of the Cochrane systematic review. Support for co-publication may be tempered by other factors such as the possibility that CEVG reviews with a co-publication covered more clinically important and timely topics than those without a co-publication. Assuming that citations are a valid measure of dissemination effectiveness, the 15-year CEVG experience with co-publication of systematic reviews suggests that Cochrane authors should be encouraged to co-publish in traditional medical journals.

Objective: To evaluate the characteristics of the design, analysis, and reporting of crossover trials for inclusion in a meta-analysis of treatment for primary open-angle glaucoma and to provide empirical evidence to inform the development of tools to assess the validity of the results from crossover trials and reporting guidelines., Methods: We searched MEDLINE, EMBASE, and Cochrane's CENTRAL register for randomized crossover trials for a systematic review and network meta-analysis we are conducting. Two individuals independently screened the search results for eligibility and abstracted data from each included report., Results: We identified 83 crossover trials eligible for inclusion. Issues affecting the risk of bias in crossover trials, such as carryover, period effects and missing data, were often ignored. Some trials failed to accommodate the within-individual differences in the analysis. For a large proportion of the trials, the authors tabulated the results as if they arose from a parallel design. Precision estimates properly accounting for the paired nature of the design were often unavailable from the study reports; consequently, to include trial findings in a meta-analysis would require further manipulation and assumptions., Conclusions: The high proportion of poorly reported analyses and results has the potential to affect whether crossover data should or can be included in a meta-analysis. There is pressing need for reporting guidelines for crossover trials.

Background: Age-related macular degeneration (AMD) is the most common cause of uncorrectable severe vision loss in people aged 55 years and older in the developed world. Choroidal neovascularization (CNV) secondary to neovascular AMD accounts for most AMD-related severe vision loss. Anti-vascular endothelial growth factor (anti-VEGF) agents, injected intravitreally, aim to block the growth of abnormal blood vessels in the eye to prevent vision loss and, in some instances, improve vision., Objectives: To investigate: (1) the ocular and systemic effects of, and quality of life associated with, intravitreally injected anti-VEGF agents (pegaptanib, ranibizumab, and bevacizumab) for the treatment of neovascular AMD compared with no anti-VEGF treatment; and (2) the relative effects of one anti-VEGF agent compared with another when administered in comparable dosages and regimens., Search Methods: We searched Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Group Trials Register) (2014, Issue 3), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to March 2014), EMBASE (January 1980 to March 2014), Latin American and Caribbean Health Sciences Literature Database (LILACS) (January 1982 to March 2014), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov) and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We used no date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 27 March 2014., Selection Criteria: We included randomized controlled trials (RCTs) that evaluated pegaptanib, ranibizumab, or bevacizumab versus each other or a control treatment (e.g., sham treatment or photodynamic therapy). All trials followed participants for at least one year., Data Collection and Analysis: Two review authors independently screened records, extracted data, and assessed risks of bias. We contacted trial authors for additional data. We analyzed outcomes as risk ratios (RRs) or mean differences (MDs). We used the standard methodological procedures expected by The Cochrane Collaboration., Main Results: We included 12 RCTs including a total of 5496 participants with neovascular AMD (the number of participants per trial ranged from 28 to 1208). One trial compared pegaptanib, three trials ranibizumab, and two trials bevacizumab versus controls; six trials compared bevacizumab with ranibizumab. Four trials were conducted by pharmaceutical companies; none of the eight studies which evaluated bevacizumab were funded by pharmaceutical companies. The trials were conducted at various centers across five continents (North and South America, Europe, Asia and Australia). The overall quality of the evidence was very good, with most trials having an overall low risk of bias.When compared with control treatments, participants who received any of the three anti-VEGF agents were more likely to have gained 15 letters or more of visual acuity, lost fewer than 15 letters of visual acuity, and had vision 20/200 or better after one year of follow up. Visual acuity outcomes after bevacizumab and ranibizumab were similar when the same regimens were compared in the same RCTs, despite the substantially lower cost for bevacizumab compared with ranibizumab. No trial directly compared pegaptanib with other anti-VEGF agents; however, when compared with controls, ranibizumab or bevacizumab yielded larger improvements in visual acuity outcomes than pegaptanib.Participants treated with anti-VEGFs showed improvements in morphologic outcomes (e.g., size of CNV or central retinal thickness) compared with participants not treated with anti-VEGF agents. There was less reduction in central retinal thickness among bevacizumab-treated participants than among ranibizumab-treated participants after one year (MD -13.97 μm; 95% confidence interval (CI) -26.52 to -1.41); however, this difference is within the range of measurement error and we did not interpret it as being clinically meaningful.Ocular inflammation and increased intraocular pressure after intravitreal injection were the most frequently reported serious ocular adverse events. Endophthalmitis was reported in fewer than 1% of anti-VEGF treated participants; no cases were reported in control groups. The occurrence of serious systemic adverse events was comparable across anti-VEGF-treated groups and control groups; however, the numbers of events and trial participants may have been insufficient to detect a meaningful difference between groups. Data for visual function, quality of life, and economic outcomes were sparsely measured and reported., Authors' Conclusions: The results of this review indicate the effectiveness of anti-VEGF agents (pegaptanib, ranibizumab, and bevacizumab) in terms of maintaining visual acuity; ranibizumab and bevacizumab were also shown to improve visual acuity. The information available on the adverse effects of each medication do not suggest a higher incidence of potentially vision-threatening complications with intravitreal injection compared with control interventions; however, clinical trial sample sizes may not have been sufficient to detect rare safety outcomes. Research evaluating variable dosing regimens with anti-VEGF agents, effects of long-term use, combination therapies (e.g., anti-VEGF treatment plus photodynamic therapy), and other methods of delivering the agents should be incorporated into future Cochrane reviews.

Background: Cataract formation or acceleration can occur after intraocular surgery, especially following vitrectomy, a surgical technique for removing the vitreous which is used in the treatment of disorders that affect the posterior segment of the eye. The underlying problem that led to vitrectomy may limit the benefit from cataract surgery., Objectives: The objective of this review was to evaluate the effectiveness and safety of surgery for post-vitrectomy cataract with respect to visual acuity, quality of life, and other outcomes., Search Methods: We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library 2013, Issue 4), Ovid MEDLINE, Ovid MEDLINE in-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily Update, Ovid OLDMEDLINE (January 1946 to May 2013), EMBASE (January 1980 to May 2013, Latin American and Caribbean Health Sciences Literature Database (LILACS) (January 1982 to May 2013), PubMed (January 1946 to May 2013), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrial.gov) and the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 22 May 2013., Selection Criteria: We planned to include randomized and quasi-randomized controlled trials comparing cataract surgery with no surgery in adult patients who developed cataract following vitrectomy., Data Collection and Analysis: Two authors screened the search results independently according to the standard methodological procedures expected by The Cochrane Collaboration., Main Results: We found no randomized or quasi-randomized controlled trials comparing cataract surgery with no cataract surgery for patients who developed cataracts following vitrectomy surgery., Authors' Conclusions: There is no evidence from randomized or quasi-randomized controlled trials on which to base clinical recommendations for surgery for post-vitrectomy cataract. There is a clear need for randomized controlled trials to address this evidence gap. Such trials should stratify participants by their age, the retinal disorder leading to vitrectomy, and the status of the underlying disease process in the contralateral eye. Outcomes assessed in such trials may include gain of vision on the Early Treatment Diabetic Retinopathy Study (ETDRS) scale, quality of life, and adverse events such as posterior capsular rupture. Both short-term (six-month) and long-term (one-year or two-year) outcomes should be examined.

EPA recommends sensitivity analyses when applying the toxic equivalency factor (TEF) method to evaluate exposures to dioxin-like compounds (DLCs). Applying the World Health Organization's (WHO) 2005 TEF values and estimating average U.S. daily dietary intakes of 25 DLCs from eight food categories, we estimate a toxic equivalency (TEQ) intake of 23 pg/day. Among DLCs, PCB 126 (26%) and 1,2,3,7,8-PeCDD (23%) dominate TEQ intakes. Among food categories, milk (14%), other dairy (28%), beef (25%), and seafood (18%) most influenced TEQ intakes. We develop two approaches to estimate alternative TEF values. Based on WHO's assumption regarding TEF uncertainty, Approach1 estimates upper and lower TEFs for each DLC by multiplying and dividing, respectively, its individual TEF by ± half a log. Based on compiled empirical ranges of relative potency estimates, Approach2 uses percentile values for individual TEFs. Total TEQ intake estimates using the lower and upper TEFs based on Approach1 were 8 and 68 pg TEQ/day, respectively. The 25th and 75th percentile TEFs from Approach2 yielded 12 and 28 pg TEQ/day, respectively. The influential DLCs and food categories remained consistent across alternative TEFs, except at the 90th percentile using Approach2. We highlight the need for developing underlying TEF probability distributions., (Published by Elsevier Inc.)

Background: Glaucoma is an acquired degeneration of the optic nerve and a leading cause of blindness worldwide. Medical and surgical treatments that decrease intraocular pressure may prevent visual impairment and blindness., Purpose: To compare the effectiveness of medical, laser, and surgical treatments in adults with open-angle glaucoma with regard to decreasing intraocular pressure and preventing optic nerve damage, vision loss, and visual impairment., Data Sources: MEDLINE, CENTRAL, and an existing database for systematic reviews (through 2 March 2011); MEDLINE, EMBASE, LILACS, and CENTRAL for primary studies (through 30 July 2012)., Study Selection: English-language systematic reviews; randomized, controlled trials; and quasi-randomized, controlled trials for most outcomes and observational studies for quality of life and harms., Data Extraction: Two investigators abstracted or checked information about study design, participants, and outcomes and assessed risk of bias and strength of evidence., Data Synthesis: High-level evidence suggests that medical, laser, and surgical treatments decrease intraocular pressure and that medical treatment and trabeculectomy reduce the risk for optic nerve damage and visual field loss compared with no treatment. The direct effect of treatments on visual impairment and the comparative efficacy of different treatments are not clear. Harms of medical treatment are primarily local (ocular redness, irritation); surgical treatment carries a small risk for more serious complications., Limitation: Heterogeneous outcome definitions and measurements among the included studies; exclusion of many treatment studies that did not stratify results by glaucoma type., Conclusion: Medical and surgical treatments for open-angle glaucoma lower intraocular pressure and reduce the risk for optic nerve damage over the short to medium term. Which treatments best prevent visual disability and improve patient-reported outcomes is unclear.

Background: Although findings from observational studies published in the 1970s and early 1980s suggested that length of remaining life after a diagnosis of uveal melanoma was similar following enucleation (removal of the eye) and local eye-conserving radiotherapy, the majority of ophthalmologists in the United States were not convinced that "saving the eye" would not compromise survival., Purpose: The Collaborative Ocular Melanoma Study (COMS) was designed to compare enucleation and radiotherapy among similar patients with respect to survival outcomes., Methods: A multicenter randomized trial of primary treatment with iodine-125 brachytherapy versus enucleation (i.e., a comparative effectiveness trial) was conducted to provide the evidence required to answer the concerns of ophthalmologists and their patients. Eligibility criteria adopted for the trial were intended to apply to the majority of patients diagnosed with choroidal melanoma who would be suitable candidates for either form of primary treatment., Results: Accrual to this COMS trial began in 1986 and ended in 1998. Participating patients were followed for 5 to 15 years, depending upon date of enrollment, before all clinical follow-up ended in 2003. No difference in survival outcomes and little difference in quality-of-life outcomes were observed between patients in the brachytherapy arm and those in the enucleation arm. Five-year survival was substantially better than anticipated based on a review of the literature when the trial was designed., Limitations: The choice of brachytherapy for delivery of radiation to the tumor had important advantages but also imposed restrictions regarding eligibility., Conclusions: The multidisciplinary COMS Group not only successfully conducted a randomized trial that answered the primary study questions but also has contributed to clinical and epidemiologic knowledge of choroidal melanoma through numerous publications. As a consequence of the COMS, a standard approach to I-125 brachytherapy for treatment of choroidal melanoma became widely available to affected patients.

Objective: To compare 2-year changes from baseline scores on the National Eye Institute Visual Function Questionnaire (NEI-VFQ) between similar participants assigned to sham and no-treatment control arms in randomized clinical trials of treatment of subfoveal choroidal neovascularization secondary to age-related macular degeneration., Methods: We retrospectively matched sham controls from a randomized trial to no-treatment controls (no sham or placebo) from another trial on 7 baseline prognostic criteria. Two-year changes in overall and subscale scores were compared using data from those who had 2-year interviews and also using the last follow-up observation carried forward to impute missing 2-year interview scores., Results: A match to a no-treatment control on all 7 criteria was identified for 62 of 238 sham controls. Among the 42 matched pairs of controls interviewed at 2 years, no important difference in 2-year change in NEI-VFQ scores overall or by subscale was observed. Findings were similar for the 56 matched pairs of controls who could be analyzed for 2-year changes in scores using the method of last follow-up observation carried forward., Conclusions: Findings from this retrospective matched-pairs analysis suggest that sham treatment to mask patient participants in clinical trials may be unnecessary when patient-reported outcomes are of interest and standard instruments are administered by interviewers masked to treatment assignment. This analysis, together with our earlier analysis of visual acuity outcomes, questions the necessity for sham (placebo) controls in randomized clinical trials in ophthalmology when other methods to minimize outcome assessment bias are incorporated into the design.

Objective: To identify characteristics predictive of progression to advanced age-related macular degeneration (AMD) in second (fellow) eyes of participants in the Submacular Surgery Trials (SST) who had unilateral neovascular AMD at study entry., Methods: Review of baseline fluorescein angiograms confirmed the absence of advanced AMD in 370 fellow eyes. All participants were eligible for 2 years of follow-up; follow-up angiograms of eyes at risk were evaluated to estimate incidence rates of advanced AMD. Baseline nonocular and ocular AMD characteristics were evaluated to identify those that predicted development of advanced AMD., Results: Of 110 eyes that progressed to advanced AMD, choroidal neovascularization (CNV) developed in 98 eyes and foveal geographic atrophy (GA) in 15 eyes. No nonocular characteristic (age, gender, history of hypertension or smoking) or ocular feature of the study eye at baseline (lesion composition, lesion size, or visual acuity) was predictive of progression to advanced AMD in this cohort. Multivariate analysis identified three baseline fellow eye ocular features that had a significant and independent relationship with progression to advanced AMD: drusen size, focal hyperpigmentation, and nonfoveal GA., Conclusion: Recognition of factors that predict advanced AMD in the second eye may identify those individuals at greater risk of progression so that treatment can be provided before vision is severely compromised.

Objective: To identify risk factors associated with the development of rhegmatogenous retinal detachment (RRD) in patients enrolled in the Submacular Surgery Trials., Methods: One thousand fifteen patients with eligible subfoveal neovascular lesions in the study eye were assigned randomly to observation or to surgery. Eyes were examined at 3 months, 6 months, 12 months, and 24 months after enrollment to assess study outcomes and adverse events, including RRDs. Adverse events also were reported at other times as clinical personnel became aware of them. Potential risk factors for the development of RRD in study eyes were evaluated using recursive partitioning and logistic regression analysis., Results: Among 506 eyes assigned to surgery, RRD developed in 44 (8.7%) compared with 4 (0.8%) of 509 eyes assigned to observation. Of the 44 eyes in which RRD developed, 27 had age-related macular degeneration (AMD) and large (>3.5 MPS disk areas) hemorrhagic subfoveal neovascular lesions at baseline and represented 16.1% of all eyes with such lesions assigned to surgery. Eyes with AMD and larger hemorrhagic lesions (>16 MPS disk areas) together with relatively poor visual acuity (best-corrected visual acuity < or =20/1280) had a higher risk of RRD (odds ratio = 6.2, 95% confidence interval: 2.2-16.7) compared with those with smaller lesions and better visual acuity at baseline., Conclusion: Poor visual acuity and very large, predominantly hemorrhagic subfoveal neovascular AMD lesion type were the greatest risk factors for RRD after submacular surgery. Submacular surgery should be undertaken in such eyes with full awareness of the risk of RRD during subsequent follow-up.

Objective: To compare 2-year visual acuity outcomes between similar participants assigned to sham and no-treatment control arms in randomized clinical trials., Methods: We retrospectively matched sham controls from 2 randomized trials to no-treatment controls (no sham or placebo) from 3 trials on 8 baseline prognostic criteria (full matches) or on 4 to 7 criteria (partial matches). Outcomes were compared using data from those who had 2-year visual acuity measurements and also using the last observation carried forward method to impute missing 2-year measurements., Results: A full match to a no-treatment control was identified for 72 of 321 sham controls (22%); a partial match was identified for another 93 sham controls (29%). Among the fully matched pairs, no important difference in 2-year visual acuity outcomes was observed. However, 2-year outcomes differed somewhat between sham and no-treatment controls within the partially matched pairs., Conclusions: Findings from fully matched pairs suggest that sham treatment to mask participants in clinical trials may be unnecessary when visual acuity is the outcome of interest. However, findings from the partially matched pairs do not fully support this conclusion. This analysis challenges the necessity for sham (placebo) controls in randomized clinical trials in ophthalmology when visual acuity is the primary outcome of interest.

Objective: To determine whether patients receiving observation vs surgery for subfoveal choroidal neovascularization that was idiopathic or associated with histoplasmosis differed in preference values assigned to their health and vision status., Methods: Before and after enrollment, patients rated their current vision on a scale from 0 (blind) to 100 (perfect vision) and rated blindness and perfect vision on a scale from 0 (dead) to 100 (perfect health and vision). Scores for current vision were converted to a preference value scale (0 represents death; 100, perfect health and vision)., Results: In 170 patients, no significant difference existed between the observation and surgery arms in median vision preference values at baseline (74 vs 70) or at the 12- (74 vs 78) or 24-month follow-up (77 vs 73) (P > .05). Preference values did not differ between arms for subgroups defined by age, unilateral vs bilateral choroidal neovascularization, or good vs poor baseline visual acuity., Conclusions: Submacular surgery was no better than observation in the preference values patients assigned to their health status, despite previously reported improvements in vision-specific quality of life., Trial Registration: (clinicaltrials.gov) Identifier: NCT00000150., Clinical Relevance: Ophthalmologists should consider the effects on different measures of quality of life when determining treatment for patients similar to those in the Submacular Surgery Trials Group H Trial.

Objective: To show that low luminance visual dysfunction is predictive of subsequent visual acuity (VA) loss in eyes with geographic atrophy (GA) resulting from age-related macular degeneration (AMD)., Design: Cohort study examining the prospective natural history study of GA from 1992 through 2000 at the Wilmer Eye Institute., Participants: Ninety-one participants with GA resulting from AMD without choroidal neovascularization in at least 1 eye who completed a 2-year study examination., Methods: Annual examinations included measurement of best-corrected VA, low luminance VA, Pelli-Robson contrast sensitivity, reading speed, examination, and fundus photography. The total GA area was quantified, as was the GA within a 10.2-mm(2) circle centered on the fovea., Main Outcome Measures: Visual acuity loss at 2 years and risk factors for visual loss., Results: Participants with baseline VA of 20/50 or more had a 40% 2-year rate of VA loss of 3 lines or more, compared with 13% for the participants with worse baseline acuities. The baseline low-luminance deficit (LLD) in VA was a strong predictor of subsequent VA loss for all levels of baseline VA. Within the good baseline VA group, the relative risk (RR) of 3-line loss for the worse LLD group compared with the better LLD group was 2.88 (95% confidence interval [CI], 1.13-7.35). The LLD is a stable and reproducible measure. Other significant visual function predictors of subsequent VA loss in eyes with good baseline VA included foveal dark-adapted sensitivity (RR, 4.20; 95% CI, 1.39-12.71) and reduced reading rate (RR, 2.43; 95% CI, 1.11-5.31). The rate of VA loss within the good acuity group was higher when the GA included 25% to 75% of the central 10.2 mm(2) than in eyes with GA including less than 25% or more than 75% of the central 10.2 mm(2). The following were not significant predictors of subsequent VA loss among these participants: age, gender, fellow eye diagnosis, fellow eye VA, baseline GA area, and GA enlargement rate., Conclusions: Visual function measures can predict the risk of future VA loss in subjects with GA and good baseline VA. They may allow identification of the highest risk group for VA loss, enabling more efficient design of clinical trials. They also may be appropriate surrogate measures of foveal health in short-term treatment trials.

Purpose: To report baseline echographic characteristics of tumors in patients enrolled in the Collaborative Ocular Melanoma Study (COMS) randomized trials, to determine how often these characteristics matched prespecified criteria for choroidal melanoma, to explore associations between echographic variables, and to compare specific echographic characteristics with pathologic characteristics of tumors in enucleated eyes., Design: Retrospective analyses of baseline data from multicenter randomized clinical trials., Participants: Patients enrolled in the COMS large trial or medium tumor trials (N = 2320)., Methods: Standardized echography was used to document selected characteristics of tumors at baseline. Criteria were established to assess the consistency of echographic features with the diagnosis of melanoma. For eyes assigned to enucleation, the echographic diagnosis and evaluation for extraocular extension by the Echography Center were compared with gradings made by the Pathology Center and Pathology Review Committee., Main Outcome Measures: Presence of various echographic and pathologic characteristics., Results: Two thousand forty-three tumors (88%) exhibited low to medium reflectivity (n = 1409), a mushroom shape (n = 101), or both (n = 533). Tumors with apical height > 10 mm were more likely (P<0.001) to have a mushroom shape and less likely to have a posterior location (P<0.001) than less elevated tumors. One thousand five hundred fifty-nine (99.7%) of 1563 tumors judged by echography to be consistent with the diagnosis of melanoma were confirmed by pathology to be choroidal melanoma. For measurable extrascleral tumors < 1.5 mm in height by pathology, the Echography Center graders judged extrascleral extension as possibly present in only 1 of 16 (6%) tumors, compared with 57% (4/7) of eyes with extrascleral extension measuring > or = 1.5 mm in height., Conclusions: Eighty-eight percent of the tumors in the COMS exhibited features characteristic for melanoma: low to medium reflectivity, the classic mushroom shape, or both. Using additional preset criteria, 96% of tumors exhibited baseline echographic characteristics consistent with the diagnosis of melanoma. Echography graders were able to detect extrascleral nodules > or = 1.5 mm in elevation but not minimally elevated extraocular tumor extension. Clinicians and echographers can use these data to improve their understanding of the echographic features of untreated uveal melanomas.

Purpose: To assess the reproducibility of the evaluation of color photographs and fluorescein angiograms of the macula of each eye for patients enrolled in the Macular Photocoagulation Study (MPS) trials of laser photocoagulation of subfoveal choroidal neovascularization (CNV) secondary to age-related macular degeneration., Methods: A total of 65 pre-enrollment and 26 posttreatment sets of photographs were regraded. The two gradings were compared on selected items judged to be of primary importance with respect to the role of the MPS Reading Center., Results: Agreement on eligibility of the neovascular lesion for an MPS trial was 88% (kappa statistic = 0.59); agreement on the size of the lesion was 86% (kappa statistic = 0.80); agreement on whether the lesion was covered by heavy treatment was 69% (kappa statistic = 0.35); and agreement on whether the treatment was in compliance with the study protocol was 73% (kappa statistic = 0.06)., Conclusions: Interpretation of photographs of eyes with CNV secondary to age-related macular degeneration for eligibility and size of the lesion was reproducible in the MPS. However, adequacy of laser photocoagulation treatment could not be determined reliably from photographs.

Purpose: To describe and compare methods used to monitor development and progression of presumed vision-limiting lens opacity in study eyes of Submacular Surgery Trials (SST) patients., Design: Prospective study of patients enrolled in a set of randomized clinical trials., Participants: Patients enrolled in the SST who were phakic in the study eye at the time of enrollment (n = 690). In a subset of 114 patients, lens photographs were obtained at baseline and 2 years after enrollment., Methods: Data collection at baseline and annual follow-up examinations included ocular history, ophthalmologic examination including the SST ophthalmologist's assessment of presence or absence of vision-limiting opacity, fundus photography, and lens photography (13 of 27 clinics only). All photographs were assessed by masked graders centrally using the Lens Opacities Classification System III (LOCS III). kappa statistics were calculated to compare LOCS III cataract classifications with fundus photograph quality and with the ophthalmologist's assessment of lens opacity, with the LOCS III classification considered the gold standard., Main Outcome Measure: Incidence of cataract in study eyes., Results: Baseline lens photographs were available and graded for 312 (45%) of 690 patients with phakic study eyes; 2-year lens photographs were available for 156 (23%) of 690 initially phakic eyes. Both baseline and 2-year lens photographs were available for 114 eyes that remained phakic. Submacular surgery was associated with significant progression of nuclear color and nuclear opalescence characteristics within 2 years of enrollment. The reliability of fundus photograph quality versus cataract classification using a 4.5 LOCS III score threshold for cataract was poor to good at each time point and for all groups (kappa, 0-0.51), but sensitivity of the photograph quality score as a surrogate was low, and both positive and negative predictive values were low. Agreement between the ophthalmologists' assessments of lens opacity and the 4.5 LOCS III score threshold for cataract was good (kappa, 0.42-0.78)., Conclusions: In the SST, clinical identification of severe cataract (LOCS III scores of 4.5 or worse for nuclear opacity or nuclear color) by the examining ophthalmologist was valid based on comparison with LOCS III scores and may be an adequate method to use in similar trials.

Objective: To describe incident choroidal neovascular lesions in fellow eyes of participants in the Submacular Surgery Trials who had age-related macular degeneration (AMD)., Methods: Review of baseline fluorescein angiograms confirmed the absence of neovascular AMD in fellow eyes of 364 participants at risk. Subjects were eligible for a minimum of 2 years of follow-up with angiograms of eyes at risk reevaluated to estimate incidence rates of choroidal neovascularization (CNV) and to characterize these lesions., Main Outcome Measures: Incidence of CNV during follow-up, characteristics of the incident lesion (composition, size, and location), and visual acuity at the time of incidence., Results: Incident lesions were confirmed in 98 fellow eyes of participants, yielding 2- and 4-year cumulative incidence rates of 22% and 37%. Incident lesions were predominantly CNV in 87 fellow eyes (90%), extrafoveal in 29 fellow eyes (30%), and juxtafoveal in 9 fellow eyes (9%). Occult without classic CNV lesions were found in 64 eyes (67%), minimally classic CNV and predominantly classic CNV lesions in 12 eyes (13%) each, and predominantly blood lesions in 4 eyes (4%). Nearly two-thirds of all incident lesions were 3 disc areas or smaller in size. Median visual acuity decreased from 20/25 at baseline to 20/250 at the 4-year follow-up in fellow eyes with incident CNV. CONCLUSIONS AND APPLICATION TO CLINICAL PRACTICE: Frequent angiographic follow-up of fellow eyes at risk for CNV may lead to earlier detection and treatment of neovascular AMD and better visual acuity outcomes.

Purpose: To compare survival between patients enrolled in the Collaborative Ocular Melanoma Study (COMS) randomized trial of pre-enucleation radiation therapy (PERT) for large choroidal melanoma and eligible patients who did not enroll., Methods: COMS clinical center personnel prospectively reported to the COMS Coordinating Center all patients with choroidal melanoma examined between November 1986 and December 1994. Deaths of enrolled patients were reported prospectively by clinical center personnel. In a COMS ancillary study, we retrospectively searched medical records of participating clinical centers, the Social Security Death Index, and the National Death Index to determine vital status of eligible patients not enrolled. Cox proportional hazards analysis was used to compare survival within 10 years of baseline reporting and before July 31, 2000, of enrolled patients versus eligible patients not enrolled., Results: Clinical centers that received local institutional review board approval to participate in this ancillary study prospectively reported on 129 of 299 eligible patients not enrolled in the COMS PERT trial. The baseline characteristics of the 129 patients included in this ancillary study were similar to those of the 170 patients not included; 73 patients were reported as deceased. Previously identified prognostic covariates, i.e., age and longest tumor diameter, were confirmed to predict survival in both enrolled patients and eligible patients not enrolled; trial enrollment was not predictive. After adjusting for prognostic covariates and stratifying by clinical center, the estimated hazard ratio (enrolled vs. not-enrolled) was 1.12 (95% confidence interval: 0.83 to 1.51)., Conclusions: The results of the COMS PERT trial should be generalizable to all patients with choroidal melanoma meeting the eligibility criteria for that trial. While the methods we used may not be generalizable to all clinical trials because of unique features of the COMS, other researchers may be able to use similar methods to determine the generalizability of their trial results.

Purpose: To report the enlargement rate of geographic atrophy (GA) over time, its relationship to size of atrophy at baseline and to prior enlargement rate, and the implications for designing future treatment trials for GA., Design: Prospective natural history study of GA resulting from age-related macular degeneration., Participants: Two hundred twelve eyes of 131 patients were included in the analysis., Methods: Annual follow-up included stereo color fundus photographs. The areas of GA were identified and measured, and the rate of enlargement of the atrophy was assessed. Sample sizes for clinical trials using systemic treatment and uniocular treatment were determined., Main Outcome Measure: Rate of enlargement of the atrophy., Results: The median overall enlargement rate was 2.1 mm2/year (mean, 2.6 mm2/year). Eyes with larger areas of atrophy at baseline tended to have larger enlargement rates, but knowledge of prior rates of enlargement was the most significant factor in predicting subsequent enlargement rates. There was high concordance between the enlargement rates in the 2 eyes of patients with bilateral GA (correlation coefficient, 0.76). To detect a 25% reduction in enlargement rate for a systemic treatment (alpha, 0.05; power, 0.80; losses to follow-up, 15%), 153 patients each in a control and treatment group would be required for a trial with a 2-year follow-up period for each patient. For a uniocular treatment, 38 patients with bilateral GA would be required, with the untreated eye serving as a control for the treated eye., Conclusions: Treatment trials for GA with an outcome variable of change in enlargement rate are feasible.

Purpose: To derive information from the Geographic Atrophy (GA) Natural History Study that is relevant to recruiting patients and designing clinical trials for GA., Methods: A prospective natural history study with annual follow-up enrolled patients with GA and no choroidal neovascularization (CNV) in at least one eye. Characteristics of recruited and enrolled patients are analyzed, in the context of progression data from the study., Results: The data show that GA from age-related macular degeneration (AMD) was seen in 82% of the referred patients, there was an attrition rate of 14%, and 60% of the patients with GA from AMD had bilateral GA without CNV. Within the 83 patients in the bilateral GA group with follow-up, 50 patients (60%) met both the proposed visual acuity and the proposed GA area criteria for a treatment trial in one or both eyes., Conclusion: These data should be helpful in planning future treatment trials for GA.

Objective: To describe the time between treatment for choroidal melanoma and first diagnosis of metastatic disease, sites of metastasis, treatments for metastasis, and time between diagnosis of metastasis and death., Design: Prospective, longitudinal follow-up of patients diagnosed with choroidal melanoma who were enrolled in 2 randomized trials conducted by the Collaborative Ocular Melanoma Study Group., Methods: Systemic and laboratory evaluations were performed during follow-up according to a standard protocol for 2320 patients enrolled in the Collaborative Ocular Melanoma Study trials without evidence of melanoma metastasis or other primary cancer at baseline., Results: Seven hundred thirty-nine patients were diagnosed with at least 1 site of metastasis during follow-up after treatment for choroidal melanoma. Five- and 10-year cumulative metastasis rates were 25% (95% confidence interval, 23%-27%) and 34% (95% confidence interval, 32%-37%), respectively. Liver was the most common site (89%). The death rate following the report of melanoma metastasis was 80% at 1 year (95% confidence interval, 77%-83%) and 92% at 2 years (95% confidence interval, 89%-94%). Overall survival after metastasis did not vary by baseline size of primary tumor nor treatment for metastasis (when known). Long-term survival after diagnosis of metastasis was uncommon; only 8 patients survived 5 or more years., Conclusion: Metastasis rate increased significantly with increasing primary tumor dimensions at time of patient enrollment. Prognosis after metastatic disease remains poor. Effective methods are needed to prevent, diagnose, and treat metastasis from choroidal melanoma.