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The advent of anti-vascular endothelial growth factor (VEGF) agents has revolutionized the treatment of retinal neovascular diseases including neovascular age-related macular degeneration (nAMD), a leading cause of irreversible blindness. Multiple agents and methods for drug delivery are emerging to increase the duration of treatment effect and treatment interval, reducing the overall treatment burden on patients and clinicians. The newest agent on the market is faricimab. This medication targets two distinct pathways in retinal angiogenesis, VEGF-A and Ang-2, to create a more durable effect. Phase 3 trials for this drug compared treatment intervals up to 16 weeks against aflibercept dosed at 8-week intervals for both nAMD and diabetic macular edema (DME). While the drug shows similar functional and anatomic outcomes with a low adverse effect profile and trial data demonstrating increased treatment duration, its exact place in the VEGF marketplace is yet to be determined. In this article, we discuss the mechanism of action, pivotal clinical trials leading to approval, and the anticipated role for faricimab in the treatment of retinal neovascular disease.

ImportanceThe 21st Century Cures Act Final Rule mandates the immediate electronic availability of test results to patients, likely empowering them to better manage their health. Concerns remain about unintended effects of releasing abnormal test results to patients.ObjectiveTo assess patient and caregiver attitudes and preferences related to receiving immediately released test results through an online patient portal.Design, Setting, and ParticipantsThis large, multisite survey study was conducted at 4 geographically distributed academic medical centers in the US using an instrument adapted from validated surveys. The survey was delivered in May 2022 to adult patients and care partners who had accessed test results via an online patient portal account between April 5, 2021, and April 4, 2022.ExposuresAccess to test results via a patient portal between April 5, 2021, and April 4, 2022.Main Outcomes and MeasuresResponses to questions related to demographics, test type and result, reaction to result, notification experience and future preferences, and effect on health and well-being were aggregated. To evaluate characteristics associated with patient worry, logistic regression and pooled random-effects models were used to assess level of worry as a function of whether test results were perceived by patients as normal or not normal and whether patients were precounseled.ResultsOf 43 380 surveys delivered, there were 8139 respondents (18.8%). Most respondents were female (5129 [63.0%]) and spoke English as their primary language (7690 [94.5%]). The median age was 64 years (IQR, 50-72 years). Most respondents (7520 of 7859 [95.7%]), including 2337 of 2453 individuals (95.3%) who received nonnormal results, preferred to immediately receive test results through the portal. Few respondents (411 of 5473 [7.5%]) reported that reviewing results before they were contacted by a health care practitioner increased worry, though increased worry was more common among respondents who received abnormal results (403 of 2442 [16.5%]) than those whose results were normal (294 of 5918 [5.0%]). The result of the pooled model for worry as a function of test result normality was statistically significant (odds ratio [OR], 2.71; 99% CI, 1.96-3.74), suggesting an association between worry and nonnormal results. The result of the pooled model evaluating the association between worry and precounseling was not significant (OR, 0.70; 99% CI, 0.31-1.59).Conclusions and RelevanceIn this multisite survey study of patient attitudes and preferences toward receiving immediately released test results via a patient portal, most respondents preferred to receive test results via the patient portal despite viewing results prior to discussion with a health care professional. This preference persisted among patients with nonnormal results.

To determine the effectiveness of bevacizumab step therapy for neovascular age-related macular degeneration (nAMD) in routine clinical practice.In this retrospective case series, eyes initiating treatment for nAMD at an academic medical centre from 2011-2019 were included. Exclusion criteria included previous intravitreal anti-VEGF injections, prior non-cataract intraocular surgery,1 year of treatment, and not starting on monthly bevacizumab therapy. Of 895 eligible eyes, 548 were excluded, yielding 347 eyes in the study population. These eyes were treated for nAMD under the bevacizumab step therapy protocol with an option to switch to another agent in the event of predefined treatment failure. Treatment failure was defined as losing 15 or more Early Treatment Diabetic Retinopathy Study letters or switching to an alternative anti-VEGF agent. Eyes that did not meet these criteria were deemed treatment successes. Annual change in mean VA from baseline (ΔVA) was the primary outcome. Secondary outcomes included treatment success rate, medication switch rate, and post-switch ΔVA.After 1 year, mean ΔVA was +8.4 letters (95% CI: +6.1 to +10.6 letters). 86% had treatment success, and 6% of eyes had switched to aflibercept. In years 2-7, ΔVA ranged from +7.0 to -0.7 letters, and treatment success rates ranged from 68 to 82%. 11% (n = 38) of eyes were switched to aflibercept. The post-switch ΔVA in these eyes was -7.1 letters (95% CI: -13.3 to -0.1) after a mean of 17.7 ± 12.6 injections over an average of 2.7 ± 2.0 years.A bevacizumab step therapy protocol in routine clinical practice is effective for long-term treatment of nAMD.

Diapause arrest in animals such as Caenorhabditis elegans is tightly regulated so that animals make appropriate developmental decisions amidst environmental challenges. Fully understanding diapause requires mechanistic insight of both entry and exit from the arrested state. Although a steroid hormone pathway regulates the entry decision into C. elegans dauer diapause, its role in the exit decision is less clear. A complication to understanding steroid hormonal regulation of dauer has been the peculiar fact that steroid hormone mutants such as daf-9 form partial dauers under normal growth conditions. Here, we corroborate previous findings that daf-9 mutants remain capable of forming full dauers under unfavorable growth conditions and establish that the daf-9 partial dauer state is likely a partially exited dauer that has initiated but cannot complete the dauer exit process. We show that the steroid hormone pathway is both necessary for and promotes complete dauer exit, and that the spatiotemporal dynamics of steroid hormone regulation during dauer exit resembles that of dauer entry. Overall, dauer entry and dauer exit are distinct developmental decisions that are both controlled by steroid hormone signaling.

Objective This study aimed to analyze the effectiveness of the American Academy of Ophthalmology (AAO)'s Leadership Development Program (LDP), report the program's impact on participants in attaining ophthalmic leadership positions, and identify opportunities to improve future LDP programming. Design An open cohort study was performed on AAO LDP graduates by using an online questionnaire and retrospective monitoring. Participants and Methods AAO LDP graduates from 1999 to 2019 participated in the study. A Likert-scale survey was distributed via email. Online responses were submitted anonymously to a team at the Berkeley Haas School of Business for analysis. A separate review of gender demographics and ophthalmic leadership positions held by graduates was performed. Main Outcomes Measures Regression analysis was performed to determine whether survey results supported a meaningful relationship between the measured impact and the AAO LDP program's perceived effectiveness. Ascension into leadership positions of AAO-related organizations at the national, regional, state, and subspecialty level by AAO LDP graduates was collated. Results Of 381 potential respondents, 203 survey responses were returned (53.3%). 158 reported that they are currently holding a leadership position (77.8%). Statistical analyses indicated that the overall value of the program was seen as highly effective (M = 4.6), and that the development programs combined contributed significantly to AAO LDP being judged as effective overall, F (11,191) = 24.79; p Conclusion The AAO LDP has fulfilled its initial goals of effectively developing a large cohort of ophthalmologists interested in and prepared to take on leadership roles across the profession. Development of more specific outcome measures to evaluate the program, as well as direct optimal programming, are needed to further the success of its aims.

Vanderbilt University Medical Center (VUMC) launched a new electronic health record (EHR) in a “big bang” implementation that saw the new software go live across multiple hospitals, clinics and geographic locations in a single morning. The organization rightly focused most of its energy on preparing its nearly 25,000 employees for the impacts of the transition, but it also considered the effects that would be felt by its patients and families. Survey data indicate that patient satisfaction scores demonstrably dip before, during and after an EHR implementation, and take approximately a year to recover. A team at DMC employed a seven-step approach to preparing patients for the impacts of the transition, which led to a return to pre-implementation patient satisfaction scores in about half the time of its peer institutions. The article explores these seven steps in detail and offers recommendations for how healthcare organizations facing large-scale change can use a similar structured approach to mitigate negative impacts to patients. Experience Framework This article is associated with the Culture & Leadership lens of The Beryl Institute Experience Framework. (http://bit.ly/ExperienceFramework) Access other PXJ articles related to this lens. Access other resources related to this lens

Purpose To investigate the natural history and genetic associations of drusenoid pigment epithelial detachment (DPED) associated with age-related macular degeneration (AMD). Design Retrospective analysis of a prospective cohort study. Participants Of the 4203 Age-Related Eye Disease Study 2 (AREDS2) participants, 391 eyes (325 participants) had DPED without late AMD at the time of DPED detection. Genetic analyses included 120 white AREDS2 participants and 145 Age-Related Eye Disease Study (AREDS) participants with DPED. Methods Baseline and annual stereoscopic fundus photographs were graded centrally to detect DPED, a well-defined yellow elevated mound of confluent drusen ≥433 μm in diameter, and to evaluate progression rates to late AMD: geographic atrophy (GA) and neovascular (NV)-AMD. Five single nucleotide polymorphisms (CFH [rs10611670], C3 [rs2230199], CFI [rs10033900], C2/CFB [rs114254831], ARMS2 [rs10490924]) and genetic risk score (GRS) group were investigated for association with DPED development. Kaplan–Meier analyses and multivariable proportional hazard regressions were performed. Main Outcome Measures Progression rates to late AMD and decrease of ≥3 lines in visual acuity (VA) from the time of DPED detection; association of rate of DPED development with genotype. Results Mean (standard deviation [SD]) follow-up time from DPED detection was 4.7 (0.9) years. DPED was associated with increased risk of progression to late AMD (hazard ratio [HR], 2.36; 95% confidence interval [CI], 1.98–2.82; P Conclusions This study replicates the results of previous natural history studies of eyes with DPED including the high rates of progression to late AMD and vision loss (regardless of progression to late AMD). The genetic associations are consistent with genes associated with AMD progression.

Purpose To analyze the prevalence, incidence, and clinical characteristics of eyes with geographic atrophy (GA) in age-related macular degeneration (AMD), including clinical and genetic factors affecting enlargement. Design Prospective cohort study within a controlled clinical trial. Participants Age-Related Eye Disease Study 2 (AREDS2) participants, aged 50–85 years. Methods Baseline and annual stereoscopic color fundus photographs were evaluated for GA presence and area. Analyses included GA prevalence and incidence rates, Kaplan-Meier rates, mixed-model regression, and multivariable analysis of the square root of GA, area adjusted for covariates, including clinical/imaging characteristics and genotype. Main Outcome Measures (1) Presence or development of GA; (2) change in the square root of GA area over time. Results At baseline, 517 eyes (6.2%) of 411 participants (9.8%) had pre-existing GA (without neovascular AMD), with the following characteristics: 33% central, 67% noncentral; and the following configurations: 36% small, 26% solid/unifocal, 24% multifocal, 9% horseshoe/ring, and 6% indeterminate. Of the remaining 6530 eyes at risk, 1099 eyes (17.3%) of 883 participants developed incident GA without prior neovascular disease during mean follow-up of 4.4 years. The Kaplan-Meier rate of incident GA was 19% of eyes at 5 years. In eyes with incident GA, 4-year risk of subsequent neovascular AMD was 29%. In eyes with incident noncentral GA, 4-year risk of central involvement was 57%. GA enlargement rate (following square root transformation) was similar in eyes with pre-existing GA (0.29 mm/year; 95% confidence interval 0.27–0.30) and incident GA (0.28 mm/year; 0.27–0.30). In the combined group, GA enlargement was significantly faster with noncentrality, multifocality, intermediate baseline size, and bilateral GA (P Conclusions Analyses of AREDS2 data on natural history of GA provide representative data on GA evolution and enlargement. GA enlargement, which was influenced by lesion features, was relentless, resulting in rapid central vision loss. The genetic variants associated with faster enlargement were partially distinct from those associated with risk of incident GA. These findings are relevant to further investigations of GA pathogenesis and clinical trial planning.

Purpose The recent exponential growth in teleophthalmology has been limited in part by the lack of a validated method to measure visual acuity (VA) remotely. We investigated the validity of a self-administered Early Treatment Diabetic Retinopathy Study (ETDRS) home VA test. We hypothesized that a home VA test with a printout ETDRS chart is equivalent to a standard technician-administered VA test in clinic. Design Prospective cohort study. Participants Two hundred nine eyes from 108 patients who had a scheduled in-person outpatient ophthalmology clinic visit at an academic medical center. Methods Enrolled patients were sent a .pdf document consisting of instructions and a printout ETDRS vision chart calibrated for 5 feet. Patients completed the VA test at home before the in-person appointment, where their VA was measured by an ophthalmic technician using a standard ETDRS chart. Survey questions about the ease of testing and barriers to completion were administered. For the bioequivalence test with a 5% nominal level, the 2 1-sided tests procedure was used, and an equivalent 90% confidence interval (CI) was constructed and compared with the prespecified 7-letter equivalence margin. Main Outcome Measures The primary outcome was the mean adjusted letter score difference between the home and clinic tests. Secondary outcomes included the unadjusted letter difference, absolute letter difference, and survey question responses. Results The mean adjusted VA letter score difference was 4.1 letters (90% CI, 3.2–4.9 letters), well within the 7-letter equivalence margin. Average unadjusted VA scores in clinic were 3.9 letters (90% CI, 3.1–4.7 letters) more than scores at home. The absolute difference was 5.2 letters (90% CI, 4.6–5.9 letters). Ninety-eight percent of patients agreed that the home test was easy to perform. Conclusions An ETDRS VA test self-administered at home following a standardized protocol was equivalent to a standard technician-administered VA test in clinic in the examined population.

Importance There is a lack of peer-reviewed literature on leadership development programs (LDP) in ophthalmology. Research into LDP demographics, outcomes, and methodology is needed. Objective The aim of the study is to evaluate the extent to which LDPs targeting ophthalmologists meet the needs of emerging leaders. Design The design type of the study is cross-sectional analysis. Setting This study involves international setting. Participants The participants involved were ophthalmologists at any career level. Methods Routine internet search was used to identify LDPs targeting ophthalmologists. LDPs identified were categorized by the outcome data available into four levels based on prior literature. Participants were assessed using previously validated software for gender (Gender-API, 2020) and race or ethnicity (NamSor, 2020) Results Nine programs were identified which were classified into LDP generations. The first LDP in ophthalmology was the American Academy of Ophthalmology (AAO) LDP, which served as the nidus for the formation of four multinational LDPs, together forming the Global LDP. These LDPs were similar in size and scope; program size ranging from nine to 30 participants; a length of 1 to 2 years; with similar curricular offerings; with funding primarily derived from cost-sharing with a nominating society. The second generation of ophthalmology LDPs in the United States has targeted female scientists or faculty (Women's LDP by ARVO) and academic ophthalmology leaders (Academic LDP by Association of University Professors of Ophthalmology).The AAO's LDP appears increasingly diverse with approximately 13% women at inception, gradually increasing from 40 to 65% women in the last 5 years (n = 389). There has also been a notable increase in ethnic diversity. Conclusion and Relevance AAO LDP is the preeminent leadership training program for ophthalmologists, and it has influenced the creation of a new generation of LDP offerings. There remains a paucity of LDP evaluation metrics and reported outcomes. Newer iterations are successfully targeting academic leadership and attempting to address known disparities in gender and race or ethnicity. Further expansion of LDPs and related research can ensure equity and diversity in the pipeline.

IMPORTANCE: Visit adherence has been shown to play a significant role in patient health outcomes. The effect of missing visits on visual acuity (VA) in individuals with neovascular age-related macular degeneration has yet to be characterized. OBJECTIVE: To quantify the association between patients’ adherence to randomized clinical trial visits and VA in individuals with neovascular age-related macular degeneration based on 4 visit adherence metrics. DESIGN, SETTING, AND PARTICIPANTS: This is a secondary analysis of the Comparison of Age-Related Macular Degeneration Treatment Trial randomized clinical trial. Individuals with age-related macular degeneration were recruited from 44 clinical centers in the United States between February 2008 and December 2009. The 2-year study protocol required 1 visit every 4 weeks (every 21-35 days for a total of 26 visits) for monthly vs pro re nata treatments of bevacizumab vs ranibizumab. Analysis took place from November 2018 through May 2019. EXPOSURES: Visit adherence was measured in 4 ways: total number of missed visits, average number of days (avg days) between each visit, longest duration in days (max days) between visits, and visit constancy (the tally of 3-month periods with at least 1 visit attended). Average and max days were also categorized as on time (28-35 days), late (36-60 days), and very late (>60 days). MAIN OUTCOMES AND MEASURES: Change in Early Treatment Diabetic Retinopathy Study VA between the baseline and the last visit. Linear multivariate regression models were applied to analyze the association between visit adherence and change in VA, controlling for age, sex, baseline VA, anti–vascular endothelial growth factor drug, number of injections, and dosing regimen. RESULTS: Of 1178 patients, the mean (SD) age was 79.1 (7.3) years, and 727 (61.7%) were women. The mean (SD) number of missed visits was 2.4 (3.1). Overall, 1091 patients (92.6%) had complete visit constancy during the entire study period. Average days were categorized with 1060 patients (90.0%) classified as on time, 108 (9.2%) were late, and 10 (0.8%) were very late. For max days between visits, 197 patients (16.7%) were on time, 773 (65.6%) were late, and 208 (17.7%) were very late. After controlling for covariates, the late (avg days = −6.1; max days = −2.0) and very late (avg days = −12.5; max days = −5.9) groups saw fewer letters in both the avg and max days categories than patients in the on-time group (P

Importance Understanding the distribution of patient complaints by physician age may provide insight into common patient concerns characteristic of early, middle, and late stages of careers in ophthalmology. Most previous studies of patient dissatisfaction have not addressed the association with physician age or controlled for other characteristics (eg, practice setting, subspecialty) that may contribute to the likelihood of patient complaints, unsafe care, and lawsuits. Objective To assess the association between ophthalmologist age and the likelihood of generating unsolicited patient complaints (UPCs) among a cohort of ophthalmologists. Design, Setting, and Participants Retrospective cohort study with variable duration of follow-up. The study assessed time to first complaint between 2002 and 2015 in 1342 attending ophthalmologists or neuro-ophthalmologists who had graduated from medical school before 2010 and were affiliated with an organization that participates in Vanderbilt University Medical Center’s Patient Advocacy Reporting System. Participants were stratified into 5 age bands and were followed up from the time of their employment to receipt of their first complaint. Trained coders categorized UPCs into 34 specific types under 6 major categories. Main Outcomes and Measures Time to first recorded complaint. Multivariable Cox proportional hazards model was used to measure the association between time to first complaint and ophthalmologist age after adjustment for predetermined covariates. Results The median physician age was 47 years, with 9% who were 71 years or older. The cohort was 74% male, 90% held MD degrees, and 73% practiced in academic medical centers. The mean follow-up period was 9.8 years. Ophthalmologists older than 70 years had the lowest complaint rate (0.71 per 1000 follow-up days vs 1.41, 1.84, 2.02, and 1.88 in descending order of age band). By 2000 days of follow-up (or within 5.5 years), the youngest group had an estimated UPC risk of 0.523. By 4000 days (>10 years), participants in the older than 70 years age band had an estimated risk of UPC of only 0.364. The 2 youngest age bands were associated with a statistically significant shorter time to first complaint. Compared with those aged 71 years or older, the risk of incurring a UPC for those aged 41 to 50 years was 1.73-fold higher (hazard ratio [HR], 1.73; 95% CI, 1.21-2.46;P = .002). Similarly, participants aged 31 to 40 years had a 2.36 times higher risk of incurring a UPC (HR, 2.36; 95% CI, 1.64-3.40;P Conclusions and Relevance This study suggests that older ophthalmologists are less likely to receive UPCs than younger ones. Although limitations in the study design could affect the interpretation of these conclusions, the findings may have practical implications for patient safety, clinical education, and clinical practice management.

Importance Drug overdoses have become the number 1 cause of mortality in American adults 50 years and younger. Prescription opioid abuse is a growing concern that has garnered widespread attention among policymakers and the general public. Objective To determine the opioid prescribing patterns among ophthalmologists and elucidate their role in the prescription opioid abuse epidemic. Design, Setting, and Participants In this observational cohort study, beneficiaries and their physicians were analyzed using 2013 to 2015 Medicare Part D Prescriber Data. The Centers for Medicare and Medicaid Services Medicare Part D Prescriber Public Use Files for 2013, 2014, and 2015 were accessed. Analysis began in June 2017. Data were collected and analyzed regarding the prescribing patterns for opioid drugs (eg, number of prescriptions written including refills, number of days’ supply, and prescriber rates) for all participating ophthalmologists. Main Outcomes and Measures The mean number of opioid prescriptions written annually by ophthalmologists; prescriber rates compared with all prescriptions written; and geographic distribution of opioid prescriptions written per ophthalmologist. Results In 2013, 4167 of 19 615 ophthalmologists were women (21.2%). Consistently, most ophthalmologists (88%-89%) wrote 10 opioid prescriptions or fewer annually. Approximately 1% (0.94%-1.03%) of ophthalmologists wrote more than 100 prescriptions per year. On average, ophthalmologists wrote 7 opioid prescriptions per year (134 290 written annually by 19 638 physicians, on average) with a mean supply of 5 days. The 6 states with the highest volume of opioid prescriptions written annually per ophthalmologist were located in the southern United States. Conclusions and Relevance In general, ophthalmologists show discretion in their opioid prescribing patterns. The present opioid abuse epidemic should prompt physicians to consider revisiting their prescribing protocols given the high risk for dependency.

Importance The frequency of anti–vascular endothelial growth factor (VEGF) injections has grown exponentially with the introduction of bevacizumab, ranibizumab, and most recently aflibercept. The cost associated with these medications has garnered significant national attention, warranting a granular analysis of their use. Objective To analyze trends in anti-VEGF injections for US Medicare Part B beneficiaries from 2012 to 2015. Design, Setting, and Participants This observational cohort study used 2012-2015 data from the Centers for Medicare & Medicaid Services Medicare Part B Provider Utilization Files to analyze trends in intravitreal injections of anti-VEGF medications among Medicare Part B beneficiaries and their health care professionals. Main Outcomes and Measures The primary outcome measure was distribution of and change over time in the number of anti-VEGF injections performed for ranibizumab, aflibercept, and bevacizumab. Results A total of 2 574 124 intravitreal injections were performed by 3348 ophthalmologists in the outpatient setting for Medicare Part B beneficiaries during the 2015 calendar year; 100 ophthalmologists (3.0%) performed the highest volume of intravitreal injections. The total number of intravitreal injections administered in 2015 was 870 843 for aflibercept, 697 412 for ranibizumab, and 1 147 432 for bevacizumab. Ranibizumab injections decreased by 7.1% from 2012 to 2015 and bevacizumab injections decreased by 17.1%. From 2013 to 2015, aflibercept injections increased by 69.4%. The 100 ophthalmologists performing the highest volume of ranibizumab injections, as gauged by number of injections administered, accounted for 31.0% (95% CI, 30.994%-30.997%) of all ranibizumab injections nationally. The 100 ophthalmologists performing the highest volume of aflibercept injections accounted for 17.6% (95% CI, 17.638%-17.641%) of all aflibercept injections and the 100 ophthalmologists performing the highest volume of bevacizumab injections accounted for 19.6% (95% CI, 19.649%-19.653%) of all bevacizumab injections administered nationally to Medicare Part B beneficiaries. The highest number of injections per 1000 Medicare Part B beneficiaries occurred in Nebraska (aflibercept), Tennessee (ranibizumab), and South Dakota (bevacizumab). Conclusions and Relevance A total of 3.0% of ophthalmologists account for 17.6% to 31.0% of the total number of anti-VEGF injections administered nationally in the Medicare Part B population. Overall, bevacizumab and ranibizumab injections have decreased, coinciding with a 69.4% increase in aflibercept injections.

Purpose To provide a perspective on the impact of the Comparison of Age-related Macular Degeneration Treatments Trial (CATT) on future clinical practices. Design Interpretation of trial outcomes relative to clinical use of neovascular age-related macular degeneration (AMD) treatments, assessment of the influence of study design and execution on results, and review of unanalyzed safety data in the online supplement. Methods Expert opinion. Results The CATT study supports the selection of either ranibizumab or bevacizumab for treatment of AMD based on factors other than efficacy, such as cost, because monthly administration of bevacizumab was noninferior to the reference treatment of monthly ranibizumab in improving visual acuity at 1 year. Visual acuity results for bevacizumab as needed were inconclusive for noninferiority relative to monthly administration of either drug. The secondary outcome of decrease in thickness at the foveal center as measured by time-domain optical coherence tomography significantly favored the monthly ranibizumab group vs the bevacizumab-as-needed group but is more difficult to interpret as it did not correlate with visual acuity and is less appropriate for a noninferiority design. Bevacizumab groups had a statistically higher observed risk of serious adverse events; however, scrutiny of the online supplements shows similar numbers of cardiac and neurologic events in bevacizumab and ranibizumab users. Information regarding fellow eye treatment with anti-VEGF agents was not given. Conclusions CATT provides the first level I evidence for bevacizumab in a large number of patients with neovascular AMD. The trial supports use of either drug as primary therapy and suggests that modification of monthly dosing regimens is feasible. A difference in cardiovascular safety between the 2 drugs was not apparent on inspection of the supplementary safety data.

Purpose Inhibiting mechanistic target of rapamycin (mTOR) by pharmacological or genetic approaches can extend lifespan in mammals. The kinase activity of mTOR is controlled by upstream regulatory proteins and its subcellular localization. The purpose of this study was to characterize age-related alterations and functional consequences of mTOR signaling in the postmitotic RPE cells. Methods Activity of mTOR complex 1 (mTORC1) was monitored by measuring phosphorylation status of its downstream effector protein S6, in either cultured human RPE cells or RPE explants prepared from mice at different ages. Subcellular distribution of mTOR was investigated by immunofluorescent staining of RPE culture or flatmount. The signaling of mTORC1 was modulated by either overexpression of a small guanosine triphosphatase, Ras homolog enriched in brain (Rheb), or disruption of the Ragulator complex with small interference RNA targeting p18. The effects of mTOR pathway on degradation of phagocytosed photoreceptor outer segments (POS) were determined by measuring the turnover rate of rhodopsin. Results Aged RPE cells had more lysosome-associated mTOR and had increased response to amino acid stimulation. The lysosome distribution was essential for mTORC1 function, as disruption of the Ragulator complex abolished mTORC1 activation by amino acids. Increased mTORC1 activity caused decreased rate of degradation of internalized POS in the RPE. Conclusions Aging changes the subcellular localization and function of mTOR in the RPE. Increased mTORC1 inhibits POS degradation and may further exacerbate lysosome dysfunction of aged RPE.

PURPOSE To present visual acuity (VA) and related findings from patients enrolled in one of the Submacular Surgery Trials (SST) evaluating surgical removal versus observation of subfoveal choroidal neovascularization secondary to age-related macular degeneration (SST Group N Trial). DESIGN Randomized clinical trial. PARTICIPANTS Eligible patients had age-related macular degeneration with subfoveal choroidal neovascularization, some with a classic pattern on fluorescein angiography, and best-corrected VA (BCVA) of 20/100 to 20/800 in one eye (study eye) that had received no treatment in the macula. Any contiguous blood had to account for

This cohort study compares changes in diabetic retinopathy severity after participants have received 1 and 2 years of treatment with aflibercept, bevacizumab, or ranibizumab.

PURPOSE: Experience is reported with intraoperative pharmacologic lysis of recent submacular hemorrhage with tissue plasminogen activator followed by surgical drainage of the unclotted blood in patients with retinal arterial macroaneurysms. METHODS: Nine eyes (nine patients) with a recent (≤7 days old) submacular hemorrhage involving the center of the fovea secondary to retinal arterial macroaneurysm that were managed with recombinant tissue plasminogen activator–assisted subretinal hemorrhage evacuation, including subretinal injection of tissue plasminogen activator and removal of the liquefied blood. Patients were followed for a mean 18 ± 7 months (range, 7 to 30 months). RESULTS: All nine eyes had improved final corrected visual acuity after surgery, and eight eyes (89%) attained a corrected visual acuity of 20/60 or better (mean, 20/40; range, 20/20 to 20/200). Final corrected visual acuity was limited to 20/200 in one eye. Two eyes developed a cataract that required surgery. CONCLUSIONS: Submacular surgery with tissue plasminogen activator-assisted thrombolysis achieved improved best-corrected visual acuity in eyes with recent submacular hemorrhage involving the center of the fovea associated with retinal arterial macroaneurysm.

To evaluate a tissue sealant (autologous cryoprecipitate activated with bovine thrombin) as an adjuvant in macular hole surgery.Sixty-nine patients with stage 2, 3, or 4 full-thickness macular hole were enrolled consecutively in a prospective pilot study. Anatomic closure of the macular holes with a single operation was the primary outcome. Fifty-eight patients had pre- and postoperative standardized measurements including best refracted visual acuity, reading speed, and contrast sensitivity. Group A patients (45) had primary macular holes; Group B patients (13) had recurrent macular holes or macular holes with "other" retinal pathology. Surgical technique was standardized and membrane dissections were optional.The anatomic closure rate was 80% with a minimum of 6 months follow-up. Mean improvement in visual acuity for Group A (2.9+/-0.4 lines) was significantly better than for Group B (0.8+/-0.5 lines; P = 0.008). Eyes that underwent internal limiting membrane (ILM) dissections had an anatomic closure rate of 96% (23/24), compared with 71% (32/45) in "non-ILM" cases (P = 0.034). Adverse reactions included sterile hypopyon (10%), intraretinal hemorrhage (9%), pigmentary hyperplasia (3%), and retinal detachment (3%).Tissue sealants should be evaluated as an adjuvant in macular hole surgery in a randomized clinical trial. Inflammatory reactions may occur in some patients. Internal limiting membrane dissection may improve anatomic closure rates without adversely affecting the visual acuity.

Retinal pigment epithelium (RPE) is a single layer of epithelial cells lined between the neurosensory retina and choriocapillaris. It is part of the blood-retinal barrier and is a central component of the visual phototransduction pathway. RPE cells regenerate 11-cisretinal by RPE65 isomerase and its related enzymes and chaperones (Moiseyev et al., 2006; Xue et al., 2004). They are professional phagocytes and are responsible for the clearance of daily shed photoreceptor outer segments (POS) (Young, 1967; Young & Bok, 1969). The multi-step process of phagocytosis includes receptor-mediated binding of POS to the RPE (Finnemann et al., 1997), internalization (Feng et al., 2002; Finnemann & Silverstein, 2001), transport to lysosome and degradation. The importance of RPE phagocytosis has been clearly illustrated by the Royal College of Surgeons (RCS) rats, which carry a mutation in Mertk gene (D'Cruz et al., 2000). MERTK is a membrane-associated receptor tyrosine kinase and is activated upon binding of POS to the RPE (Feng et al. 2002). In RCS rats, loss-offunction mutation of Mertk causes defects in phagocytosis and consequently these animals develop inherited retinal dystrophy and photoreceptor apoptosis (Tso et al., 1994). In addition to their roles in the visual cycle, RPE cells provide vital support for the structure and function of the outer retina. They transport ions, water and nutrients between choroidal blood supply and the retina, and synthesize melanin which absorbs light and shields the retina. RPE-produced growth factors, such as vascular endothelial growth factor (VEGF), are indispensable for the choroidal vasculature (Saint-Geniez et al., 2009).

Purpose: The purpose of this study is to assess the benefit of vitreous surgery in preventing full-thickness macular holes in patients with impending (stage 1) macular holes. Methods: A prospective randomized multicenter clinical trial was conducted on patients with full-thickness macular holes in their first eye (stage 3 or 4) and signs and symptoms of stage 1 macular holes in their fellow eye (study eye). The study eye was randomized to vitreous surgery or observation. Outcome was assessed by standardized measurement of visual acuity, detailed clinical examination, fundus photographs, and fluorescein angiography. Results: A full-thickness macular hole developed in 10 (37%) of 27 patients in the vitrectomy group compared with 14 (40%) of 35 patients randomized to observation ( P = 0.81). This difference of 3% has a 95% confidence interval of (-21%,27%). Conclusion: The study was terminated because of low recruitment. The authors were unable to prove (or disprove) the benefit of vitreous surgery in patients with stage 1 macular holes. The authors can state, however, that should a beneficial effect from vitrectomy exist, it would probably be minimal. Considering the cost and morbidity of vitreous surgery, a conservative approach for stage 1 macular hole might be appropriate.

Purpose To determine if short-term Age-Related Eye Disease Study (AREDS) antioxidant and zinc supplementation affects biomarkers of oxidative stress, possibly serving as a predictor of their efficacy. Design Prospective interventional case series. Methods Nineteen subjects, 12 with intermediate or advanced age-related macular degeneration (AMD) (AREDS categories 3 or 4) and 7 non-AMD controls, were admitted to the Vanderbilt General Clinical Research Center and placed on a controlled diet for 7 days. Antioxidant and zinc supplements were stopped 2 weeks prior to study enrollment. Dietary supplementation with 500 mg vitamin C, 400 IU vitamin E, 15 mg β-carotene, 80 mg zinc oxide, and 2 mg cupric oxide per day was instituted on study day 2. Blood was drawn on study days 2 and 7, and plasma concentrations of cysteine (Cys), cystine (CySS), glutathione (GSH), isoprostane (IsoP), and isofuran (IsoF) were determined. Results Short-term AREDS supplementation significantly lowered mean plasma levels of CySS in participants on a regulated diet ( P = .034). No significant differences were observed for Cys, GSH, IsoP, or IsoF. There were no significant differences between AMD patients and controls. Conclusions This pilot interventional study shows that a 5-day course of antioxidant and zinc supplements can modify plasma levels of CySS, suggesting that this oxidative stress biomarker could help predict how likely an individual is to benefit from AREDS supplementation. Further, CySS may be useful for the evaluation of new AMD therapies, particularly those hypothesized to affect redox status.

prospective pathological study could better describe the in- cidence of this malformation and its clinical correlates. Tina Rutar, MD Susan Huang, MD Michele Bloomer, MD J. Brooks Crawford, MD Author Affiliations: Departments of Ophthalmology (Drs Rutar, Huang, Bloomer, and Crawford) and Pediatrics (Dr Rutar), University of California, San Francisco. Correspondence: Dr Rutar, Department of Ophthalmol- ogy, Division of Pediatric Ophthalmology and Strabis- mus, University of California, San Francisco, 10 Koret Way, K 301, San Francisco, CA 94143-0730 (rutart @vision.ucsf.edu). Financial Disclosure: None reported. 1. Spencer WH. Primary neoplasms of the optic nerve and its sheaths: clinical features and current concepts of pathogenetic mechanisms. Trans Am Oph- thalmol Soc. 1972;70:490-528. 2. Margo CE, Kincaid MC. Angiomatous malformation of the retrolaminar op- tic nerve. J Pediatr Ophthalmol Strabismus. 1988;25(1):37-39. Letter From the DSMC Regarding a Clinical Trial of Lutein in Patients With Retinitis Pigmentosa W e, the members of the Data Safety Monitor- ing Committee (DSMC) for Berson and col- league’s clinical trial of lutein in patients with retinitis pigmentosa who are receiving vitamin A, 1 share many of the concerns Massof and Fishman 2 expressed in their editorial. We served as the DSMC from 2002 through 2009. We reviewed the protocol, the statistical analysis plan, and the emerging data. We were im- pressed by the conduct of the trial, especially the excel- lent patient retention and adherence to the protocol. We reviewed and approved the manuscript before the authors submitted it for publication; however, we note some substantive changes made between the time of our review and the time of publication. For example, the ar- ticle’s new section on “Conclusions” is not consistent with our interpretation of the data, which emphasizes that the trial showed no effect of lutein on the primary outcome. We have carefully evaluated the data from the trial and view that the authors’ conclusion and the section on “Ap- plication to Clinical Practice” overstate the strength of evidence for the use of lutein. We wish to remind the clini- cal community that the evidence adduced for benefit comes from one of several secondary outcomes in a trial in which the primary outcome showed no evidence of benefit (the P value for the effect on Humphrey field ana- lyzer 30-2 field, dB/y was .66). Janet Wittes, PhD Michael B. Gorin, MD, PhD Susan T. Mayne, PhD Cynthia S. McCarthy, DHCE, MA Paul Sternberg Jr, MD Michael Wall, MD Author Affiliations: Statistics Collaborative, Inc, Wash- ington, DC (Dr Wittes); Jules Stein Eye Institute- University of California, Los Angeles (Dr Gorin); De- partment of Epidemiology and Public Health, Yale University, New Haven, Connecticut (Dr Mayne); Pri- vate consultant, Glenshaw, Pennsylvania (Ms McCarthy); Vanderbilt University Medical Center, Nashville, Ten- nessee (Dr Sternberg); and University of Iowa College of Medicine, Iowa City (Dr Wall). Correspondence: Dr Wittes, Statistics Collaborative, Inc, 1625 Massachusetts Ave NW, Ste 600, Washington, DC 20036 (janet@statcollab.com). Financial Disclosure: None reported. 1. Berson EL, Rosner B, Sandberg MA, et al. Clinical trial of lutein in patients with retinitis pigmentosa receiving vitamin A. Arch Ophthalmol. 2010;128 2. Massof RW, Fishman GA. How strong is the evidence that nutritional supple- ments slow the progression of retinitis pigmentosa [editorial]? Arch Ophthalmol. In reply The DSMC acknowledges approval of our draft manuscript. The publication 1 contained what we regard as minor adjust- ments requested by the journal, including a “Conclusion” sec- tion in the “Abstract” that restated results. The “Application to Clinical Practice” section was in the draft manuscript ap- proved by the DSMC. Throughout the publication we stated that the treatment effect of lutein was observed only on the secondary endpoint of midperipheral field sensitivity. The DSMC suggests that if significant differences be- tween the treatment groups are not seen with respect to the primary endpoint, then the results of the trial are negative and should have little or no affect on clinical practice. Pre- cedent exists for modifying practice based on results seen with secondary endpoints and subgroup analyses. 2,3 In the Physicians’ Health Study evaluating aspirin, the paucity of cardiovascular deaths led to revision of the primary end- point to include nonfatal myocardial infarction; aspirin was then found effective in preventing primary heart attacks. 2 The Women’s Health Study assessed aspirin’s efficacy in pre- venting heart attack in women older than 45 years. Al- though results of the analysis of the entire study cohort were negative, subgroup analyses showed that aspirin reduced the risk of major cardiovascular events, ischemic stroke, and myocardial infarction in women older than 65 years. 3 Similarly, results of the lutein trial should not be con- sidered negative simply because the beneficial effect was based on a secondary endpoint. A significant benefit of lutein on preserving midperipheral field sensitivity was observed in randomized comparisons using both parametric (P=.05) and nonparametric analyses (P = .03). Furthermore, observa- tional analyses showed that those with the highest serum lutein level and those with the highest increase in intrareti- nal macular pigment optical density (ie, a measure of in- traretinal lutein) had the least decline in midperipheral field sensitivity (P=.01 and P=.006, respectively). 1 Based on our results, 1,4,5 we reaffirm that most adults with typical retinitis pigmentosa should take 15 000 IU/d of vi- tamin A palmitate. They should avoid high-dose vitamin E supplementation. 4 Adults who start taking vitamin A for the first time should also take 1200 mg/d of docosahexaenoic acid (DHA) for 2 years; after 2 years, they should stop tak- ARCH OPHTHALMOL / VOL 129 (NO. 5), MAY 2011 WWW.ARCHOPHTHALMOL.COM ©2011 American Medical Association. All rights reserved. Downloaded From: http://jamanetwork.com/pdfaccess.ashx?url=/data/journals/ophth/10240/ by a University of California - Los Angeles User on 04/06/2017

Objective To describe the clinical courses of patients who received intravitreal injections of highly concentrated amphotericin B deoxycholate for suspected fungal endophthalmitis. Methods Retrospective medical record review of 3 cases of intraocular toxicity from highly concentrated amphotericin B. Results The first patient developed posttraumatic endophthalmitis and received an undiluted dose (500 μg) of amphotericin B. He developed severe intraocular inflammation and required a pars plana lensectomy, vitrectomy, and scleral buckle after developing a cataract and retinal detachment. Six years later, his visual acuity stabilized at 20/30. The second patient developed endogenous endophthalmitis and was treated with 5 intravitreal injections of amphotericin B and underwent 3 surgical procedures. The surgeon later discovered that the patient had received 55 μg of amphotericin B during the second injection. Three months after the injection, the patient's visual acuity was 20/60. The third patient developed chronic postoperative endophthalmitis following cataract extraction. He received 160 μg of amphotericin B and was immediately treated with a vitreous washout. Two years later, his visual acuity improved to 20/30. The vitreous culture results were negative in each case. A key finding was that the amphotericin B solution appeared to be yellow instead of nearly colorless. Conclusions We present 3 cases of intraocular toxicity from highly concentrated amphotericin B. In every case, the overly concentrated amphotericin B solution was yellow in color. Although severe noninfectious panophthalmitis resulted in every case, the visual acuity outcomes were good. Physicians should examine the color of amphotericin B solution prior to intraocular administration. If the solution appears to be yellow, the medication should not be injected.

Advanced age is a major risk factor for a number of vision-threatening eye diseases, including cataract, glaucoma, diabetic retinopathy, and age-related macular degeneration (AMD). Although the mechanistic link between aging and AMD remains elusive, age-dependent degeneration of the RPE is a hallmark pathologic change of AMD, especially in the atrophic form.1–3 The RPE is part of the blood-retina barrier and is responsible for nutrient support and metabolism.4 With aging, the RPE monolayer loses cells, whereas the remaining cells are subjected to increased metabolic demand.5,6 Decreased mitochondrial function and compromised antioxidant capacity are evident in the aged RPE.7 The production of neurotrophic and angiogenic factors secreted by the RPE shows age-related changes.8,9 Recently, it has been shown that the RPE/choroid complex becomes immunoreactive with aging10; this may be associated with chronic inflammation and abnormal immune responses under certain genetically susceptible backgrounds such as complement factor H mutation. The molecular mechanisms underlying these age-related changes are largely unknown. The process of aging is determined by a genetically programmed molecular clock and is subjected to regulation by multiple pathways in which TOR-mediated signaling is one of the central players.11,12 TOR is a large serine/threonine protein kinase that integrates upstream signals from nutrients, growth factors, and energy levels to control cell growth and proliferation.13,14 In mammals, mTOR resides in two distinct signaling complexes (mTORC): mTORC1 (mTOR/Raptor/GβL) and mTORC2 (mTOR/Rictor/GβL/SIN1). The rapamycin-sensitive mTORC1 regulates translation and protein synthesis largely through the downstream effector proteins S6K and 4E-BP1.15 The phosphorylation status of these two proteins and substrate S6, further downstream, are commonly used as indicators of mTORC1 activity. In contrast to mTORC1, mTORC2 is resistant to short-term exposure to rapamycin16 and is a principal kinase responsible for the phosphorylation of Akt at Ser473.17–19 Negative regulation of aging by TOR signaling has been firmly established in various invertebrate models.12 Very recently, it has been shown that knocking out S6K increases life span in mice.20 Consistently, reduced mTOR/S6K activity has been observed in mice with extended longevity.21 However, whether mTOR regulates tissue-specific degeneration of the retina has not been well studied. In the present study, we have performed an initial characterization of the mTOR pathway in both immortalized ARPE-19 cells and human RPE cells isolated from donor eye tissues. Our results demonstrate that the RPE cells contain mTOR complexes that can be activated by various upstream stimuli. Cultured primary RPE cells entered replicative senescence after serial passages, and downregulation of mTORC1 signaling relieved senescence-associated phenotypical changes. Furthermore, we found that the response of mTORC1 to nutrient signal was upregulated in the aged RPE cells. Our data indicate that changes in the mTOR-related signaling network will likely contribute to degeneration of the RPE.

Ten years ago WormBase^1^ started as a repository for sequence data for the model organism Caenorhabditis elegans and has since striven to include the curation of all genetic and molecular data published for this nematode. With a publication rate in the C. elegans field of approximately 800 papers per year, WormBase (WB) has the opportunity to include information from every paper published. Currently there are ~11,000 full text research papers (mid-1970's to the present) downloaded into the WB curation database, from which over 27 data types (i.e. genetic interactions, transgene objects, gene expression patterns, mutant phenotypes etc.) are extracted by curators. Textpresso^2^ is an open source text-mining tool capable of rapid searches for keywords, as well as concepts, from the full text of research papers. Curators at WB use Textpresso on a daily basis for many aspects of literature curation, from simple keyword searches to semi- or fully automated entity and fact extraction, which feed into curation pipelines or directly into the curation database itself. In addition, Textpresso greatly aids prioritization of literature curation by retrieving papers based on their full contents rather than solely on their abstracts. Such retrievable contents can range from the very particular (such as a gene simply being mentioned in the Materials and Methods section of a paper) to the complex (such as molecular functions that involve cellular components). As WB expands to incorporate the genomes of other nematodes, we will be working with Textpresso developers to set up a library of literature for related nematodes. We expect Textpresso to be crucial for most efficiently directing our efforts in literature curation, and for most quickly providing data to users searching the literature. In this workshop we will show how we use Textpresso in our curation pipeline to help with literature queries, to prioritize our workflow, and to automate data and fact extraction. 1 "WormBase":http://www.wormbase.org 2 "Textpresso":http://www.textpresso.org

The objective of this study was to determine if MTND2*LHON4917G (4917G), a specific non-synonymous polymorphism in the mitochondrial genome previously associated with neurodegenerative phenotypes, is associated with increased risk for age-related macular degeneration (AMD). A preliminary study of 393 individuals (293 cases and 100 controls) ascertained at Vanderbilt revealed an increased occurrence of 4917G in cases compared to controls (15.4% vs.9.0%, p = 0.11). Since there was a significant age difference between cases and controls in this initial analysis, we extended the study by selecting Caucasian pairs matched at the exact age at examination. From the 1547 individuals in the Vanderbilt/Duke AMD population association study (including 157 in the preliminary study), we were able to match 560 (280 cases and 280 unaffected) on exact age at examination. This study population was genotyped for 4917G plus specific AMD-associated nuclear genome polymorphisms in CFH, LOC387715 and ApoE. Following adjustment for the listed nuclear genome polymorphisms, 4917G independently predicts the presence of AMD (OR = 2.16, 95%CI 1.20–3.91, p = 0.01). In conclusion, a specific mitochondrial polymorphism previously implicated in other neurodegenerative phenotypes (4917G) appears to convey risk for AMD independent of recently discovered nuclear DNA polymorphisms.

Retinitis pigmentosa (RP) is a group of genetically and clinically heterogeneous retinal diseases and a common cause of blindness. Among the 12 autosomal dominant RP (adRP) genes identified, four encode ubiquitously expressed proteins involved in pre-mRNA splicing, demonstrating the important role that pre-mRNA splicing plays in the pathogenesis of retinal degeneration. This review focuses on recent progress in identifying adRP mutations in genes encoding pre-mRNA splicing factors and the potential underlying molecular mechanisms.

Purpose To determine the effects of zinc supplementation on plasma thiol metabolites and their redox status in a cohort of patients with age-related macular degeneration (AMD). Design Randomized clinical trial that evaluated the effects of high doses of zinc and antioxidants on plasma biomarkers of oxidative stress. Methods This was an ancillary study of the Age-Related Eye Disease Study (AREDS). Subjects with AMD were randomized to one of four treatment groups: (1) antioxidants (vitamin C, 500 mg; vitamin E, 400 IU; and beta carotene, 15 mg), (2) zinc (80 mg zinc oxide, 2 mg cupric oxide), (3) antioxidants plus zinc, or (4) placebo. At 20 and 80 months after randomization, blood specimens were collected and analyzed for glutathione (GSH), oxidized glutathione (GSSG), cysteine (Cys), and cystine (CySS). Results Although zinc supplementation had no apparent effect on plasma thiol/disulfide redox status at the first blood draw, the group of patients receiving zinc supplementation at the second blood draw had significantly less CySS compared with those not receiving zinc (54.9 vs 64.1 μM; P = .01). There was a time-dependent oxidation of the plasma GHS pool and was not affected by zinc supplementation. Conclusions Because increased CySS level is associated with aging, oxidative stress, and age-related diseases, the apparent prevention of increased CySS by zinc supplementation warrants additional investigation.

Purpose To determine the molecular mechanisms underlying the protective effects of zinc against oxidative stress in cultured retinal pigment epithelial (RPE) cells. Methods Cultured ARPE-19 cells were treated with different concentrations of zinc for various times. Cellular glutathione (GSH) and glutathione disulfide (GSSG) levels were measured by high-performance liquid chromatography (HPLC). Glutamate-cysteine ligase (GCL) expression was measured by quantitative reverse transcription-PCR (RT-PCR). Nuclear factor erythroid2-related factor (Nrf2) activity was measured in a dual luciferase assay after transfection of reporter plasmids containing the antioxidant response element (ARE). The small interference (si)RNA approach was used to knock down the expression of Nrf2. Results Zinc significantly increased GSH levels in ARPE-19 cells through induction of the de novo synthesis pathway. At 150 microM, zinc increased the GSH level by 70%. At similar concentrations, zinc upregulated the mRNA level of GCL and activated the ARE-Nrf2 pathway. The effects of zinc on ARE activation and GSH synthesis were inhibited by knockdown of Nrf2 expression using the siRNA approach. Conclusions Induction of the ARE-Nrf2 pathway by zinc provides powerful and prolonged antioxidation and detoxification that may explain the beneficial effects of zinc observed in the treatment of age-related macular degeneration (AMD).

Purpose To present best-corrected visual acuity (BCVA) findings and other clinical outcomes from eyes of patients enrolled in one of the Submacular Surgery Trials (SST) evaluating surgical removal versus observation of predominantly hemorrhagic subfoveal choroidal neovascularization (CNV) associated with age-related macular degeneration. Design Randomized clinical trial (SST Group B Trial). Participants Eligible patients had subfoveal choroidal neovascular lesions greater than 3.5 disk areas (8.9 mm2) composed of at least 50% blood (either blood or CNV underlying the center of the foveal avascular zone) and BCVA of 20/100 to light perception in the study eye. Intervention Patients were assigned randomly at time of enrollment to observation or surgical removal of blood and any associated CNV. Main outcome measure A successful outcome was defined a priori as either improvement in visual acuity (VA), no change in VA, or a decline in VA of no more than 1 line (7 letters) from baseline to the 24-month examination based on an intent-to-treat analysis. Results Of 336 patients enrolled, 168 were assigned to each treatment arm; treatment arms were balanced by baseline characteristics. Of 1501 expected examinations 3 months through 36 months after baseline, 1370 (91%) were performed. Loss of > or =2 lines (> or =8 letters) of VA occurred in 56% of surgery eyes, versus 59% of observation eyes examined at 24 months. Although severe loss of VA was not the primary outcome of interest, surgery more often prevented such loss: 36% in the observation arm versus 21% in the surgery arm at the 24-month examination (chi2 P = 0.004). Of initially phakic eyes, the cumulative percentage that had undergone cataract surgery by 24 months was 44% in the surgery arm, compared with 6% in the observation arm. Twenty-seven eyes (16%) in the surgical arm, compared with 3 eyes (2%) in the observation arm, had a rhegmatogenous retinal detachment (RD). Conclusions Submacular surgery as performed in the SST Group B Trial did not increase the chance of stable or improved VA (the primary outcome of interest) and was associated with a high risk of rhegmatogenous RD, but did reduce the risk of severe VA loss in comparison with observation. This article contains additional online-only material available at http://www.ophsource.com/periodicals/ophtha.

Purpose Glutathione (GSH) plays a key role in protection against oxidative stress. L-cysteine is thought to be rate-limiting for the synthesis of glutathione (GSH) and therefore may be a critical component in protection against oxidative stress. The purpose of this study was to investigate the role of L-cysteine in GSH metabolism and oxidative stress in human retinal pigment epithelial (hRPE) cells. Methods To identify the role of cysteine in GSH metabolism in hRPE cells, a strategy of cysteine starvation was used to determine (1) GSH levels and oxidative stress by measuring reactive oxygen species (ROS) production, (2) mitochondrial membrane potential (Deltapsim) and mitochondrial ultrastructure by using conventional electron microscopy (EM), and (3) indices of cell viability and apoptosis including analysis of cells containing hypodiploid amounts of DNA. Results Cysteine starvation resulted in approximately a 95% decrease in GSH concentrations over 24 hours. The GSH Nernst redox potential (Eh) increased approximately 70 mV (Eh=-248 +/- 2.9 mV in control cells compared with Eh=-179 +/- 2.0 mV in cysteine-starved cells) indicating significant intracellular oxidation. Cysteine starvation increased the production of ROS by mitochondrial respiratory complex III (cytochrome bc1), determined using a pharmacological strategy that resulted in the loss of Deltapsim and cell death. The loss of Deltapsim and cell death was prevented with bongkrekic acid, an inhibitor of the adenine nucleotide translocator inhibitor, suggesting activation of the mitochondrial permeability transition (MPT). This conclusion was further supported by electron microscopic studies that showed significant mitochondrial swelling, a hallmark of MPT activation. Cell death was not prevented with either the broad-spectrum caspase inhibitor zVADfmk or the caspase 3-specific inhibitor DEVD-CHO, indicating that cytochrome bc1-mediated ROS production results in the MPT and necrosis. Conclusions These results show that cysteine is a required component for normal GSH metabolism and protection against oxidative stress in hRPE cells.

To determine whether oltipraz (4-methyl-5-pyrazinyl-3H-1,2-dithiole-3-thione) protects against oxidative injury in cultured human retinal pigment epithelial (hRPE) cells.Primary cultured hRPE cells were incubated with various concentrations of oltipraz followed by treatment with the chemical oxidant tert-butylhydroperoxide (tBH). Cell viability was assessed by release of lactate dehydrogenase (LDH) and cleavage of WST-1. Intracellular and mitochondrial levels of glutathione (GSH) were measured by HPLC. Glutathione S-transferase (GST), NADPH-quinone reductase (NQR), and glutathione peroxidase (GPx) were measured by specific enzyme activity assays.Treatment of hRPE cells with oltipraz inhibited tBH-induced cell death in a concentration-dependent manner with significant inhibition at 50 micro M. Olitpraz (50 micro M) increased GSH levels in hRPE cells by approximately 18% and in hRPE mitochondrial fractions by approximately 50% after 24 hours of exposure. Treatment with oltipraz increased GST and NQR activities by approximately 21% and 11%, respectively.Oltipraz protects hRPE cells against tBH induced injury. The mechanism of protection is likely to include increased cellular and mitochondrial GSH levels and induction of detoxification enzymes, including GST and NQR. Dietary supplementation with oltipraz or other dithiolethiones may help protect the hRPE against oxidant induced injury.

To determine whether long-term cultured nondividing human retinal pigment epithelial (hRPE) cells are sensitive to oxidant-induced apoptosis and whether the Fas pathway is involved in the process.Confluent hRPE cells were maintained for 2 to 3 months in the basal medium (DMEM containing 2% fetal bovine serum) with one medium change per week. DNA synthesis was measured by incorporation of bromodeoxyuridine (BrdU) and the cell cycle was analyzed by flow cytometry. Intracellular glutathione (GSH) and glutathione disulfide (GSSG) were measured by HPLC. Apoptosis was triggered with the oxidant tert-butylhydroperoxide (tBH), recombinant soluble Fas ligand (sFasL), or agonistic anti-Fas antibody (CH-11). Cell viability was assessed by tetrazolium salt (WST-1) assay, and apoptosis was determined by measuring DNA cleavage or phosphatidylserine exposure. FasL and Fas proteins were detected by flow cytometry and Western blot. FasL and Fas transcripts were analyzed by RT-PCR.After incubation in basal medium for more than 2 months, hRPE cells were largely nondividing and accumulated autofluorescent granules identified by electron microscopy to be lysosomes. Compared with proliferating hRPE cells, the nondividing cells had lower intracellular GSH, GSSG, and GSH/GSSG and a more oxidized redox potential (E(h)). Downregulation of Fas but upregulation of FasL was observed in these cells. The nondividing hRPE cells appeared more susceptible to tBH-induced apoptosis. Similar to proliferating hRPE cells, the apoptosis induced by tBH was preceded by induction of FasL, and antioxidants inhibited both FasL increase and apoptosis. Apoptosis was also inhibited with the antagonistic anti-Fas antibody ZB4. However, the nondividing hRPE cells had decreased sensitivity to apoptosis triggered by sFasL or CH-11.Long-term hRPE culture created cells that were nondividing and accumulated autofluorescent granules. The increased sensitivity to tBH-induced apoptosis in these cells was associated with intracellular oxidation and upregulation of FasL. These results suggest that an increase in FasL may contribute to the vulnerability of nondividing hRPE cells to oxidant-induced apoptosis.