The Age-Related Eye Disease Study 2 (AREDS2) Research Group * IMPORTANCE The Age-Related Eye Disease Study (AREDS) formulation for the treatment of age-related macular degeneration (AMD) contains vitamin C, vitamin E, beta carotene, and zinc with copper. The Age-Related Eye Disease Study 2 (AREDS2) assessed the value of substituting lutein/zeaxanthin in the AREDS formulation because of the demonstrated risk for lung cancer from beta carotene in smokers and former smokers and because lutein and zeaxanthin are important components in the retina.OBJECTIVE To further examine the effect of lutein/zeaxanthin supplementation on progression to late AMD. DESIGN, SETTING, PARTICIPANTSThe Age-Related Eye Disease Study 2 is a multicenter, double-masked randomized trial of 4203 participants, aged 50 to 85 years, at risk for developing late AMD; 66% of patients had bilateral large drusen and 34% had large drusen and late AMD in 1 eye. INTERVENTIONSIn addition to taking the original or a variation of the AREDS supplement, participants were randomly assigned in a factorial design to 1 of the following 4 groups: placebo; lutein/zeaxanthin, 10 mg/2 mg; omega-3 long-chain polyunsaturated fatty 3 acids, 1.0 g; or the combination. MAIN OUTCOMES AND MEASURES Documented development of late AMD by central, masked grading of annual retinal photographs or by treatment history.RESULTS In exploratory analysis of lutein/zeaxanthin vs no lutein/zeaxanthin, the hazard ratio of the development of late AMD was 0.90 (95% CI, 0.82-0.99; P = .04). Exploratory analyses of direct comparison of lutein/zeaxanthin vs beta carotene showed hazard ratios of 0.82 (95% CI, 0.69-0.96; P = .02) for development of late AMD, 0.78 (95% CI, 0.64-0.94; P = .01) for development of neovascular AMD, and 0.94 (95% CI, 0.70-1.26; P = .67) for development of central geographic atrophy. In analyses restricted to eyes with bilateral large drusen at baseline, the direct comparison of lutein/zeaxanthin vs beta carotene showed hazard ratios of 0.76 (95% CI, 0.61-0.96; P = .02) for progression to late AMD, 0.65 (95% CI, 0.49-0.85; P = .002) for neovascular AMD, and 0.98 (95% CI, 0.69-1.39; P = .91) for central geographic atrophy. CONCLUSION AND RELEVANCEThe totality of evidence on beneficial and adverse effects from AREDS2 and other studies suggests that lutein/zeaxanthin could be more appropriate than beta carotene in the AREDS-type supplements. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00345176

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IMPORTANCE A unique pigmentary maculopathy was recently described in 6 patients with long-term exposure to pentosan polysulfate sodium (PPS), a long-standing oral therapy for interstitial cystitis.OBJECTIVE To characterize the exposure characteristics and clinical manifestations of PPS-associated maculopathy. DESIGN, SETTING, AND PARTICIPANTSIn this multi-institutional case series, medical records of patients who exhibited the characteristic maculopathy in the setting of prior PPS exposure were retrospectively reviewed.

Global Retinoblastoma Study Group IMPORTANCE Early diagnosis of retinoblastoma, the most common intraocular cancer, can save both a child's life and vision. However, anecdotal evidence suggests that many children across the world are diagnosed late. To our knowledge, the clinical presentation of retinoblastoma has never been assessed on a global scale.OBJECTIVES To report the retinoblastoma stage at diagnosis in patients across the world during a single year, to investigate associations between clinical variables and national income level, and to investigate risk factors for advanced disease at diagnosis. DESIGN, SETTING, AND PARTICIPANTSA total of 278 retinoblastoma treatment centers were recruited from June 2017 through December 2018 to participate in a cross-sectional analysis of treatment-naive patients with retinoblastoma who were diagnosed in 2017. MAIN OUTCOMES AND MEASURESAge at presentation, proportion of familial history of retinoblastoma, and tumor stage and metastasis. RESULTSThe cohort included 4351 new patients from 153 countries; the median age at diagnosis was 30.5 (interquartile range, 18.3-45.9) months, and 1976 patients (45.4%) were female. Most patients (n = 3685 [84.7%]) were from low-and middle-income countries (LMICs). Globally, the most common indication for referral was leukocoria (n = 2638 [62.8%]), followed by strabismus (n = 429 [10.2%]) and proptosis (n = 309 [7.4%]). Patients from high-income countries (HICs) were diagnosed at a median age of 14.1 months, with 656 of 666 (98.5%) patients having intraocular retinoblastoma and 2 (0.3%) having metastasis. Patients from low-income countries were diagnosed at a median age of 30.5 months, with 256 of 521 (49.1%) having extraocular retinoblastoma and 94 of 498 (18.9%) having metastasis. Lower national income level was associated with older presentation age, higher proportion of locally advanced disease and distant metastasis, and smaller proportion of familial history of retinoblastoma. Advanced disease at diagnosis was more common in LMICs even after adjusting for age (odds ratio for low-income countries vs upper-middle-income countries and HICs, 17.92 [95% CI,, and for lower-middle-income countries vs upper-middle-income countries and HICs, 5.74 [95% CI,). CONCLUSIONS AND RELEVANCEThis study is estimated to have included more than half of all new retinoblastoma cases worldwide in 2017. Children from LMICs, where the main global retinoblastoma burden lies, presented at an older age with more advanced disease and demonstrated a smaller proportion of familial history of retinoblastoma, likely because many do not reach a childbearing age. Given that retinoblastoma is curable, these data are concerning and mandate intervention at national and international levels. Further studies are needed to investigate factors, other than age at presentation, that may be associated with advanced disease in LMICs.

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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.

Age-related changes in the skeleton often lead to an increase in the susceptibility of bone to fracture. The purpose of this study was to determine whether differences in material properties between the osteonal and interstitial regions of bone have an effect on bone fracture properties. Parameters such as longitudinal fracture toughness, transverse fracture toughness, porosity, interstitial microhardness, osteonal microhardness, bone density, and weight fractions of the mineral and organic phases of bone were examined as a function of age using female baboon femurs. With increasing age, the longitudinal fracture toughness decreased significantly as did transverse fracture toughness, whereas the interstitial microhardness increased. However, no significant differences in the other parameters were observed as a function of age. Using the ratio of interstitial microhardness to osteonal microhardness as a measure of the differences in the material properties in these two regions, correlation analysis revealed that the longitudinal fracture toughness of bone has a significant correlation with the microhardness ratio. Localized differences in material properties between osteonal and interstitial regions of bone increase with age; such differences may result in high stress concentrations at cement lines and facilitate longitudinal crack propagation.

Purpose: To evaluate the efficacy of a single intravitreal injection of rAAV2/2-ND4 in subjects with visual loss from Leber hereditary optic neuropathy (LHON).Design: RESCUE is a multicenter, randomized, double-masked, sham-controlled, phase 3 clinical trial.Participants: Subjects with the m.11778G>A mitochondrial DNA mutation and vision loss 6 months from onset in 1 or both eyes were included.Methods: Each subject's right eye was randomly assigned (1:1) to treatment with rAAV2/2-ND4 (single injection of 9 Â 10 10 viral genomes in 90 ml) or to sham injection. The left eye received the treatment not allocated to the right eye. Main Outcome Measures: The primary end point was the difference of the change from baseline in bestcorrected visual acuity (BCVA) between rAAV2/2-ND4etreated and sham-treated eyes at week 48. Other outcome measures included contrast sensitivity, Humphrey visual field perimetry, retinal anatomic measures, and quality of life. Follow-up extended to week 96.Results: Efficacy analysis included 38 subjects. Mean age was 36.8 years, and 82% were male. Mean duration of vision loss at time of treatment was 3.6 months and 3.9 months in the rAAV2/2-ND4etreated eyes and sham-treated eyes, respectively. Mean baseline logarithm of the minimum angle of resolution (logMAR) BCVA (standard deviation) was 1.31 (0.52) in rAAV2/2-ND4etreated eyes and 1.26 (0.62) in sham-treated eyes, with a range from À0.20 to 2.51. At week 48, the difference of the change in BCVA from baseline between rAAV2/2-ND4etreated and sham-treated eyes was À0.01 logMAR (P ¼ 0.89); the primary end point of a À0.3 logMAR (15-letter) difference was not met. The mean BCVA for both groups deteriorated over the initial weeks, reaching the worst levels at week 24, followed by a plateau phase until week 48, and then an improvement of þ10 and þ9 Early Treatment Diabetic Retinopathy Study letters equivalent from the plateau level in the rAAV2/2-ND4etreated and sham-treated eyes, respectively.Conclusions: At 96 weeks after unilateral injection of rAAV2/2-ND4, LHON subjects carrying the m.11778G>A mutation treated within 6 months after vision loss achieved comparable visual outcomes in the injected and uninjected eyes.