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Background: Investigate retinal fluid changes via a novel deep-learning algorithm in real-world patients receiving faricimab for the treatment of neovascular age-related macular degeneration (nAMD)., Methods: Multicenter, retrospective chart review and optical coherence tomography (OCT) image upload from participating sites was conducted on patients treated with faricimab for nAMD from February 2022 to January 2024. The Notal OCT Analyzer (NOA) algorithm provided intraretinal, subretinal and total retinal fluid for each scan. Results were segregated based on treatment history and fluid compartments, allowing for multiple cross-sections of evaluation., Results: A total of 521 eyes were included at baseline. The previous treatments prior to faricimab were aflibercept, ranibizumab, bevacizumab, or treatment-naive for 52.3%, 21.0%, 13.3%, and 11.2% of the eyes, respectively. Of all 521 eyes, 49.9% demonstrated fluid reduction after one injection of faricimab. The mean fluid reduction after one injection was -60.7nL. The proportion of eyes that saw reduction in fluid compared to baseline after second, third, fourth and fifth faricimab injections were 54.4%, 51.9%, 51.4% and 52.2%, respectively. The mean (SD) retreatment interval after second, third, fourth and fifth faricimab injection were 53.4 (34.3), 56.6 (36.0), 57.1 (35.3) and 61.5 (40.2) days, respectively., Conclusion: Deep-learning algorithms provide a novel tool for evaluating precise quantification of retinal fluid after treatment of nAMD with faricimab. Faricimab demonstrates reduction of retinal fluid in multiple groups after just one injection and sustains this response after multiple treatments, along with providing increases in treatment intervals between subsequent injections., Competing Interests: Competing interests: AAA reports other from REGENXBIO INC, outside the submitted work; paid summer internship. AMK reports personal fees from AbbVie, grants and personal fees from Adverum Biotechnologies, personal fees from Alcon, personal fees from Amgen, personal fees from Annexin, personal fees from Annexon, grants and personal fees from Apellis Pharmaceuticals, grants, financial interest, and personal fees from Aviceda Therapeutics, personal fees from Beacon Therapeutics, personal fees from Clearside Biomedical, personal fees from Complement Therapeutics, grants and personal fees from Genentech, grants and personal fees from Gyroscope Therapeutics, personal fees from i-Lumen Scientific, grants and personal fees from Iveric Bio, grants and personal fees from Janssen Pharmaceuticals, grants from personal fees from Kodiak Sciences, personal fees from Kriya Therapeutics, personal fees from Nanoscope, personal fees from Novartis, grants and personal fees from Ocular Therapeutix, grants, financial interest, and personal fees from Oculis, personal fees from Ocuphire, grants and personal fees from OcuTerra, personal fees from Olive Biopharma, grants, financial interest and personal fees from Opthea, grants and personal fees from Oxular, grants and personal fees from Oxurion, personal fees from Perfuse, personal fees from Ray Therapeutics, financial interest and personal fees from Recens Medical, personal fees from Regeneron Pharmaceuticals, grants, financial interest, and personal fees from Regenexbio, personal fees from Revive, financial interest and personal fees from RevOpsis, grants and personal fees from Roche, personal fees from Sanofi, personal fees from Stealth BioTherapeutics, personal fees from Thea Pharma, grants and personal fees from Unity Biotechnology, grants from personal fees from Vanotech, financial interest and personal fees from Vial, grants from Aviceda, grants from Alexion, grants from 4DMT, grants from Eyepoint, grants from Exegenesis, grants from Neurotech, financial interest from PolyPhotonix. Ms. HK reports other from Genentech, outside the submitted work; paid summer internship. EL reports employment with Notal Vision. Mr. Khanani has nothing to disclose. OM has nothing to disclose. Ms. Khanani has nothing to disclose. Ms. Khan has nothing to disclose. GMG reports personal fees from REGENXBIO. Mr. Graff has nothing to disclose. AMA reports personal fees from Genentech, outside the submitted work. DRPA reports personal fees and other from ACELYRIN, personal fees from ALCON, personal tees and other from ALIMERA SCIENCES, personal fees and other from ALLERGAN/ABBVIE, personal fees from BAUSCH + LOMB, personal fees from BAYER, personal fees and other from BOEHRINGER INGELHEIM, personal fees, non-financial support and other from CITRUS THERAPEUTICS, personal fees, non-financial support and other from CLINICAL TRIALS NETWORK, personal fees and other from EYEPOINT PHARMACEUTICALS, personal fees and other from GENENTECH, personal fees and other from GYROSCOPE THERAPEUTICS, personal fees and other from NOVARTIS, personal fees from OCUGEN, personal fees and other from OPTHEA, personal fees from REGENERON, personal fees and other from REGENXBIO, personal fees and other from ROCHE, personal fees and other from SAMSARA VISION, personal fees from SPHERIX CONSULTING GROUP, outside the submitted work. MRB reports personal fees from Alcon, personal fees from Allegro, personal fees from Allergan, personal fees from Alimera, personal fees from Bausch & Lomb, grants and personal fees from Clearside Biomedical, grants and personal fees from EyePoint Pharmaceuticals, grants and personal fees from Kodiak Sciences, grants and personal fees from Genentech, grants and personal fees from Novartis, other from NeuBase, grants and personal fees from Ocular Therapeutix, grants and other from Oxurion, grants and personal fees from RegenxBio, grants and personal fees from Adverum Biotechnologies, personal fees from Regeneron, grants and personal fees from CalciMedica, personal fees from Palatin Technologies, personal fees from AbbVie Inc, grants from Annexon Biosciences, personal fees from Apellis, personal fees from Arctic Vision, personal fees from Biogen, personal fees from Coherus Biosciences, grants from Gemini Therapetucis, grants from Gyroscope Therapeutics, grants from Oxular, grants from Oculis, grants and personal fees from Opthea, personal fees from Outlook Therapeutics, grants from ReNeuron, personal fees and other from RevOpsis Therapeutics, grants from Ribomic, personal fees from Roche, grants and personal fees from Stealth Biotherapeutics, grants from Unity Biotechnology, personal fees from Astellas, personal fees from Cencora, personal fees from Biocryst, personal fees from Celltrion, grants from EyeBio, grants and personal fees from Janssen, grants from Kanghong/Vanotech, personal fees from Neurotech, grants from Perfuse, outside the submitted work. GC reports personal fees from Nidek. Dr Graff reports grants and personal fees from Genentech, grants and personal fees from Roche, grants and personal fees from RegenxBio, grants from Ocular Therapeutix, grants from Kyowa Kirin, personal fees from Hi-Health, personal fees from Alimera, personal fees from Regeneron, personal fees from IvericBio. SJH has nothing to disclose. JSN reports grants from AbbVie, personal fees from Alcon, grants from Alexion, grants and personal fees from Apellis, grants and personal fees from Astellas, grants from Bayer, personal fees from Bausch and Lomb, grants from Clearside Biomedical, grants and personal fees from Genentech/Roche, grants from Gyroscope Therapeutics, grants from Novartis, grants from NovoNordisk, grants from Ocular Therapeutics, grants and personal fees from Regeneron, grants from RegenexBio. VSS reports grants and personal fees from Genentech, grants and personal fees from Alimera, grants and personal fees from Novartis, grants and personal fees from Iveric Bio, grants and personal fees from Regeneron, grants from Gyroscope, grants from RegenXBio, grants from Chengdu Kanghong, grants from NGM Biopharmaceuticals, grants from SamChungDang, grants from Sandoz, grants from Alkahest, grants and personal fees from Apellis, grants from EyePoint, grants from Oxurion, grants from 4D Molecular Therapeutics, grants from Ashvattha Therapeutics, grants from NGM Biopharmaceuticals, grants from Olix Pharmaceuticals, grants from Janssen, from OcuTerra, outside the submitted work. SRS reports personal fees from Apellis, personal fees from Amgen, personal fees from Abbvie/Allergan, personal fees from Alexion, personal fees from Samsung Bioepis, personal fees from Biogen, personal fees from Boerhinger Ingelheim, personal fees from Astellas/IvericBio, personal fees from Novartis, personal fees from Roche/Genentech, personal fees from Bayer, personal fees from Regeneron, personal fees from Pfizer, personal fees from Nanoscope, personal fees from Jannsen, personal fees fees and research instruments from iCare, personal fees and research instruments from Optos, personal fees fees and research instruments from Heidelberg, personal fees from NotalVision, personal fees fees and research instruments from Topcon, personal fees from Eyepoint, personal fees from Character, personal fees from Ocular Therapeutics, personal fees from Neurotech, personal fees from Nidek, personal fees from RegenxBio, research instruments from Carl Zeiss Meditec, personal fees and research instruments from Nidek. IH reports employment with Notal Vision. Mr Benyamini reports employment with Notal Vision. KN reports employment with Notal Vision. NM reports employment with Notal Vision., (© 2024. The Author(s).)

Purpose: To evaluate the safety and tolerability of a single dose of axitinib injectable suspension (CLS-AX), a pan-anti-VEGF tyrosine kinase inhibitor (TKI), administered via suprachoroidal injection in patients with neovascular age-related macular degeneration (nAMD)., Design: Phase I/IIa, open-label, sequential dose escalation., Participants: Anti-VEGF treatment-experienced patients with active subfoveal choroidal neovascularization secondary to nAMD., Methods: The study included 4 cohorts (0.03, 0.10, 0.50, and 1.0 mg) of approximately 5 patients each enrolled in a dose-escalating fashion. Enrolled patients received intravitreal aflibercept (2 mg) followed by a single unilateral dose of CLS-AX 1 month later. All patients were followed monthly for 3 months with the option of an additional 3 months of extended follow-up for cohorts 2 to 4. End points included systemic and ocular safety and tolerability, visual acuity, retinal thickness, and need for aflibercept therapy., Main Outcome Measures: The number of patients reporting treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs), changes in ophthalmic examinations, and the number of patients qualifying for additional therapy for nAMD based on protocol-defined criteria., Results: OASIS enrolled 27 patients with nAMD with mean age of 81 years, mean duration of nAMD diagnosis of 54 months, and between 5 and 90 prior anti-VEGF treatments. Twenty-six patients completed through 3 months, with 14 entering and completing the 3-month extension. No SAEs, drug-related TEAEs, or TEAEs leading to discontinuation were observed after CLS-AX administration; there were no adverse events related to ocular inflammation, vasculitis, intraocular pressure, or dispersion of drug into the vitreous or anterior chamber. Through 6 months, stable mean best-corrected visual acuity and stable mean central subfield thickness (CST) were observed, suggestive of TKI biologic effect. No aflibercept therapy was administered up to 3 months in 58% (15/26) of patients who completed 3 months of follow-up in OASIS. In the Extension, 57% (8/14) of patients went up to 6 months without receiving aflibercept therapy., Conclusions: Up to 1.0 mg CLS-AX, a highly potent TKI targeted to the suprachoroidal space (SCS) via the SCS Microinjector, was well tolerated, with stable mean visual acuity and mean CST. A majority of patients followed for 6 months did not require aflibercept therapy., Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article., (© 2024 by the American Academy of Ophthalmology.)

Purpose: To develop professional guidelines for best practices for suprachoroidal space (SCS) injection, an innovative technique for retinal therapeutic delivery, based on current published evidence and clinical experience., Methods: A panel of expert ophthalmologists reviewed current published evidence and clinical experience during a live working group meeting to define points of consensus and key clinical considerations to inform the development of guidelines for in-office SCS injection., Results: Core consensus guidelines for in-office SCS injection were reached and reported by the expert panel. Current clinical evidence and physician experience supported SCS injection as a safe and effective method for delivering retinal and choroidal therapeutics. The panel established consensus on the rationale for SCS injection, including potential benefits relative to other intraocular delivery methods and current best practices in patient preparation, pre- and peri-injection management, SCS-specific injection techniques, and postinjection management and follow-up., Conclusion: These expert panel guidelines may support and promote standardization of SCS injection technique, with the goal of optimizing patient safety and outcomes. Some aspects of the procedure may reasonably be modified based on the clinical setting and physician judgment, as well as additional study., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Opthalmic Communications Society, Inc.)

A series of novel 1,2,4-oxadiazole-based derivatives were synthesized and evaluated for their potential anti-Alzheimer disease activity. The results revealed that compounds 2b, 2c, 2d, 3a, 4a, 6, 9a, 9b, and 13b showed excellent inhibitory activity against acetylcholinesterase (AChE) with IC 50 values in the range of 0.0158 to 0.121 μM. They were 1.01 to 7.78 times more potent than donepezil (IC 50 = 0.123 μM). The newly synthesized compounds exhibited lower activity towards butyrylcholinesterase (BuChE) when compared to rivastigmine. Compounds 4b and 13b showed the most prominent inhibitory potential against BuChE with IC 50 values of 11.50 and 15 μM, respectively. Moreover, 4b, and 9b were found to be more potent antioxidant agents (IC 50 values of 59.25, and 56.69 μM, respectively) in comparison with ascorbic acid (IC 50 = 74.55 μM). Compounds 2b and 2c exhibited monoamine oxidase-B (MAO-B) inhibitory activity with IC 50 values of 74.68 and 225.48 μM, respectively. They were 3.55 and 1.17 times more potent than biperiden (IC 50 = 265.85 μM). The prominent interactions of the compounds with the AChE active site can be used to computationally explain the high AChE inhibitory activity. The results unveiled 1,2,4-oxadiazole derivatives 2c and 3a as multitarget anti-AD agents. The predicted ADME properties for compounds 2b and 4a were satisfactory, and 4a had the highest likelihood of crossing the blood-brain barrier (BBB), making it the optimum compound for future optimization., Competing Interests: “The authors declare that none of their relationships or conflicting financial interests could have influenced the findings of this study”., (This journal is © The Royal Society of Chemistry.)

Purpose: To evaluate safety and tolerability of EYP-1901, an intravitreal insert containing vorolanib, a pan-VEGF receptor inhibitor packaged in a bioerodible delivery technology (Durasert E™) for sustained delivery, in patients with wet age-related macular degeneration (wAMD) previously treated with anti-VEGF therapy., Design: Phase I, multicenter, prospective, open-label, dose-escalation trial., Participants: Patients with wAMD and evidence of prior anti-VEGF therapy response., Methods: Patients received a single intravitreal injection of EYP-1901., Main Outcome Measures: The primary objective was to evaluate safety and tolerability of EYP-1901. Secondary objectives assessed biologic activity of EYP-1901 including best-corrected visual acuity (BCVA) and central subfield thickness (CST). Exploratory analyses included reduction in anti-VEGF treatment burden and supplemental injection-free rates., Results: Seventeen patients enrolled in the 440 μg (3 patients), 1030 μg (1 patient), 2060 μg (8 patients), and 3090 μg (5 patients) dose cohorts. No dose-limiting toxicity, ocular serious adverse events (AEs), or systemic AEs related to EYP-1901 were observed. There was no evidence of ocular or systemic toxicity related to vorolanib or the delivery technology. Moderate ocular treatment-emergent AEs (TEAEs) included reduced visual acuity (2/17) and retinal exudates (3/17). One patient with reduced BCVA had 3 separate reductions of 17, 18, and 16 letters, and another had a single drop of 25 letters. One severe TEAE, neovascular AMD (i.e., worsening/progressive disease activity), was reported in 1 of 17 study eyes but deemed unrelated to treatment. Mean change from baseline in BCVA was -1.8 letters and -5.4 letters at 6 and 12 months. Mean change from baseline in CST was +1.7 μm and +2.4 μm at 6 and 12 months. Reduction in treatment burden was 74% and 71% at 6 and 12 months. Of 16 study eyes, 13, 8, and 5 were injection-free up to 3, 6, and 12 months., Conclusion: In the DAVIO trial (ClinicalTrials.gov identifier, NCT04747197), EYP-1901 had a favorable safety profile and was well tolerated in previously treated eyes with wAMD. Measures of biologic activity remained relatively stable following a single EYP-1901 injection. These preliminary data support ongoing phase II and planned phase III trials to assess efficacy and safety., Financial Disclosures: The author(s) have no proprietary or commercial interest in any materials discussed in this article., (© 2024 by the American Academy of Ophthalmology.)

Indicated for colorectal cancer for decades, bevacizumab has been widely used off label to treat retinal diseases, and the benefits of its use, specifically in neovascular age-related macular degeneration, have been demonstrated in multiple clinical trials. The intravitreal delivery of bevacizumab requires it to be aseptically repackaged into individual syringes by compounding pharmacies for use in the eye. Although the repackaging process is permitted by the US Food and Drug Administration, the resultant product does not meet the specific standards of products approved for use as ophthalmic injectables nor is the parenteral innovator solution compliant with ophthalmic standards. Studies have also demonstrated variability in the quality and quantity of repackaged bevacizumab. This narrative review summarizes the evidence and discusses the role of off-label bevacizumab in the treatment and management of retinal diseases, its mechanism of action, current challenges and provides a critical appraisal of current evidence, clinical implications, and future directions. [ Ophthalmic Surg Lasers Imaging Retina 2024;55:155-162.] .

Objective: To investigate preclinical data regarding the efficacy and biocompatibility of a bispecific protein, RO-101, with effects on VEGF-A and angiopoietin-2 (Ang-2) for use in retinal diseases., Design: Experimental study., Subjects: Brown Norway rats and New Zealand White Cross rabbits., Methods: Preclinical study data of RO-101 in terms of target-specific enzyme-linked immunosorbent assay binding affinity to VEGF-A and Ang-2, vitreous half-life, inhibition of target-receptor interaction, laser choroidal neovascular membrane animal model, human umbilical vein endothelial cell migration, and biocompatibility was obtained. Where applicable, study data were compared with other anti-VEGF agents., Main Outcome Measures: Binding affinity, half-life, biocompatibility, and efficacy of RO-101. Neovascularization prevention by RO-101., Results: RO-101 demonstrated a strong binding affinity for VEGF-A and Ang-2 and in vitro was able to inhibit binding to the receptor with higher affinity than faricimab. The half-life of RO-101 is comparable to or longer than current VEGF inhibitors used in retinal disease. RO-101 was found to be biocompatible with retinal tissue in Brown Norway rats. RO-101 was as effective or more effective than current anti-VEGF therapeutics in causing regression of neovascular growth in vivo., Conclusions: RO-101 is a promising candidate for use in retinal diseases. In preclinical models, RO-101 demonstrated similar or higher regression of neovascular growth to current anti-VEGF therapeutics with comparable or longer half-life. It also demonstrates a strong binding affinity for VEGF-A and Ang-2. It also was shown to be biocompatible with retinal tissue in animal studies, indicating potential compatibility for use in humans., Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article., (© 2024 by the American Academy of Ophthalmology.)

Importance: Despite the effectiveness of existing anti-vascular endothelial growth factor (VEGF) therapies, a need remains for further treatment options to improve response rates and/or reduce injection or monitoring frequency in patients with diabetic macular edema (DME)., Objective: To evaluate the efficacy and safety of brolucizumab vs aflibercept dosed every 4 weeks in participants with DME., Design, Participants, and Setting: This 52-week, double-masked, phase 3 randomized clinical trial included treatment-naive adults and adults who had previously received anti-VEGF therapy. Data were collected from September 2019 to March 2020, and data were analyzed from April 2020 to February 2021., Intervention: Brolucizumab, 6 mg, intravitreal injection every 4 weeks or aflibercept, 2 mg, intravitreal injection every 4 weeks., Main Outcomes and Measures: Participants were randomized 2:1 to brolucizumab, 6 mg, or aflibercept, 2 mg. The primary end point was change from baseline in best-corrected visual acuity at week 52. Secondary end points were the proportion of participants with a 2-step improvement or greater from baseline in Diabetic Retinopathy Severity Scale score, the proportion of eyes with absence of both subretinal fluid and intraretinal fluid, change from baseline in central subfield thickness, and safety at week 52., Results: A total of 517 participants were randomized to brolucizumab (n = 346) or aflibercept (n = 171); 299 (57.8%) were male, and the mean (SD) age was 60.7 (10.2) years. Brolucizumab was noninferior to aflibercept in best-corrected visual acuity (Early Treatment Diabetic Retinopathy Study letter score) change from baseline at week 52 (brolucizumab, 12.2-letter improvement; aflibercept, 11.0-letter improvement; difference, 1.1; 95% CI, -0.6 to 2.9; noninferiority margin, 4; P < .001). Brolucizumab was superior to aflibercept for the proportion of eyes without subretinal and intraretinal fluid (brolucizumab, 144 of 346 [41.6%]; aflibercept, 38 of 171 [22.2%]; difference, 20.0%; 95% CI, 12.5to 28.6; P < .001) and mean central subfield thickness change from baseline at week 52 (brolucizumab, -237.8 μm; aflibercept, -196.5 μm; difference, -41.4; 95% CI, -58.9 to -23.8; P < .001). Incidence of intraocular inflammation was 4.0% (14 of 346) in the brolucizumab arm and 2.9% (5 of 171) in the aflibercept arm, incidence of retinal vasculitis was 0.9% (3 of 346) and 0.6% (1 of 171), respectively, and incidence of retinal vascular occlusion was 0.3% (1 of 346) and 0.6% (1 of 171). One participant in the brolucizumab arm had retinal artery occlusion., Conclusions and Relevance: In these study participants with DME, no clinically meaningful differences in visual outcomes were noted between the brolucizumab and aflibercept arms; some superior anatomic improvements were noted in the brolucizumab arm. No new safety concerns were identified., Trial Registration: ClinicalTrials.gov Identifier: NCT03917472.

Background/objective: Investigate real-world patients receiving faricimab for the treatment of neovascular age-related macular degeneration (nAMD)., Subjects/methods: Multicenter, retrospective chart review was conducted on patients treated with faricimab for nAMD from February 2022 to September 2022. Collected data includes background demographics, treatment history, best-corrected visual acuity (BCVA), anatomic changes, and adverse events as safety markers. The main outcome measures are changes in BCVA, changes in central subfield thickness (CST) and adverse events. Secondary outcome measures included treatment intervals and presence of retinal fluid., Results: After one injection of faricimab, all eyes (n = 376), previously-treated (n = 337) and treatment-naïve (n = 39) eyes demonstrated a + 1.1 letter (p = 0.035), a + 0.7 letter (p = 0.196) and a + 4.9 letter (p = 0.076) improvement in BCVA, respectively, and a - 31.3 μM (p < 0.001), a - 25.3 μM (p < 0.001) and a - 84.5 μM (p < 0.001) reduction in CST, respectively. After three injections of faricimab, all eyes (n = 94), previously-treated (n = 81) and treatment-naïve (n = 13) eyes demonstrated a + 3.4 letter (p = 0.03), a + 2.7 letter (p = 0.045) and a + 8.1 letter (p = 0.437) improvement in BCVA, and a - 43.4 μM (p < 0.001), a - 38.1 μM (p < 0.001) and a - 80.1 μM (p < 0.204) reduction in CST, respectively. One case of intraocular inflammation was observed after four injections of faricimab and resolved with topical steroids. One case of infectious endophthalmitis was treated with intravitreal antibiotics and resolved., Conclusions: Faricimab has demonstrated improvement or maintenance of visual acuity for patients with nAMD, along with rapid improvement of anatomical parameters. It has been well-tolerated with low incidence of treatable intraocular inflammation. Future data will continue to investigate faricimab for real-world patients with nAMD., (© 2023. The Author(s).)

Controlling the activity of the CRISPR-Cas9 system is essential to its safe adoption for clinical and research applications. Although the conformational dynamics of Cas9 are known to control its enzymatic activity, details of how Cas9 influences the catalytic processes at both nuclease domains remain elusive. Here we report five cryo-electron microscopy structures of the active Acidothermus cellulolyticus Cas9 complex along the reaction path at 2.2-2.9 Å resolution. We observed that a large movement in one nuclease domain, triggered by the cognate DNA, results in noticeable changes in the active site of the other domain that is required for metal coordination and catalysis. Furthermore, the conformations synchronize the reaction intermediates, enabling coupled cutting of the two DNA strands. Consistent with the roles of conformations in organizing the active sites, adjustments to the metal-coordination residues lead to altered metal specificity of A. cellulolyticus Cas9 and commonly used Streptococcus pyogenes Cas9 in cells.

Purpose: Retinal vasculitis or vascular occlusion (RV/RO) have been reported after brolucizumab for neovascular age-related macular degeneration. This systematic literature review evaluated RV/RO events after brolucizumab in real-world practice., Methods: Systematic literature searches identified 89 publications; 19 were included., Results: Publications described 63 patients (70 eyes) with an RV/RO event following brolucizumab. Mean age was 77.6 years and 77.8% of patients were women; 32 eyes (45.7%) received one brolucizumab injection before RV/RO. Mean (range) time to event from last brolucizumab injection was 19.4 (0-63) days, with 87.5% of events occurring within 30 days. Among eyes with preevent and postevent visual acuity (VA) assessments, 22/42 eyes (52.4%) showed unchanged (±0.08 logMAR) or improved vision from last recorded preevent assessment at latest follow-up, whereas 15/42 eyes (35.7%) showed ≥0.30 logMAR (≥15 letters) VA reduction. Patients with no VA loss were on average slightly younger and had a higher proportion of nonocclusive events., Conclusion: Most RV/RO events reported after brolucizumab in early real-world practice occurred in women. Among eyes with VA measurements, approximately half experienced VA loss; overall, about one-third had VA reduction of ≥0.30 logMAR at latest follow-up, with indications of regional variations., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Opthalmic Communications Society, Inc.)

Purpose: To assess the extended efficacy and safety of suprachoroidal triamcinolone acetonide injectable suspension (CLS-TA) among patients with macular oedema (ME) secondary to non-infectious uveitis (NIU)., Methods: Patients with uveitic ME were treated with suprachoroidal CLS-TA at baseline and week 12 of the Efficacy and Safety of Suprachoroidal CLS-TA for Macular Edema Secondary to Noninfectious Uveitis: Phase 3 Randomized Trial (PEACHTREE) study. Time to rescue was evaluated over 24 additional weeks for MAGNOLIA. Safety data, visual acuity and retinal central subfield thickness (CST) reduction were also evaluated. Of the 53 eligible patients (46 CLS-TA and 7 control), 33 patients were enrolled (28 CLS-TA and 5 control)., Results: Over the entire 48-week period for PEACHTREE and MAGNOLIA, the median time to rescue therapy was 257 days versus 55.5 days for the CLS-TA and sham-control arms, respectively. Of 28 CLS-TA treated patients who participated in MAGNOLIA, 14 (50%) did not require rescue therapy through approximately 9 months after the second treatment. Among CLS-TA patients not requiring rescue, there was a mean gain of 12.1 letters and mean CST reduction of 174.5 µm at week 48. No serious adverse events related to study treatment were observed., Conclusion: Approximately 50% of patients did not require additional treatment for up to 9 months following the last CLS-TA administration., Competing Interests: Competing interests: RNK reports receiving consulting fees from Allergan, Genentech and Regeneron. He also reports receiving grant support from Allergan, Chengdu Kanghong, Clearside Biomedical, Roche and Santen. PM reports receiving consulting fees from Eyepoint, Alimera and Allergan. She also reports receiving grant support from Clearside, Gilead, Santen and NEI. SY reports receiving consulting fees from Clearside Biomedical and Santen. He also reports receiving grant support from Bayer. ES reports receiving consulting fees from Clearside Biomedical, Abbvie, Eyegate, Eyepoint and Gilead. He also reports receiving grant support from Aldeyra. MRB reports receiving consulting fees from Allegro, Allergan, Alimera, Bausch and Lomb, Genentech, Novartis and Regenxbio. EU reports receiving consulting fees from Abbvie, Novartis, Eyepoint, Regeneron, GlaxoSmithKline and Bausch and Lomb. He also reports receiving grant support from Novartis and Roche/Genentech. CRH reports receiving consulting fees from Clearside Biomedical. MS reports receiving grant support from Clearside Biomedical. RCW has nothing to disclose. TC and BK are employees of Clearside Biomedical and hold stock in Clearside Biomedical., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: To evaluate local and systemic safety of suprachoroidal (SC) triamcinolone acetonide injectable suspension (CLS-TA) injections in subjects with non-infectious uveitis (NIU)., Design: Open-label, prospective multicentre safety study., Participants: Thirty-eight subjects with NIU, with and without macular oedema (MO)., Methods: Treatment consisted of two suprachoroidal injections of CLS-TA 4 mg, 12 weeks apart. Best-corrected visual acuity (BCVA), adverse event (AE) assessment, ophthalmic examinations and optical coherence tomography (OCT) were conducted every 4 weeks for 24 weeks. Blood samples were analysed for plasma triamcinolone acetonide (TA) concentrations., Main Outcome Measures: The main outcome measure was frequency of AEs. Other endpoints included plasma TA concentrations, change in signs of inflammation, BCVA and retinal central subfield thickness (CST)., Results: Based on a CST of >300 µm, 20 out of 38 subjects had MO at baseline. Mean intraocular pressure (IOP) was 13.3 mm Hg at baseline and 15.2 mm Hg at week 24 in the study eye. A total of six (15.8%) subjects had an IOP rise >10 mm Hg compared with baseline, in the study eye, and two (5.3%) subjects had IOP >30 mm Hg (maximum 34 mm Hg at week 8 and 38 mm Hg at week 20). Cataract formation AEs were reported in four study eyes; one of which was deemed treatment-related. No serious ocular AEs in the study eye occurred in the study. Quantifiable post-injection TA plasma concentration was <1 ng/mL. Efficacy parameters showed improvement over the 24-week study period., Conclusions: Suprachoroidally administered CLS-TA was safe and well tolerated over the 24-week, open-label study in NIU subjects with and without MO., Competing Interests: Competing interests: CRH reports receiving consulting fees from Clearside Biomedical and Bausch & Lomb. MS reports receiving grant support from Clearside Biomedical. MRB reports receiving consulting fees from Allegro, Allergan, Alimera, Bausch & Lomb, Genentech, Novartis and Regenxbio. RNK reports receiving consulting fees from Allergan, Clearside Biomedical, Genentech and Regeneron. He also reports receiving grant support from Allergan, Chengdu Kanghong, Clearside Biomedical, Roche and Santen. LR reports receiving consulting fees from Bausch & Lomb. SY reports receiving consulting fees from Clearside Biomedical and Santen. He also reports receiving grant funding from Clearside Biomedical. CH and TC are employees of Clearside Biomedical., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: To assess the relationship between best-corrected visual acuity (BCVA) and optical coherence tomography (OCT) features in noninfectious uveitis (NIU)-related macular edema., Design: Clinical cohort study from post hoc analysis of 2 phase 3 clinical trials., Methods: Correlation and longitudinal treatment analyses were performed. Of 198 patients with NIU, 134 received suprachoroidal CLS-TA (proprietary formulation of a triamcinolone acetonide injectable suspension), and 64 received sham, with 12.9% and 72%, respectively, receiving rescue therapy., Results: At baseline, mean BCVA progressively worsened with each ordinal drop in central subfield ellipsoid zone (EZ) integrity. Eyes with normal baseline EZ experienced greater 24-week change in BCVA versus those with some degree of baseline EZ disruption (11.9 vs 9.4 letters, P = .006). In contrast, eyes with baseline central subfield cystoid spaces and/or subretinal fluid showed more improvement (13.7 or 17.2 letters, respectively) at 24 weeks, versus those without such findings (5.5 [P = .012] or 9.5 letters [P < .001], respectively). Longitudinal modeling for CLS-TA-treated eyes showed that central subfield thickness (CST) reached 90% of maximal improvement by week 3, whereas 90% maximal response in BCVA was not reached until week 9. CLS-TA-treated eyes that showed CST reduction of ≥50 µm at 4 weeks experienced a greater 24-week improvement in BCVA versus those without such an early response (14.6 vs 6.5 letters, P = .006 for difference)., Conclusions: Pretreatment EZ integrity and the presence of central subfield cystoid spaces or subretinal fluid each predict improved therapeutic response to treatment in eyes with NIU. In CLS-TA treated eyes, longitudinal modeling shows CST improvement preceding BCVA improvement., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Importance: Limited data exist on the real-world safety outcomes of patients with neovascular age-related macular degeneration treated with brolucizumab (Beovu)., Objective: To determine the real-world incidence of intraocular inflammation (IOI), including retinal vasculitis (RV) and/or retinal vascular occlusion (RO), for patients with neovascular age-related macular degeneration who underwent brolucizumab treatment. Additionally, potential risk factors associated with these adverse events were evaluated., Design, Setting, and Participants: This cohort study included patients with neovascular age-related macular degeneration in the Intelligent Research in Sight (IRIS) Registry and Komodo Healthcare Map. Patients initiating and receiving 1 or more brolucizumab injections from October 8, 2019, to June 5, 2020, with up to 6 months of follow-up were included., Intervention: Brolucizumab injections., Main Outcome and Measures: Incidence of IOI (including RV) and/or RO and RV and/or RO and risk stratification for the identified risk factors., Results: Of 10 654 and 11 161 included eyes (from the IRIS Registry and Komodo Health database, respectively), the median follow-up times were 97 and 95 days. Most eyes switched from another anti-vascular endothelial growth factor agent (9686 of 10 654 [90.9%] and 10 487 of 11 161 [94.0%], respectively), most commonly aflibercept (7160 of 9686 [73.9%] and 7156 of 10 487 [68.2%]), and most were from women (6105 of 10 654 [57.3%] and 6452 of 11 161 [57.8%]). The overall incidence of IOI and/or RO was 2.4% (255 of 10 654 eyes) and 2.4% (268 of 11 161 eyes) for the IRIS and Komodo groups, respectively, and RV and/or RO, 0.6% (59 of 10 654 eyes and 63 of 11 161 eyes), respectively. Patients with a history of IOI and/or RO in the 12 months before brolucizumab initiation had an increased observed risk rate (8.7% [95% CI, 6.0%-11.4%] and 10.6% [95% CI, 7.5%-13.7%]) for an IOI and/or RO event in the 6 months following the first brolucizumab treatment compared with patients without prior IOI and/or RO (2.0% in both data sets). There was an increased estimated incidence rate in women (2.9% [95% CI, 2.5%-3.3%] and 3.0% [95% CI, 2.6%-3.4%]) compared with men (1.3% [95% CI, 1.0%-1.7%] and 1.4% [95% CI, 1.0%-1.7%]), but this risk was not as large as that of a prior IOI and/or RO. Similar findings were observed for patients with RV and/or RO events., Conclusions and Relevance: The incidence rate of IOI and/or RO was approximately 2.4%. Patient eyes with IOI and/or RO in the 12 months prior to first brolucizumab injection had the highest observed risk rate for IOI and/or RO in the early months after the first brolucizumab treatment. However, given study limitations, the identified risk factors cannot be used as predictors of IOI and/or RO events, and causality with brolucizumab cannot be assessed.

Importance: The American Academy of Ophthalmology (AAO) indicated that urgent or emergent vitreoretinal surgical procedures should continue during the coronavirus disease 2019 (COVID-19) pandemic. Although decreases in the frequency of critical procedures have been reported outside the field of ophthalmology, analyses are limited by volume, geography, and time., Objective: To evaluate whether the frequency of ophthalmic surgical procedures deemed urgent or emergent by the AAO changed across the United States during the COVID-19 pandemic., Design, Setting, and Participants: Vitreoretinal practices from 17 institutions throughout the US participated in this multicenter cross-sectional study. The frequency of 11 billed vitreoretinal Current Procedural Terminology (CPT) codes across respective weeks was obtained from each practice between January 1, 2019, and May 31, 2020. Data were clustered into intravitreal injections (code 67028), lasers and cryotherapy (codes 67141, 67145, and 67228), retinal detachment (RD) repairs (codes 67107, 67108, 67110, and 67113), and other vitrectomies (codes 67036, 67039, and 67040). Institutions were categorized by region (Northeast, Midwest, South, and West Coast), practice setting (academic [tax-exempt] or private [non-tax-exempt]), and date of respective statewide stay-at-home orders., Main Outcomes and Measures: Nationwide changes in the frequency of billing for urgent or emergent vitreoretinal surgical procedures during the COVID-19 pandemic., Results: A total of 526 536 CPT codes were ascertained: 483 313 injections, 19 257 lasers or cryotherapy, 14 949 RD repairs, and 9017 other vitrectomies. Relative to 2019, a weekly institutional decrease in injections was observed from March 30 to May 2, 2020, with a maximal 38.6% decrease (from a mean [SD] of 437.8 [436.3] to 273.8 [269.0] injections) from April 6 to 12, 2020 (95% CI, -259 to -69 injections; P = .002). A weekly decrease was also identified that spanned a longer interval, at least until study conclusion (March 16 to May 31, 2020), for lasers and cryotherapy, with a maximal 79.6% decrease (from a mean [SD] of 6.6 [7.7] to 1.5 [2.0] procedures) from April 6 to 12, 2020 (95% CI, -6.8 to -3.3 procedures; P < .001), for RD repairs, with a maximal 59.4% decrease (from a mean [SD] of 3.5 [4.0] to 1.6 [2.2] repairs) from April 13 to 19, 2020 (95% CI, -2.7 to -1.4 repairs; P < .001), and for other vitrectomies, with a maximal 84.3% decrease (from a mean [SD] of 3.0 [3.1] to 0.4 [0.8] other vitrectomies) from April 6 to 12, 2020 (95% CI, -3.3 to -1.8 other vitrectomies; P < .001). No differences were identified by region, setting, or state-level stay-at-home order adjustment., Conclusions and Relevance: Although the AAO endorsed the continued performance of urgent or emergent vitreoretinal surgical procedures, the frequency of such procedures throughout the country experienced a substantial decrease that may persist after the COVID-19 pandemic's initial exponential growth phase. This decrease appears independent of region, setting, and state-level stay-at-home orders. It is unknown to what extent vitreoretinal intervention would have decreased without AAO recommendations, and how the decrease is associated with outcomes. Although safety is paramount during the COVID-19 pandemic, practices should consider prioritizing availability for managing high-acuity conditions until underlying reasons for the reduction are fully appreciated.

Purpose: This study evaluated the potential safety, efficacy, and durability advantages of investigational triamcinolone acetonide suspension (CLS-TA; Clearside Biomedical, Alpharetta, GA) administered suprachoroidally in conjunction with intravitreal aflibercept compared with aflibercept monotherapy for treatment of diabetic macular edema (DME)., Design: TYBEE was a prospective, controlled, double-masked study. Patients were randomized 1:1 to CLS-TA and aflibercept (active) or aflibercept monotherapy (control), and assessed over 24 weeks., Participants: Treatment-naive DME patients with best-corrected visual acuity (BCVA) of 20 to 70 letters and central subfield retinal thickness (CST) of more than 300 μm., Methods: Patients in the active group (n = 36) received CLS-TA and aflibercept at baseline and week 12. Patients in the control group (n = 35) received aflibercept at baseline, week 4, week 8, and week 12. To mask both groups, sham suprachoroidal and intravitreal injections were utilized. All patients were eligible to receive aflibercept as needed at weeks 4, 8, 16, and 20 per prespecified criteria., Main Outcome Measure: Mean change in BCVA from baseline. Treatment differences were assessed with a 2-sided significance level of 0.10., Results: Mean BCVA changes from baseline to week 24 were not statistically different in the active and control groups (intention-to-treat [ITT] population: +11.4 letters and +13.8 letters [P = 0.288]; per protocol [PP] population: +12.3 letters and +13.5 letters [P = 0.664]; respectively). Greater improvement in CST was seen in the active versus control group (ITT population: -212.1 μm and -178.6 μm [P = 0.089]; PP population: -226.5 μm and -176.1 μm [P = 0.035]; respectively). Compared with the control group, eyes in the active group received fewer treatments (scheduled plus as-needed treatments averaging 4.6 versus 2.6, respectively). No treatment-related serious adverse events were observed. Ocular adverse events were low for both arms. Cataract events, all assessed as unrelated to treatment, and events of elevated intraocular pressure trended higher in the active group., Conclusions: CLS-TA administered suprachoroidally in conjunction with intravitreal aflibercept for treatment of DME provides simliar visual benefit at 24 weeks' follow-up compared with aflibercept monotherapy, is well tolerated and shows modest anatomic benefit with potential to reduce treatment burden., (Copyright © 2020 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: This study assessed physician-investigator experience with suprachoroidal (SC) injections, an investigational therapeutic administration technique using a 900 or 1100 µm microneedle to inject drugs into the SC space., Methods: Datasets from six clinical trials across three diseases (noninfectious uveitis; diabetic macula edema, and retinal vein occlusion) were assessed. In addition to a user survey, retrospective correlations were performed between procedural variables (needle length), and demographics, and ocular characteristics., Results: In the user survey, 84% (31/37) of physician-investigators did not perceive the SC injections to be meaningfully more challenging than other ocular injections. For the correlation analysis, the 900 µm needle was used for 71% (412/581) of baseline injections, and switching to the longer needle occured in the remaining 29% of baseline injections. No statistical correlations were found between needle lengths and age, race, disorder, refraction, visual acuity, intraocular pressure, retinal central subfield thickness, or lens status. Patient gender and needle length were statistically associated, with 76% (210/275) versus 66% (202/306) of injections administered with 900 µm needles for female and male gender, respectively. Injection quadrant correlated to needle length with 78% (214/275) of superotemporal quadrant injections administered with 900 µm needles, compared with 65% (73/113) of inferotemporal quadrant injections., Conclusions: Both the user survey and the correlation analysis demonstrated that SC injection is well accepted by physician-investigators, and the two needle lengths accommodate a wide range of anatomic and demographic variables., Translational Relevance: These results, along with the presented ex-vivo endoscopic imaging, suggest that SC injection could be readily adopted in clinical practice for targeted compartmentalized delivery of ocular therapeutics., Competing Interests: Disclosure: Chen-rei Wan, Clearside (E, I); B. Kapik, Clearside (E, I); C.C. Wykoff, Clearside (F, C); C.R. Henry, Clearside (C), Alimera (C), Bausch & Lomb (C); M.R. Barakat, Bausch & Lomb (C), Regenxbio (C), Clearside (R); M. Shah, Clearside (F); R.V. Andino, Clearside (E, I); T.A. Ciulla, Clearside (E, I), (Copyright 2020 The Authors.)

Background: Cytogenetically normal acute myeloid leukemia (AML) represents nearly half of newly diagnosed de novo AML cases. XPD is one of the DNA repair proteins, whose genetic polymorphisms are thought to affect their function as regards response to chemotherapeutic drugs and chemotherapy-induced toxicities., Subjects and Methods: We investigated the XPD Asp312Asn and Lys751Gln polymorphisms by polymerase chain reaction-restriction fragment length polymorphism in 51 newly diagnosed cytogenetically normal de novo AML patients. The response to the standard induction chemotherapy protocol and chemotherapy-induced toxicities were monitored., Results: The XPD Asp312Asn GG genotype was the most frequent (57%) followed by the GA variant (37%), and the AA variant was the least frequent (6%). As regards the XPD Lys751Gln polymorphism, the AA genotype was the most frequent (49%), followed by the AC (39%) and CC (12%) variants. These variants were not associated with age, sex, FAB subtype, CNS infiltration, chemotherapy-induced hepatotoxicity, nephrotoxicity, or metabolic toxicity. The XPD Lys751Gln CC polymorphic variant was associated with chemotherapy-induced cardiotoxicity and lower chance to achieve response to induction chemotherapy., Conclusion: XPD Lys751Gln and not Asp312Asn polymorphism was associated with chemotherapy-induced cardiotoxicity and response to induction chemotherapy in newly diagnosed cytogenetically normal AML patients. Pretreatment assay of XPD Lys751Gln may help to anticipate cardiotoxicity in those at risk. Moreover, it may be considered a prognostic marker in AML cases. However, further large scale research is needed to verify its usefulness.

Objectives: To report a case of extensive subcutaneous emphysema introduced during vitrectomy while using an advanced feedback-controlled pressurized infusion system., Methods: Clinical case report of a 56-year-old woman undergoing pars plana vitrectomy for rhegmatogenous retinal detachment of the left eye. The clinical and radiologic findings of the patient's eyes were documented. The mechanisms of feedback-controlled pressurized infusion devices were reviewed to explain the adverse events. A search of PubMed was conducted to look for any similar cases and/or discussion., Results: In this surgical case, vitrectomy was completed with air-fluid exchange and a formed anterior chamber was observed with an estimated pressure of high teens to low 20s by the surgeon. After the undraping, the patient was noted to have severe facial crepitus extending to the clavicles. Immediate chest X-ray was done, followed by computed tomography, confirming orbital and subcutaneous emphysema, as well as the presence of perfluoro-N-octane in the left orbit., Conclusion: Integrated pressurized infusion devices using feedback sensors allow for a sophisticated method of maintaining intraocular pressure and globe formation. However, inadvertent or occult globe rupture may lead to disruption of feedback control and subsequent high rates of infusion. As the infused substances exit the site of rupture, they can lead to extensive extraocular gas or fluid accumulation, and we report a case of severe bilateral subcutaneous emphysema as a result.

Objective: To investigate the effects of a novel stereotactic radiosurgical system for pars plana delivery of microcollimated x-rays to the retina and determine the retinal radiological dose response and toxicity threshold in a pig model., Methods: The x-rays were delivered through the pars plana to the maculae of Yucatan miniswine to verify the targeting and safety of a cornea-scleral, stabilized, office-based delivery system. Twelve eyes were randomized to receive 0, 16, 24, 42, 60, or 90 Gy in a single dose to the retina. Eye examinations, fundus photography, fluorescein angiography, and spectral-domain optical coherence tomography were obtained at days 7, 30, 60, and 90. Indocyanine green angiography was done at day 90., Results: Through day 90 interim analysis, no abnormalities of external structures were noted. A small cortical lens opacity was noted in the 60-Gy group. Fundus evaluation revealed no abnormalities at 16 or 24 Gy. Beginning at day 30, circular pale retinal lesions with sharp margins were noted in the maculae of the eyes that received 42, 60, and 90 Gy. Higher-dose lesions showed late staining on fluorescein angiography, choroidal hypoperfusion on indocyanine green angiography, and defined photoreceptor loss and retinal thinning on spectral-domain optical coherence tomography., Conclusion: Transscleral stereotactic radiation dosing of porcine eyes demonstrates no apparent clinical abnormalities in doses less than 24 Gy. Doses of 42 Gy or higher led to focal choroidal and retinal damage within the target area., Clinical Relevance: Radiation can induce small-blood vessel closure and thereby has therapeutic potential in neovascular diseases such as age-related macular degeneration.

Purpose: The purpose of this study was to describe the management of a keratoplasty lenticule adhering to the retina after intraoperative dislocation., Methods: We describe the posterior dislocation of the donor lenticule during endothelial keratoplasty in a 72-year-old woman with a transscleraly sutured intraocular lens, previous pars plana vitrectomy, and a posteriorly positioned Ahmed glaucoma tube shunt. The lenticule was retrieved through a pars plana approach 2 weeks later, at which time it was tightly adherent to the extramacular retina. Concurrent keratoplasty was performed., Results: Six months after retrieval of the dislocated lenticule with repeat keratoplasty, the retinal examination is stable and the new graft remains attached., Conclusion: An iris defect, the absence of capsular support, and a history of previous vitrectomy are all potential risk factors for the intraoperative migration of a keratoplasty lenticule. The surgical view 2 weeks after dislocation was not a limiting factor in the retrieval of the lenticule. However, the tight adherence of the lenticule to the retina required extensive peeling. To avoid a more difficult surgical repair and the potential for scar formation, earlier surgical repair would be preferable, especially if dealing with a macular location.

An outbreak of peste des petits ruminants (PPR) was recorded in Kalubia province, Egypt in 2006, affecting a large population of migratory goats and sheep over a huge geographical area. Epidemiological, clinical and laboratory investigations were performed. Diseased animals showed pyrexia, erosive stomatitis, enteritis and bronchopneumonia. Clinical manifestations were more severe in goats. The overall morbidity, cumulative mortality and case fatality rates were 26.1%, 10.5% and 40.2%, respectively, and were significantly higher in young animals. Post-mortem examination showed emaciation, congested mucous membranes, lymphadenopathy, hepatosplenomegaly, haemorrhagic necrosis of the abomasal and intestinal mucosa, pleurisy and lung consolidation. Forty oculonasal swabs and 243 serum samples from diseased animals were tested for PPR antigen and antibodies using immunocapture and competitive enzyme-linked immunosorbent assays (ELISA), respectively. PPR antigen was detected in 30/40 (75%) of the swabs. PPR virus was identified in inoculated Vero cells using immunocapture ELISA and fluorescent antibody technique (FAT); 33/40 (82.5%) and 36/40 (90%) samples were positive, respectively. Of 243 sera, 154 (63.4%) contained PPR antibodies. Circulation of PPR among the migratory sheep and goat flocks was demonstrated. Strict serosurveillance and monitoring of PPR with vaccination of migratory flocks at borders is required for effective control of the disease.

Cornelia de Lange syndrome (CdLS), a congenital disorder characterized by growth and mental retardation, hirsutism, and skeletal and cardiac anomalies, has been associated with a number of ophthalmic abnormalities including synophrys, long eyelashes, myopia, nasolacrimal duct obstruction, and ptosis. Only one case of Coats' disease has been described in the setting of this syndrome.(1) We describe a second case of Coats' disease in a five-year-old boy with this condition.

Age-related macular degeneration (AMD) is the leading cause of blindness in the Western world for those patients aged 50 years or older. Neovascular AMD, a subtype characterized by the growth of new, pathologic blood vessels, results in most of the cases of severe and rapid vision loss associated with AMD. A critical activator of angiogenesis in neovascular AMD is VEGF. Several therapies have been and are now being developed for neovascular AMD, with the goal of inhibiting VEGF. These VEGF inhibitors include the RNA aptamer pegaptanib, partial and full-length antibodies ranibizumab and bevacizumab, VEGF receptor decoy VEGF Trap, small interfering RNA-based therapies bevasiranib and AGN211745, sirolimus, and tyrosine kinase inhibitors including vatalanib, pazopanib, TG100801, TG101095, AG013958 and AL39324. At present, established therapies have met with great success in reducing the vision loss associated with neovascular AMD, whereas those still investigational in nature offer the potential for further advances.

Purpose: Niacin is a B vitamin well-known for causing vasodilation and flushing. The purpose of this study was to investigate its effect on the retinal vasculature of patients with age-related macular degeneration (AMD)., Methods: Twelve patients with AMD were enrolled in a double-blind, randomized, placebo-controlled, crossover trial. Fundus photographs of the posterior pole were taken at baseline, 30 min, and 90 min after a single dose of niacin or placebo. The protocol was repeated after a washout period using the alternate study drug. The diameters of two veins and one artery on each image were measured., Results: An analysis of variance for repeated measures comparing the effects of niacin with those of placebo demonstrated a significant increase in the inferior temporal retinal artery diameter (p = 0.01), with a 5.3 +/- 7.7% increase at 30 min (p = 0.05) and 5.8 +/- 5.0% increase at 90 min (p = 0.003). No significant changes were observed in the temporal retinal veins., Conclusions: Our results suggest that niacin produces vasodilatation of retinal arterioles. Further studies are needed to ascertain whether niacin treatment may be beneficial in retinal ischemic diseases.

Purpose: To study the retinal degeneration in an 11 -year-old patient with Leber congenital amaurosis (LCA) caused by mutation in GUCY2D., Study Design: Comparative human tissue study., Participants: Two subjects with LCA; postmortem eye from one LCA patient and three normal donors., Methods: Clinical and visual function studies were performed between the ages of 6 and 10 years in the LCA eye donor and at age 6 in an affected sibling. Genomic DNA was screened for mutations in known LCA genes. The retina of the 11 -year-old subject with LCA was compared with normal retinas from donors age 3 days, 18 years, and 53 years. The tissues were processed for histopathologic studies and immunofluorescence with retinal cell-specific antibodies., Results: Vision in both siblings at the ages examined was limited to severely impaired cone function. Mutation in the GUCY2D gene was identified in both siblings. Histopathologic study revealed rods and cones without outer segments in the macula and far periphery. The cones formed a monolayer of cell bodies, but the rods were clustered and had sprouted neurites in the periphery. Rods and cones were not identified in the midperipheral retina. The inner nuclear layer appeared normal in thickness throughout the retina, but ganglion cells were reduced in number., Conclusions: An 11-year-old subject with LCA caused by mutant GUCY2D had only light perception but retained substantial numbers of cones and rods in the macula and far periphery. The finding of numerous photoreceptors at this age may portend well for therapies designed to restore vision at the photoreceptor level.

Normal human retinal development involves orderly generation of rods and cones by complex mechanisms. Cell-fate specification involves progenitor cell lineage and external signals such as soluble factors and cell-cell interactions. In most inherited human retinal degenerations, including retinitis pigmentosa, a mutant gene causes loss of visual function, death of mature rods, and eventually death of all cone subtypes. Only one inherited retinal disorder, the enhanced S cone syndrome (ESCS), shows increased visual function, involving the minority S (blue) cones, and decreased rod and L/M (red/green) cone function. This autosomal recessive disease is caused by mutations in NR2E3, a photoreceptor nuclear receptor transcription factor, and may result from abnormal cell-fate determination, leading to excess S cones at the expense of other photoreceptor subtypes. In 16 ESCS patients with the most common NR2E3 mutation, R311Q, we documented an abnormal ratio of S to L/M cone function and progressive retinal degeneration. We studied the postmortem retina of an ESCS patient homozygous for NR2E3 R311Q. No rods were identified, but cones were increased approximately 2-fold, and 92% were S cones. Only 15% of the cones expressed L/M cone opsin, and some coexpressed S cone opsin. The retina was disorganized, with densely packed cones intermixed with inner retinal neurons. The retina was also degenerate, retaining photoreceptors in only the central and far peripheral regions. These observations suggest a key role for NR2E3 in regulation of human photoreceptor development. Degeneration of the NR2E3 retina may result from defective development, known S cone fragility, or abnormal maintenance of mature photoreceptors.