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David Callanan,1 Rahul N Khurana,2 Raj K Maturi,3,4 Sunil Patel,5 Charles C Wykoff,6 David Eichenbaum,7,8 Arshad M Khanani,9,10 Tarek Hassan,11 Hanh Badger,12 Shraddha Mehta,12 Grace Le,12 Mayssa Attar,13 Jennifer Seal,13 Xiao-Yan Li12,14 1Texas Retina Associates, Arlington, TX, USA; 2Northern California Retina Vitreous Associates, Mountain View, CA, USA; 3Midwest Eye Institute, Indianapolis, IN, USA; 4Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, IN, USA; 5West Texas Retina, Abilene, TX, USA; 6Retina Consultants of Houston, Retina Consultants of America, Blanton Eye Institute, Houston Methodist Hospital, Houston, TX, USA; 7Retina Vitreous Associates of Florida, St. Petersburg, FL, USA; 8Morsani College of Medicine, University of South Florida, Tampa, FL, USA; 9Sierra Eye Associates, Reno, NV, USA; 10University of Nevada, Reno School of Medicine, Reno, NV, USA; 11Associated Retinal Consultants, Royal Oak, MI, USA; 12Allergan plc, Irvine, CA, USA, at the time of this work; 13Allergan, an AbbVie company, Irvine, CA, USA; 14VivaVision Biotech, Inc, Shanghai, People’s Republic of ChinaCorrespondence: David Callanan, Texas Retina Associates, 801 West Randol Mill Road, Suite 101, Arlington, TX, USA, 76012, Tel +1 817-261-9625, Fax +1 817-261-9586, Email dcallanan@gmail.comPurpose: To evaluate the impact of modifying the abicipar pegol (abicipar) manufacturing process on the safety and treatment effect of abicipar in patients with neovascular age-related macular degeneration (nAMD).Methods: A new process for manufacturing abicipar was developed to reduce host cell impurities. In a prospective, Phase 2, multicenter, open-label, 28-week clinical trial, patients (n=123) with active nAMD received intravitreal injections of abicipar 2 mg at baseline (day 1) and weeks 4, 8, 16, and 24. Outcome measures included proportion of patients with stable vision (< 15-letter loss from baseline; primary endpoint), change from baseline in best-corrected visual acuity (BCVA) and central retinal thickness (CRT), and adverse events.Results: Overall, 8.9% (11/123) of patients experienced intraocular inflammation (IOI) and discontinued treatment. IOI cases were assessed as mild (2.4% [3/123]), moderate (4.9% [6/123]), or severe (1.6% [2/123]) and resolved with steroid treatment. Visual acuity in most patients with IOI (8 of 11) recovered to baseline BCVA or better by study end. No cases of endophthalmitis or retinal vasculitis were reported. Stable vision was maintained for ≥ 95.9% (≥ 118/123) of patients at all study visits. At week 28, treatment-naïve patients showed a greater mean improvement from baseline in BCVA compared with previously treated patients (4.4 vs 1.8 letters) and a larger mean CRT reduction from baseline (98.5 vs 45.5 μm).Conclusion: Abicipar produced using a modified manufacturing process showed a moderately lower incidence and severity of IOI compared with Phase 3 abicipar studies. Beneficial effects of treatment were demonstrated.Keywords: abicipar, age-related macular degeneration, inflammation

Daniel L Chao,1 Nicolas T Rinella,1 Arshad M Khanani,2 Charles C Wykoff,3 Gun-Ho Kim4,5 1Viterbi Family Department of Ophthalmology, University of California, San Diego, CA, USA; 2Sierra Eye Associates and University of Nevada, Reno School of Medicine, Reno, NV, USA; 3Retina Consultants of Texas, Retina Consultants of America; Blanton Eye Institute, Houston Methodist Hospital & Weill Cornell Medical College, Houston, TX, USA; 4RecensMedical, Ulsan, Korea; 5Department of Biomedical Engineering, Ulsan National Institute of Science and Technology, Ulsan, KoreaCorrespondence: Daniel L Chao; Gun-Ho Kim Tel +1- 858-534-6290; +82 31 8043 3036Email Daniel.chao3@gmail.com; gunho.kim@recensmedical.comPurpose: To evaluate the safety and efficacy of a novel medical device to provide cooling anesthesia to the eye as local anesthesia for intravitreal injections.Study Design: First in human, open-label study of 43 subjects assessed at three different doses: − 10°C for 20 seconds (group 1), − 15°C for 15 seconds (group 2), and − 15°C for 20 seconds (group 3). Main outcome measures were safety and pain of injection using a numeric rating scale (NRS).Results: Cooling anesthesia did not result in any serious ocular adverse events. One grade 1 adverse event was a vasovagal response during cooling administration which resolved immediately after cooling. Mean NRS scores at the time of injection for each group ranged from 2.5 to 4.3 There was a statistically significant difference between pain scores of the 3 groups at injection in aggregate but not in pairwise comparisons (P value = 0.047). There was a statistically significant decrease in pain from injection to 5 minutes post injection in all groups (P value = 0.00008, 0.003, 0.0005 for groups 1, 2, 3, respectively) as well as from 5 minutes to 24– 48 hours (P value = 0.00001, 0.018, and 0.0545 for groups 1, 2, 3, respectively).Conclusion: The rapid cooling anesthesia device was well tolerated for achieving local anesthesia among patients receiving intravitreal injections with no serious ocular adverse events.Keywords: intravitreal injection, anesthesia, cooling, pain

Diabetic retinopathy (DR) is one of the leading causes of vision loss among people of working age. However, people with diabetes are often unaware of the importance of DR screening for preserving vision, highlighting the importance of patient education about DR and DR-related ocular and systemic comorbidities. In this podcast, three patients with different stages of DR and two ophthalmologists exchanged their views on diagnosis, treatment, and progression of DR and diabetic macular edema. The discussion revealed that DR affects not only the physical aspects of patients' lives but also their mental wellbeing. The challenges of a DR diagnosis can be compounded by communication gaps that exist between patients, physicians, and the pharmaceutical industry. Development of new therapies is currently informed mainly by physician perspectives. However, the large burden of current treatments calls for new therapeutic approaches that meet patients' needs better. The preferred method of treatment administration can differ from patient to patient and the choices between treatments that necessitate repeated visits, monitoring, and at-home care must be discussed. As such, going forward it is crucial to consider both the physician and patient perspectives in shaping the clinical landscape of DR., (© 2024. The Author(s).)

Objective: The fragility index (FI) of a meta-analysis evaluates the extent that the statistical significance can be changed by modifying the event status of individuals from included trials. Understanding the FI improves the interpretation of the results of meta-analyses and can help to inform changes to clinical practice. This review determined the fragility of ophthalmology-related meta-analyses., Methods: Meta-analyses of randomized controlled trials with binary outcomes published in a journal classified as 'Ophthalmology' according to the Journal Citation Report or an Ophthalmology-related Cochrane Review were included. An iterative process determined the FI of each meta-analysis. Multivariable linear regression modeling evaluated the relationship between the FI and potential predictive factors in statistically significant and non-significant meta-analyses., Results: 175 meta-analyses were included. The median FI was 6 (Q1-Q3: 3-12). This meant that moving 6 outcomes from one group to another would reverse the study's findings. The FI was 1 for 18 (10.2%) of the included meta-analyses and was ≤5 for 75 (42.4%) of the included meta-analyses. The number of events (p < 0.001) and the p-value (p < 0.001) were the best predictors of the FI in both significant and non-significant meta-analyses., Conclusion: The statistical significance of meta-analyses in ophthalmology often hinges on the outcome of a few patients. The number of events and the p-value are the most important factors in determining the fragility of the evidence. The FI is an easily interpretable measure that can supplement the reader's understanding of the strength of the evidence being presented., Prospero Registration: CRD42022377589., (© 2024. The Author(s), under exclusive licence to The Royal College of Ophthalmologists.)

Age-related macular degeneration (AMD), a complex neurodegenerative disease, is a leading cause of visual impairment worldwide with a strong genetic component. Genetic studies have identified several loci, but few causal genes with functional characterization. Here we highlight multiple lines of evidence which show a causal role in AMD for SLC16A8, which encodes MCT3, a retinal pigment epithelium (RPE) specific lactate transporter. First, in an unbiased, genome-wide analysis of rare coding variants we show multiple SLC16A8 rare variants are associated with AMD risk, corroborating previous borderline significant reports from AMD rare variant studies. Second, we report a novel SLC16A8 mutation in a three-generation family with early onset macular degeneration. Finally, mis-expression in multiple model organisms shows functional and anatomic retinal consequences. This study highlights the important role for SLC16A8 and lactate regulation towards outer retina/RPE health and highlights a potential new therapeutic opportunity for the treatment of AMD., (© 2024. The Author(s).)

Objective: To describe the sequential morphological changes of the outer retina after full-thickness macular hole formation, utilizing a novel, objective staging system based on optical coherence tomography (OCT), and to determine its association with baseline visual acuity, duration of symptoms, and postoperative visual acuity at 3 months., Design: Retrospective, observational, multicenter study., Participants: Patients with idiopathic full-thickness macular hole (FTMH) presenting to St. Michael's Hospital, Toronto, Canada, and Retina Consultants of Texas, Houston, USA, from 2009-2022., Methods: The medical charts of 1000 patients with FTMH were reviewed and those with at least two preoperative SD-OCTs were analyzed. A staging system was developed by assessing outer retinal morphology on successive SD-OCT central foveal scans., Main Outcome Measures: Sequential outer retinal morphological changes with SD-OCT over time and their association with baseline visual acuity, duration of symptoms, and postoperative functional outcomes., Results: Fifty-two eyes of 52 patients with a mean age of 65.4 ±8.4 years were included. Sequential outer retinal morphologic changes at the FTMH borders occurred in 4 distinct and reproducible stages as follows: Stage A: separation of the neurosensory retina from the RPE with the well-defined external limiting membrane (ELM), ellipsoid zone (EZ) and interdigitation zone (IDZ) (4/52, 7.6%); Stage B: thickening of EZ (27/52, 51.9%); Stage C: patchy (moth-eaten) photoreceptor loss (16/52, 30.7%) and Stage D: severe or complete loss of ISs and OSs and/or bare ELM (5/52, 9.6%). When assessing the preoperative OCT scans closest to the time of surgery, over a mean follow-up period of 288.9 days (SD 350.4,[5 -1841]), 28.8%(15/52 ) of eyes were in Stage B, 28.8% (15/52) were in Stage C and 42.3 %(22/52 ) were in Stage D. There was a statistically significant association between increasing stage at baseline and longer duration of macular hole symptoms (p=0.032) and worse visual acuity at baseline (p<0.001). Additionally, patients presenting with Stages B and C at the time point closest to surgery had better visual acuity outcomes three months postoperatively compared to those with Stage D(P=0.04)., Conclusions: This SD-OCT staging system describes the sequential in vivo morphologic changes after FTMH formation providing a novel imaging biomarker., (Copyright © 2024. Published by Elsevier Inc.)

The application of machine learning to tasks involving volumetric biomedical imaging is constrained by the limited availability of annotated datasets of three-dimensional (3D) scans for model training. Here we report a deep-learning model pre-trained on 2D scans (for which annotated data are relatively abundant) that accurately predicts disease-risk factors from 3D medical-scan modalities. The model, which we named SLIViT (for 'slice integration by vision transformer'), preprocesses a given volumetric scan into 2D images, extracts their feature map and integrates it into a single prediction. We evaluated the model in eight different learning tasks, including classification and regression for six datasets involving four volumetric imaging modalities (computed tomography, magnetic resonance imaging, optical coherence tomography and ultrasound). SLIViT consistently outperformed domain-specific state-of-the-art models and was typically as accurate as clinical specialists who had spent considerable time manually annotating the analysed scans. Automating diagnosis tasks involving volumetric scans may save valuable clinician hours, reduce data acquisition costs and duration, and help expedite medical research and clinical applications., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

We evaluate the pharmacokinetics, safety, and optimal dosages of intravitreal agents in silicone oil (SO)-filled eyes, addressing challenges in administering such therapies. We assessed the pharmacological properties and safety profiles of intravitreal drugs in SO-filled eyes, deriving conclusions and guidance from available literature and expert consensus. Preclinical data suggest comparable half-lives of anti-vascular endothelial growth factoragents in SO-filled eyes, but clinical evidence is mainly from case reports and small series. Available research prioritizes standard dosages, particularly for bevacizumab (1.25 mg), supported by stronger evidence than aflibercept (2 mg) or ranibizumab (0.5 mg). Intravitreal steroids, especially dexamethasone at 0.7 mg, show efficacy and safety, while evidence for fluocinolone acetonide at 0.19 mg is limited. Intravitreal methotrexate has been reported at the dosage of 250-400 μg, with keratitis as the primary expected side effect. Case reports indicate tolerability of standard dosages of antivirals (foscarnet 1.2-2.4 mg/0.1 mL, ganciclovir 4 mg/0.1 mL) and the antibiotic combination piperacillin/tazobactam (250 μg/0.1 mL). We offer guidance based on current, but limited, literature. Standard dosage of intravitreal agents should be carefully considered, along with close monitoring for potential side effects, which should be discussed with patients., Competing Interests: Declaration of Competing Interest None, (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: To report the safety and efficacy of brolucizumab (Beovu) 6 mg versus aflibercept (Eylea) 2 mg administered every 4 weeks in participants with neovascular age-related macular degeneration (nAMD) and persistent retinal fluid after the week 52 up to week 104., Design: Multicenter, randomized, double-masked phase 3a study., Participants: Participants with recalcitrant nAMD (persistent residual retinal fluid despite previous frequent anti-VEGF treatment)., Methods: Study eyes were randomized 2:1 to intravitreal brolucizumab 6 mg or aflibercept 2 mg every 4 weeks for 100 weeks or until study termination., Main Outcome Measures: All available efficacy (analysis of noninferiority in mean best-corrected visual acuity [BCVA], central subfield thickness [CST], fluid-free status [no intraretinal fluid and no subretinal fluid]) and safety data up to study termination, including data up to week 104 for those participants who completed the study before its termination. All P values after week 52 were nominal and reflect observed data for the efficacy analyses., Results: Brolucizumab 6 mg every 4 weeks was noninferior to aflibercept 2 mg in mean BCVA change from baseline to week 104 (least squares mean difference, -0.4 ETDRS letters; 95% confidence interval [CI], -3.7 to 3.0; P = 0.0169). The proportion of eyes with ≥15-letter loss was 6.2% for brolucizumab and 4.7% for aflibercept (P = 0.7762), and a greater proportion of eyes were fluid free at week 104 (52.5% brolucizumab vs. 28.2% aflibercept; 95% CI, 11.9-37.3; P < 0.001) in eyes treated with brolucizumab versus aflibercept. Incidence of intraocular inflammation (IOI), including retinal vasculitis and retinal vascular occlusion, was 11.5% (0.8% and 2.2%) for brolucizumab versus 6.1% (0% and 0.6%) for aflibercept., Conclusions: Consistent with 52-week results, brolucizumab 6 mg every 4 weeks was noninferior in mean BCVA change, with anatomic outcomes superior to aflibercept 2 mg every 4 weeks from baseline to week 104 or study termination. The incidence of IOI, including retinal vasculitis and retinal vascular occlusion, was higher with brolucizumab versus aflibercept; therefore, brolucizumab should not be used more frequently than every 8 weeks after the loading regimen., Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references., (Copyright © 2024 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: This study aims to define the characteristics of acquired vitelliform lesions (AVLs) in patients with intermediate age-related macular degeneration (iAMD)., Design: Retrospective, observational, cross sectional study., Subjects: This study included 217 eyes with AVLs associated with iAMD, and an equivalent number of control patients., Methods: OCT scans were evaluated for qualitative and quantitative parameters at both the eye and lesion level. Eye-level parameters included the presence of: hyporeflective core drusen, intraretinal hyperreflective foci (IHRF), subretinal drusenoid deposits, macular pachyvessels, central retinal thickness, and central choroidal thickness. Lesion-level qualitative parameters included the presence of ellipsoid zone (EZ) and external limiting membrane disruption overlying the AVL, IHRF overlying the AVL, AVL overlying drusen, pachyvessels under the AVL, a solid core within AVL, and AVL location. Lesion-level quantitative characteristics included AVL height and width, AVL distance from the fovea, and sub-AVL choroidal thickness., Main Outcome Measures: The primary outcomes assessed included the frequency of IHRF, the presence of macular pachyvessels, central choroidal thickness, and the dimensions (both height and width) of AVLs., Results: Comparing the AVL and control groups, the frequency of IHRF (AVL: 49.3% vs. control: 26.3%) and macular pachyvessels (37.3% vs. 6.9%) was significantly higher in the AVL case group, and the central choroidal thickness (256.8 ± 88 μm vs. 207.1± 45 μm) was thicker in the AVL group. Acquired vitelliform lesions located over drusen, with overlying IHRF, or situated subfoveally, and AVL lesions with EZ disruption were found to have a greater lesion height and width compared with AVL lesions lacking these characteristics (P value < 0.001 for all). Additionally, a significant negative correlation was observed between the distance from the fovea and AVL height (Spearman rho: -0.19, P = 0.002) and width (Spearman rho: -0.30, P = 0.001)., Conclusions: This study represents the largest reported cohort of AVL lesions associated with iAMD. Novel findings include the higher frequency of pachyvessels in addition to the presence of a thicker choroid in these eyes, as well as the greater height and width of AVL closer to the foveal center. These findings may offer insights into pathophysiologic mechanisms underlying the development of AVL., Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article., (Copyright © 2024 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Introduction: This study reports our experiences with systematic retinal screening in Denmark through optometrists with access to tele-ophthalmological services before, during, and after the COVID-19 pandemic., Methods: We evaluated an optometrist-based retinal screening system with a referral option for tele-ophthalmological service by a consultant ophthalmologist within the time period of August 1, 2018 to September 30, 2023. The optometrist collected patient history, refraction, best-corrected visual acuity, intraocular pressure, basic slit-lamp examination, 4-in-1 visual field report, and retinal imaging using color fundus 45° photography. Tele-ophthalmological services were provided by consultant ophthalmologists. Within pre-defined periods of pre-COVID-19, COVID-19, and post-COVID-19, we evaluated the rate of referrals to the tele-ophthalmological service, diagnoses made, and referrals to the public healthcare system., Results: A total of 1,142,028 unique individuals, which corresponded to 19.1% of the entire population of Denmark, underwent screening by the optometrists; 50,612 (4.4%) of these individuals were referred to the tele-ophthalmological examination by consultant ophthalmologists. A referral for further ophthalmic examination, either at hospital or at an ophthalmic practice, was made for 10,300 individuals (20.4% of those referred for tele-ophthalmology, corresponding to 0.9% of the population screened). The referral rate from the screening to the tele-ophthalmological service increased from before COVID-19 (3.4%) to during COVID-19 (4.3%) and further after COVID-19 (6.4%). This increase coincided with an increasing prevalence of conditions seen in the tele-ophthalmological service., Conclusion: During a period of 5 years, 19.1% of the entire population of Denmark underwent retinal screening. This provided an adjunctive health service during a period of severe strain on the public healthcare system, while limiting the number of excessive referrals to the public healthcare system. Temporal trends illustrated an increased pattern of use of a large-scale tele-ophthalmological system., (© 2024. The Author(s).)

Purpose: In this study, we identify risk factors that predict the progression of acquired vitelliform lesions (AVLs) over time., Design: Retrospective cohort study., Subjects: One hundred sixty-three eyes of 132 patients with a diagnosis of intermediate age-related macular degeneration (iAMD) with AVL., Methods: This retrospective study evaluated consecutive eyes with AMD from a retina clinic population and included 1181 patients and 2362 eyes. After excluding cases with associated geographic atrophy, macular neovascularization (MNV), vitreomacular traction, and those with <2 years of follow-up data, the final analysis cohort consisted of 163 eyes (132 patients) with ≥1 AVL. The first available visit in which an AVL was evident was considered the baseline visit, and follow-up data were collected from a visit 2 years (± 3 months) later. Progression outcomes at the follow-up visit were classified into 6 categories: resorbed, collapsed, MNV, stable, increasing, and decreasing. Subsequently, we analyzed the baseline characteristics for each category and calculated odds ratios (ORs) to predict these various outcomes., Main Outcome Measures: The study focused on identifying predictive factors influencing the evolution of AVL in iAMD eyes., Results: In total, 163 eyes with AVL had follow-up data at 2 years. The collapsed group demonstrated a significantly greater baseline AVL height and width compared with other groups (P < 0.001). With regard to qualitative parameters, subretinal drusenoid deposits (SDDs) and intraretinal hyperreflective foci (IHRF) at the eye level, AVL located over drusen, and IHRF and external limiting membrane disruption over AVL were significantly more prevalent in the collapsed group compared with other groups (P < 0.05 for all comparisons). Odds ratios for progressing to atrophy after 2 years of follow-up, compared with the resorbed group, were significant for SDD (OR, 2.82; P = 0.048) and AVL height (OR, 1.016; P = 0.006)., Conclusions: The presence of SDDs and greater AVL height significantly increases the risk of developing atrophy at the location of AVL after 2 years of follow-up. These findings may be of value in risk prognostication and defining patient populations for inclusion in future early intervention trials aimed at preventing progression to atrophy., Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article., (Copyright © 2024 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: To review sustained-release intraocular platforms used to treat diseases of the retina and choroid. Methods: A literature review of the current applications of biomaterials for sustained-release therapy in retinal and choroidal diseases was performed. Results: Retinal and choroidal diseases, such as neovascular age-related macular degeneration (nAMD), diabetic retinopathy (DR), diabetic macular edema (DME), and uveitis, are commonly treated using intravitreal (IVT) therapies that require frequent IVT injections. Multiple sustained-release options for IVT therapy have been approved by the US Food and Drug Administration for the treatment of inflammatory eye diseases, including noninfectious uveitis, infectious diseases, and exudative retinal diseases (eg, retinal venous occlusive disease and DME) using drugs such as fluocinolone acetonide, ganciclovir, and dexamethasone. The platforms for these drugs are biodegradable or nonbiodegradable. They use biomaterials such as polymers and hydrogels and are typically implanted surgically or injected into the vitreous, where they release the drug gradually over months or years. Building on these technologies, novel platforms are being studied that are intended to treat conditions including nAMD, DR, DME, and uveitis. These platforms are being tested for their safety, efficacy, and ability to reduce the injection and visit burden. Conclusions: Multiple sustained-release ocular drug-delivery platforms are currently commercially available, and many new sustained-release IVT platforms are being investigated. The hope is that meaningfully reducing the injection burden by extending intervals between treatments while maintaining optimal efficacy will improve long-term outcomes., Competing Interests: Dr. Wykoff: Consulting—4DMT, AbbVie, Adverum, Aerie, AGTC, Alcon, Annexon, Apellis, Arrowhead, Ascidian, Bayer, Bausch+ Lomb, Boehringer Ingelheim, Cholgene, Clearside, Curacle, Eyebiotech, EyePoint, Foresite, Frontera, Genentech, Gyroscope, Iveric Bio, Janssen, Kato, Kiora, Kodiak, Kriya, Merck, Nanoscope, Neurotech, NGM, Notal Vision, Novartis, Ocular Therapeutix, Ocuphire, OcuTerra, ONL, Opthea, Oxular, Palatin, PerceiveBio, Perfuse, Ray, RecensMedical, Regeneron, RegenxBio, Resonance, Roche, Sanofi, SciNeuro, Stealth, Surrozen, Suzhou Raymon, THEA, TissueGen, Valo. Grants—4DMT, Adverum, AffaMed, Alexion, Alimera, Alkahest, Allgenesis, Amgen, Annexin, Annexon, Apellis, Asclepix, Bayer, Boehringer Ingelheim, Chengdu Kanghong, Clearside, Curacle, EyePoint, Gemini, Genentech, GlaxoSmithKline, Gyroscope, Ionis, iRenix, Iveric Bio, Janssen, Kodiak, LMRI, McMaster University, Nanoscope, Neurotech, NGM, Novartis, Ocular Therapeutix, Ocuphire, OcuTerra, OliX, Ophthotech, Opthea, Oxurion, Oxular, Oyster Point, PerceiveBio, Regeneron, RegenxBio, Rezolute, Roche, SamChunDang Pharm, Sandoz, Shanghai Henlius, UNITY, Verily, Xbrane. Stock options (not owner)—ONL, PolyPhotonix, RecensMedical, TissueGen, Visgenx, Vitranu. Dr. Kuppermann: Consulting—Allegro Ophthalmics, Allergan/AbbVie, Aviceda Therapeutics, Bausch+Lomb, Boehringer Ingelheim, Clearside, EyeBio, Eyedaptic, EyePoint, Genentech Inc, Glaukos Corporation, InflammX Therapeutics, Iveric Bio, jCyte, Molecular Partners, Neurotech, Novartis Pharmaceuticals, Ocular Therapeutix, Regeneron Pharmaceuticals Inc, ReVana Therapeutics, Ripple Therapeutics, Roche Pharmaceuticals, Stealth, Theravance Biopharma. Research support—Allergan, Apellis, Clearside, Genentech Inc, Ionis, Iveric Bio, Novartis Pharmaceuticals, Regeneron Pharmaceuticals Inc, RegenxBio. Speaker fees—Allergan, Genentech, Roche. Dr. Kuppermann acknowledges an unrestricted grant from Research to Prevent Blindness to the Gavin Herbert Eye Institute. Dr. Regillo: Consulting—4DMT, Adverum, Allergan, Annexon, Apellis, Aviceda, Bausch and Lomb, Clearside, Cognition, Eyepoint, Genentech, Iveric, Janssen, Kodiak, Lineage, Merck, NGM, Novartis, Ocugen, Ocuterra, Occuphire, Opthea, Ray, RegenxBio, Stealth, Thea, Zeiss. Research grant support—Adverum, Allergan, Annexon, Apellis, Astellas, EyePoint, Genentech, Gyroscope, Iveric, Janssen, Kodiak, Lineage, NGM, Notal, Novartis, Ocugen, Ocuterra, Opthea, Regeneron, RegenxBio. Dr. Chang: Consulting—Genentech, RegenxBio, Iveric Bio. Research support—Regeneron, Allergan, Novartis, NGM, Opthea, Eyebio, OcuTerra, Alexion, Mylan. Dr. Hariprasad: Consulting/speaker fees—Alimera Sciences, Allergan, EyePoint, Regeneron, Biogen, Apellis, Iveric Bio. Drs. Duker, Altaf, and Saïm are employees of EyePoint Pharmaceuticals., (© The Author(s) 2024.)

Aims: The aim of this study is to assess baseline characteristics of drusen preceding the development of intraretinal hyper-reflective foci (IHRF) in eyes with intermediate age-related macular degeneration (AMD)., Methods: In this retrospective case-control study, longitudinal optical coherence tomography (OCT) volume data from eyes with intermediate AMD in a retina clinic population were screened. All drusen that developed overlying IHRF were marked. A random number generator was used to select for further grading three drusen that did not develop IHRF., Results: Ninety eyes (from 72 patients), including 140 drusen with overlying IHRF and 270 IHRF- drusen, were analysed. Greater drusen height, basal drusen width and overlying ellipsoid zone (EZ) and external limiting membrane disruption were associated with a significantly greater risk for IHRF development (p≤0.001). Regression analysis revealed EZ disruption increased these odds by 4.1 (p≤0.001). Each 10-µm increase in drusen height and width increased the odds by 34% (p≤0.001) and 3% (p: 0.005), respectively. Each 100-µm increase in distance from the fovea decreased the odds by 10% (p: 0.013)., Conclusions: The presence of overlying EZ disruption and a greater drusen height substantially increased the risk for IHRF development, whereas drusen further from the fovea indicated reduced risk. Given the importance of IHRF as a biomarker for AMD progression, these findings may be of value in defining patient populations for future early intervention trials., Competing Interests: Competing interests: SriniVas R. Sadda receives support from 4DMT, Alexion, Allergan, Alnylam Pharmaceuticals, Amgen Inc Apellis Pharmaceuticals, Astellas, Bayer Healthcare Pharmaceuticals, Carl Zeiss Meditec, Catalyst Pharmaceuticals, Centervue, GENENTECH, Gyroscope Therapeutics, Heidelberg Engineering, Iveric Bio, Janssen Pharmaceuticals, Merck & Co., Nanoscope, Nidek Incorporated, Novartis Pharma AG, Optos, Oxurion/ Thrombogenics, Pfizer, Regeneron Pharmaceuticals, Samsung Bioepis, Topcon Medical Systems, Vertex Pharmaceuticals Incorporated. David Sarraf receives support from Amgen, Bayer, Endogena Therapeutics, Genentech, Iveric Bio, Novartis and Optovue/Visionix and receives research grants from Amgen, Boehringer, Genentech, Heidelberg, Optovue/Visionix, Regeneron, and Topcon. Charles C. Wykoff receives support from 4DMT, AbbVie, Adverum, Aerie, AGTC, Alcon, Alimera, Allergan, Allgenesis, Alnylam, Annexon, Apellis, Arrowhead, Bausch + Lomb, Bayer, Bionic Vision, Boehringer Ingelheim, Chengdu Kanghong, Cholgene, Clearside, Curacle, EyePoint, Foresite, Frontera, Genentech, Gyroscope, IACTA, IVERIC Bio, Janssen, Kato, Kiora, Kodiak, Kriya, Merck, Nanoscope, NGM, Notal Vision, Novartis, OccuRx, Ocular Therapeutix, Ocuterra, OliX, ONL, Opthea, Palatin, PerceiveBio, Perfuse, PolyPhotonix, Ray, RecensMedical, Regeneron, RegenXBio, Resonance, Roche, SciNeuro, Stealth, Surrozen, THEA, TissueGen, Valo, Verana, Vitranu. Grants from ongoing relationships as a Principal Investigator with: 4DMT, Adverum, Aerie, AffaMed, Aldeyra, Alexion, Alimera, Alkahest, Allergan, Allgenesis, Amgen, Annexin, Annexon, Apellis, Asclepix, Bayer, Boehringer Ingelheim, Chengdu Kanghong, Clearside, Curacle, EyePoint, Gemini, Genentech, Graybug Vision, Gyroscope, IONIS, iRENIX, IVERIC bio, Kodiak, LMRI, Nanoscope, Neurotech, NGM, Novartis, Ocular Therapeutix, Ocuphire, OcuTerra, Opthea, Oxurion, Oxular, Oyster Point, Perceive Biotherapeutics, RecensMedical, Regeneron, RegenXBio, Roche, SamChunDang Pharm, Sandoz, Taiwan Liposome Company, UNITY, Verily, Xbrane. Stock Options (not owner) from ongoing relationships as a Consultant from Private Companies: ONL, PolyPhotonix, RecensMedical, TissueGen, Visgenx, Vitranu. Giulia Corradetti receives support from Nidek. Muneeswar Gupta Nittala receives support from Eyenuk., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: The purpose of this study was to quantitatively analyze and compare OCT characteristics of intraretinal hyper-reflective foci (IHRF) in eyes with diabetic retinopathy (DR) versus age-related macular degeneration (AMD)., Design: a retrospective observational study., Participants: 54 treatment-naïve eyes (27 DR and 27 AMD)., Methods: The IHRF lesions in OCT B-scan were semi-automatically segmented. Mean reflectivity (MR), maximum diameter, circularity index (Cir), area, and the angle between the greatest linear dimension (GLD) and the horizontal were computed for each IHRF lesion. The presence and absence of a posterior shadow and the axial location were assessed. The MR was normalized using the vitreous and nerve fiber layer reflectance as dark and bright reference standards, respectively., Results: A total of 1149 IHRF (1051 in DR and 98 in the AMD group) were identified, with a mean of 39 ± 36 lesions in DR eyes compared to only 4 ± 4 in AMD eyes (p < 0.001). The mean area of individual IHRF lesions was greater in DR eyes (1305 ± 1647 μm² vs 1031 ± 750 μm²; p = 0.016), but IHRF in AMD eyes had higher reflectivity (1.17 ± 0.14 vs 1.03 ± 0.17; p < 0.001). The angle of the GLD relative to the horizontal was greater in AMD eyes, indicating that IHRF in AMD eyes were more horizontally oriented. In AMD eyes, 88.8% of IHRF were located beneath the inner border of the outer nuclear layer (ONL), while in DR eyes, 56.9% were located there (p < 0.001)., Conclusions: IHRF lesions in eyes with DR and AMD demonstrate significant differences, with IHRF in DR eyes tending to be larger and less hyper-reflective compared to AMD eyes., (Copyright © 2024 Canadian Ophthalmological Society. Published by Elsevier Inc. All rights reserved.)

Importance: Anti-vascular endothelial growth factor (VEGF) intravitreal injections, a mainstay of treatment for many retinal diseases to optimize visual outcomes, have been included in prior authorization (PA) initiatives. However, if clinicians are extremely accurate in their use of anti-VEGF medications, such administrative burdens may need reconsideration., Objective: To quantify PA for anti-VEGF medications (aflibercept, ranibizumab, and bevacizumab) that were approved and determine associated administrative burdens experienced by retina practices., Design, Setting, and Participants: Prospective multicenter quality improvement study conducted from January 2022 through June 2022, and participants were 9 private retina practices across the US., Main Outcomes and Measures: Overall rate of approval of PA requests, reasons for requesting PA, and overall rate of delay of care resulting from PA procedures., Results: In total, 2365 PA requests were recorded, 2225 of which met inclusion criteria. Overall, 2140 (96.2%) requests were approved. The most common reason for requesting PA, at 64% (1423 of 2225 requests), was reauthorization for a previously utilized medication. Of the 2140 approvals, 59.6% (1277) resulted in a delay in care greater than 24 hours, and 40% (863) were given on the date of service. In a granular analysis of a subset of delayed approvals, 23.9% (173 of 725) were approved within 1 day, 15.9% (115 of 725) were approved within 2 to 3 days, 21.5% (156 of 725) were approved within 4 to 7 days, 26.3% (191 of 725) were approved within 8 to 31 days, and 12.4% (90 of 725) were approved within more than 31 days. Overall, PA denial for step therapy was 2.9% (65 of 2225) of requests and uncovered diagnoses was 0.9% (20 of 2225) of requests. The median staff time spent to obtain a single PA was 100 (range, 0-200) minutes., Conclusions and Relevance: In this study, PA requests were almost always approved but led to a delay in patient care in most patients. The current study suggests that the PA process may not be effective for retina specialists if these results can be generalized to other practices in the US and if less burdensome and less costly approaches could result in similar approval rates. Potential short-term solutions may include eliminating the PA process for bevacizumab and reauthorizations for established patients.

Purpose: This study was designed to investigate retinal nerve fiber layer circumpapillary optical coherence tomography to determine posterior vitreous detachment (PVD) status and to develop a clinically relevant PVD grading scale based on retinal nerve fiber layer circumpapillary optical coherence tomography to determine the incidence of PVD by age and association with vitreomacular traction disorders., Methods: Ophthalmic images and medical records of patients with retinal diseases were retrospectively analyzed by three masked graders using retinal nerve fiber layer circumpapillary optical coherence tomography and macular optical coherence tomography. Based on PVD status, eyes were categorized into five newly defined PVD stages., Results: Among 2002 eyes, PVD stages were as follows: A) 25 (1.25%); B) 725 (36.21%); C-) 248 (12.39%); C+) 151 (7.54%); D) 851 (42.51%); X) 2 (0.1%). Posterior vitreous detachment was correlated with advanced age (P < 0.0001). Limited separation or partial separation between lamella within the posterior vitreous cortex (Stage B) was noted early (68% of eyes <18 years). Overall, 34% of eyes >70 years did not exhibit complete PVD. Of 75 eyes with tractional vitreoretinal disorders, 64 (85.3%) were Stage C-/C+, identifying Stage C as the high-risk "complication" stage., Conclusion: Imaging analyses using retinal nerve fiber layer circumpapillary optical coherence tomography and macular optical coherence tomography scans in conjunction allow rapid assessment of the PVD stage. These techniques can assist clinicians and surgeons in counseling patients and planning surgical approaches. Observations confirmed the progression of PVD through predictable stages and the progression of PVD with age., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Opthalmic Communications Society, Inc.)

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.)

Objective: To assess the effect of the COVID-19 pandemic on injection intervals among patients treated for neovascular age-related macular degeneration., Design: Retrospective cohort study., Participants: Patients treated at a single practice using a treat-and-extend regimen with intravitreal aflibercept between December 2018 and April 2021., Methods: The primary outcome was the change in injection intervals. Secondary outcomes included differences in best-recorded visual acuity (BRVA) and central subfield thickness (CST). Associations were evaluated with linear mixed-effects modelling., Results: This study included 1839 injections from 185 eyes (141 patients). The median (interquartile range) injection intervals in the pre-COVID-19 and COVID-19 periods were 60 (42-70) and 70 (49-90) days, respectively. The pandemic was associated with a mean injection interval lengthening of 7.2 days (P < 0.001), a decrease in BRVA of 3.1 Early Treatment Diabetic Retinopathy Study letters (P < 0.001), and a reduction in CST of 14.7 μm (P = 0.003). The presence of exudative intraretinal fluid was associated with a reduction in treatment intervals of 11.1 days (P < 0.001), a reduction in BRVA of 1.9 Early Treatment Diabetic Retinopathy Study letters (P < 0.001), and an increase in CST of 52.4 μm (P < 0.001). The presence of subretinal fluid was associated with a reduction in treatment intervals of 8.5 days (P < 0.001) and an increase in CST of 21.6 μm (P < 0.001)., Conclusions: This real-world study estimated that the severe acute respiratory syndrome coronavirus 2 pandemic resulted in an injection extension of 7.2 days with associated decreases in BRVA and CST that are unlikely clinically significant on a population basis. This builds on evidence suggesting that long-term vascular endothelial growth factor suppression can facilitate meaningful interval extensions while maintaining visual acuity., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background/purpose: To determine and compare the efficacy of a surgical internal limiting membrane (ILM) flap technique with the traditional ILM peel on long-term visual and anatomical outcomes for large (>400 µm) full-thickness macular holes., Methods: From October 2016 to July 2022, patients undergoing initial full-thickness macular hole repair with the ILM flap or ILM peel technique were reviewed. Final outcomes were recorded and based on size in microns: 401 to 800, 801 to 1,200, and >1,200., Results: Patients treated with ILM flap (n = 52, 94.2% closure rate) or ILM peel (n = 407, 93.6% closure rate) were followed with a mean follow-up time of 15.0 ± 10.2 and 20.0 ± 13.4 months, respectively. Success rates for ILM flaps and ILM peels were compared for full-thickness macular holes of 401 to 800 (100%, 95.8%, P = 0.39), 801 to 1,200 (95%, 93%, P = 0.74), and >1,200 (86.7%, 86.7%, P = 1.0) µm. Mean best-recorded logarithm of the minimal angle of resolution visual acuity for ILM flaps and ILM peels, respectively, was 1.02 ± 0.46 and 0.87 ± 0.47 preoperatively, with follow-up acuity of 0.48 ± 0.32 (P < 0.03) and 0.39 ± 0.42 (P < 0.01) at Year 3., Conclusion: Both techniques provide a similar anatomical closure rate and functional improvement in vision. Comparisons should be cautiously made based on difference in preoperative hole size.

Purpose: To define optical coherence tomography (OCT) biomarkers that precede the development of complete retinal pigment epithelium and outer retinal atrophy (cRORA) at that location in eyes with age-related macular degeneration (AMD)., Methods: In this retrospective case-control study, patients with dry AMD who had evidence of cRORA and OCT data available for 4 years (48 ± 4 months) prior to the first visit with evidence of cRORA were included. The visit 4 years prior to the development of cRORA was defined as the baseline visit, and the region on the OCT B-scans of future cRORA development was termed the case region. A region in the same eye at the same distance from the foveal center as the case region that did not progress to cRORA was selected as the control region. OCT B-scans at the baseline visit through both the case and control regions were evaluated for the presence of soft and cuticular drusen, drusen with hyporeflective cores (hcD), drusenoid pigment epithelial detachments (PED), subretinal drusenoid deposits (SDD), thick and thin double-layer signs (DLS), intraretinal hyperreflective foci (IHRF), and acquired vitelliform lesions (AVL)., Results: A total of 57 eyes of 41 patients with dry AMD and evidence of cRORA were included. Mean time from the baseline visit to the first visit with cRORA was 44.7 ± 6.5 months. The presence of soft drusen, drusenoid PED, AVL, thin DLS, and IHRF at the baseline visit was all associated with a significantly increased risk of cRORA at that location. Multivariable logistic regression revealed that IHRF (OR, 8.559; p < 0.001), drusenoid PED (OR, 7.148; p = 0.001), and a thin DLS (OR, 3.483; p = 0.021) were independent predictors of development of cRORA at that location., Conclusions: IHRF, drusenoid PED, and thin DLS are all local risk factors for the development of cRORA at that same location. These findings would support the inclusion of these features within a more granular staging system defining specific steps in the progression from early AMD to atrophy., (© 2024. The Author(s).)

Purpose: To evaluate the 2-year efficacy, durability, and safety of dual angiopoietin-2 and vascular endothelial growth factor (VEGF) A pathway inhibition with intravitreal faricimab according to a personalized treat-and-extend (T&E)-based regimen with up to every-16-week dosing in the YOSEMITE and RHINE (ClinicalTrials.gov identifiers, NCT03622580 and NCT03622593, respectively) phase 3 trials of diabetic macular edema (DME)., Design: Randomized, double-masked, noninferiority phase 3 trials., Participants: Adults with visual acuity loss (best-corrected visual acuity [BCVA] of 25-73 letters) due to center-involving DME., Methods: Patients were randomized 1:1:1 to faricimab 6.0 mg every 8 weeks, faricimab 6.0 mg T&E (previously referred to as personalized treatment interval), or aflibercept 2.0 mg every 8 weeks. The T&E up to every-16-week dosing regimen was based on central subfield thickness (CST) and BCVA change., Main Outcome Measures: Included changes from baseline in BCVA and CST, number of injections, durability, absence of fluid, and safety through week 100., Results: In YOSEMITE and RHINE (n = 940 and 951, respectively), noninferior year 1 visual acuity gains were maintained through year 2; mean BCVA change from baseline at 2 years (weeks 92, 96, and 100 average) with faricimab every 8 weeks (YOSEMITE and RHINE, +10.7 letters and +10.9 letters, respectively) or T&E (+10.7 letters and +10.1 letters, respectively) were comparable with aflibercept every 8 weeks (+11.4 letters and +9.4 letters, respectively). The median number of study drug injections was lower with faricimab T&E (YOSEMITE and RHINE, 10 and 11 injections, respectively) versus faricimab every 8 weeks (15 injections) and aflibercept every 8 weeks (14 injections) across both trials during the entire study. In the faricimab T&E arms, durability was improved further during year 2, with > 60% of patients receiving every-16-week dosing and approximately 80% receiving every-12-week or longer dosing at week 96. Almost 80% of patients who achieved every-16-week dosing at week 52 maintained every-16-week dosing without an interval reduction through week 96. Mean CST reductions were greater (YOSEMITE/RHINE weeks 92/96/100 average: faricimab every 8 weeks -216.0/-202.6 µm, faricimab T&E -204.5/-197.1 µm, aflibercept every 8 weeks -196.3/-185.6 µm), and more patients achieved absence of DME (CST < 325 μm; YOSEMITE/RHINE weeks 92-100: faricimab every 8 weeks 87%-92%/88%-93%, faricimab T&E 78%-86%/85%-88%, aflibercept every 8 weeks 77%-81%/80%-84%) and absence of intraretinal fluid (YOSEMITE/RHINE weeks 92-100: faricimab every 8 weeks 59%-63%/56%-62%, faricimab T&E 43%-48%/45%-52%, aflibercept every 8 weeks 33%-38%/39%-45%) with faricimab every 8 weeks or T&E versus aflibercept every 8 weeks through year 2. Overall, faricimab was well tolerated, with a safety profile comparable with that of aflibercept., Conclusions: Clinically meaningful visual acuity gains from baseline, anatomic improvements, and extended durability with intravitreal faricimab up to every 16 weeks were maintained through year 2. Faricimab given as a personalized T&E-based dosing regimen supports the role of dual angiopoietin-2 and VEGF-A inhibition to promote vascular stability and to provide durable efficacy for patients with DME., Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article., (Copyright © 2024 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

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.)

Purpose: To report a case of a suspected open-globe injury and globe penetration complicated by a rhegmatogenous retinal detachment (RRD) after administration of intraoral anesthetic injections during an endodontic procedure. Methods: A retrospective chart review was performed. Results: A 34-year-old woman presented with acute onset of flashes, floaters, and a curtain-like shadow across her field of vision. Four days previously, she had multiple left-sided anesthetic injections during an endodontic procedure. The visual acuity (VA) in the left eye was 20/25. Ophthalmoscopy showed a suspected globe-penetration site inferiorly, associated multilayered hemorrhages, and adjacent subretinal fluid. Laser demarcation of the inferior RRD was performed at sequential clinical visits. Through 8 months, the multilayered hemorrhages improved while proliferative vitreoretinopathy-associated tissue formation over the posterior pole caused macular distortion and mild visual deterioration. The VA in the left eye was 20/40 at the last follow-up. Conclusions : Iatrogenic globe penetration during intraoral anesthesia delivery associated with an endodontic procedure may result in globe injury., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2024.)

With the introduction of therapies to treat geographic atrophy (GA), GA management in clinical practice is now possible. A living systematic review can provide access to timely and robust evidence synthesis. This review found that complement factor 3 and 5 (C3 and C5) inhibition compared to sham likely reduces change in square root GA area at 12 months and untransformed GA area at 24 months. There is likely little to no difference in the rate of systemic treatment-emergent adverse events compared to sham. C3 and C5 inhibition, however, likely does not improve best-corrected visual acuity (BCVA) at 12 months, and the evidence is uncertain regarding change in BCVA at 24 months. Higher rates of ocular treatment emergent adverse effects with complement inhibition occur at 12 months and likely at 24 months. Complement inhibition likely results in new onset neovascular age-related macular degeneration at 12 months. This living meta-analysis will continuously incorporate new evidence., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023. Published by Elsevier Inc.)

Introduction: To assess real-world safety outcomes for adults with neovascular age-related macular degeneration (nAMD) treated with brolucizumab from the US-based IRIS® (Intelligent Research in Sight) Registry., Methods: In this retrospective study, 18,312 eyes (15,998 patients) treated with ≥ 1 intravitreal brolucizumab injections between 8 October 2019 (US launch date for brolucizumab) and 7 October 2021 were followed up for ≤ 2 years after first injection (index date). The study assessed the predefined incident ocular adverse events of intraocular inflammation (IOI), retinal vasculitis (RV), and retinal vascular occlusion (RO)., Results: Overall, 614/18,312 eyes (3.4%) experienced any IOI, RV, and/or RO event. Median (interquartile range [IQR]) time to an event was 84 (42-167) days; 77.4% of events (475/614) occurred within 6 months after index date. Median (IQR) number of brolucizumab injections before an event was 2 (1-4). For eyes with an adverse event and visual acuity (VA) data (n = 406), median (IQR) change in Early Treatment of Diabetic Retinopathy Study (ETDRS) letters from pre-event VA was 0 (- 7 to + 5) at the 6-month follow-up; 50 eyes (12.3%) had a VA loss of 10 or more ETDRS letters. Risk of an event (hazard ratio [95% confidence interval]) was decreased in eyes from male patients (0.61 [0.53-0.71]), from older patients (0.83 [0.76-0.90]), from treatment-naive patients (0.51 [0.38-0.69]), and from patients who started brolucizumab in the second year after launch (0.68 [0.53-0.86] vs. first year)., Conclusion: In this large real-world brolucizumab safety study, 3.4% of eyes experienced an IOI, RV, and/or RO event. Among eyes that experienced an adverse event for which VA data were available, median ETDRS vision change was 0 letters (IQR - 7 to + 5)., (© 2024. The Author(s).)

Purpose: To evaluate clinical trials in the literature that focus on suprachoroidal drug delivery for the treatment of noninfectious uveitis and other posterior segment diseases. Methods: A synthesis of the literature was performed. Results: In 2021, suprachoroidal space triamcinolone acetonide, a corticosteroid delivery system used for the treatment of uveitic macular edema (ME), was approved by the US Food and Drug Administration. The drug-delivery system targets the suprachoroidal space using a microneedle-based device and has a favorable pharmacokinetic profile. Suprachoroidally administered investigational therapies have also been assessed in clinical trials for other posterior segment diseases, including diabetic ME, retinal vein occlusion, age-related macular degeneration, and choroidal melanoma. Conclusions: The safety and efficacy of suprachoroidal corticosteroid injections to treat uveitic ME have been shown in recent phase III clinical trials. Multiple programs are also investigating this modality of drug delivery for use in many other retinal and choroidal pathologies., Competing Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Dr. Yeh reports consulting and advisory board fees from Bausch + Lomb, Clearside Biomedical, Inc, and RegenxBio. Dr. Wykoff reports consulting fees from Bausch + Lomb, Clearside Biomedical, Inc, and RegenxBio. None of the other authors declared financial conflicts of interest related to this work., (© The Author(s) 2024.)

Purpose: To report the 100-week outcomes from the KESTREL and KITE trials., Design: Two phase 3, double-masked, active-controlled, randomized trials., Methods: Patients with diabetic macular edema (DME) were randomized 1:1:1 to brolucizumab 3 mg/6 mg (BRO3/BRO6) or aflibercept 2 mg (AFL) in KESTREL (N = 566) or 1:1 to BRO6 or AFL in KITE (N = 360). BRO3/BRO6 arms received 5 loading doses every 6 weeks (q6w) followed by q12w dosing, with an option to adjust to q8w at predefined disease activity assessment visits. In KITE, at week 72, based on the disease stability assessment, treatment intervals could be extended by 4 weeks in the BRO6 arm. AFL arms received 5 monthly loading doses followed by fixed q8w dosing., Results: At week 100, change from baseline in BCVA (letters) was +8.8 for BRO6 and +10.6 for AFL in KESTREL; and +10.9 for BRO6 and +8.4 for AFL in KITE. In both studies, fewer BRO6 subjects had intraretinal fluid and/or subretinal fluid than AFL subjects. Results were achieved with 32.9% (KESTREL) and 47.5% (KITE) of BRO6 subjects maintained on q12w and q12w/q16w dosing, respectively. Intraocular inflammation rates for BRO6 vs AFL were 4.2% vs 1.1% (KESTREL) and 2.2% vs 1.7% (KITE), of which retinal vasculitis rates were 0.5% vs 0% in KESTREL, with no cases in KITE. Retinal vascular occlusion rates were 1.6% vs 0.5% (KESTREL) and 0.6% in both treatment arms in KITE., Conclusions: Results show the long-term efficacy and durability of brolucizumab in improving visual and anatomical outcomes in DME; the overall safety profile of brolucizumab remained unchanged through year 2., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: Hyperglycemia is a major risk factor for early lesions of diabetic retinal disease (DRD). Updating the DRD staging system to incorporate relevant basic and cellular mechanisms pertinent to DRD is necessary to better address early disease, disease progression, the use of therapeutic interventions, and treatment effectiveness., Design: We sought to review preclinical and clinical evidence on basic and cellular mechanisms potentially pertinent to DRD that might eventually be relevant to update the DRD staging system., Participants: Not applicable., Methods: The Basic and Cellular Mechanisms Working Group (BCM-WG) of the Mary Tyler Moore Vision Initiative carefully and extensively reviewed available preclinical and clinical evidence through multiple iterations and classified these., Main Outcome Measures: Classification was made into evidence grids, level of supporting evidence, and anticipated future relevance to DRD., Results: A total of 40 identified targets based on pathophysiology and other parameters for DRD were grouped into concepts or evaluated as specific candidates. VEGFA, peroxisome proliferator-activated receptor-alpha related pathways, plasma kallikrein, and angiopoietin 2 had strong agreement as promising for use as biomarkers in diagnostic, monitoring, predictive, prognostic, and pharmacodynamic responses as well as for susceptibility/risk biomarkers that could underlie new assessments and eventually be considered within an updated DRD staging system or treatment, based on the evidence and need for research that would fit within a 2-year timeline. The BCM-WG found there was strong reason also to pursue the following important concepts regarding scientific research of DRD acknowledging their regulation by hyperglycemia: inflammatory/cytokines, oxidative signaling, vasoprotection, neuroprotection, mitophagy, and nutrients/microbiome., Conclusion: Promising targets that might eventually be considered within an updated DRD staging system or treatment were identified. Although the BCM-WG recognizes that at this stage little can be incorporated into a new DRD staging system, numerous potential targets and important concepts deserve continued support and research, as they may eventually serve as biomarkers and/or therapeutic targets with measurable benefits to patients with diabetes., 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.)

Background: A high-dose formulation of intravitreal aflibercept (8 mg) could improve treatment outcomes in diabetic macular oedema (DMO) by requiring fewer injections than the standard comparator, aflibercept 2 mg. We report efficacy and safety results of aflibercept 8 mg versus 2 mg in patients with DMO., Methods: PHOTON was a randomised, double-masked, non-inferiority, phase 2/3 trial performed at 138 hospitals and specialty retina clinics in seven countries. Eligible patients were adults aged 18 years or older with type 1 or 2 diabetes and centre-involved DMO. Patients were randomly assigned (1:2:1) to intravitreal aflibercept 2 mg every 8 weeks (2q8), aflibercept 8 mg every 12 weeks (8q12), or aflibercept 8 mg every 16 weeks (8q16), following initial monthly dosing. From week 16, dosing intervals for the aflibercept 8 mg groups were shortened if patients met prespecified dose regimen modification criteria denoting disease activity. The primary endpoint was change from baseline in best-corrected visual acuity (BCVA) at week 48 (non-inferiority margin of 4 letters). Efficacy and safety analyses included all randomly assigned patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov (NCT04429503)., Findings: Between June 29, 2020, and June 28, 2021, 970 patients were screened for eligibility. After exclusions, 660 patients were enrolled and randomly assigned to receive aflibercept 8q12 (n=329), 8q16 (n=164), or 2q8 (n=167); two patients were randomly assigned in error and did not receive treatment. 658 (99·7%) patients were treated and included in the full analysis set and safety analysis set (8q12 n=328, 8q16 n=163, and 2q8 n=167). Mean patient age was 62·3 years (SD 10·4). 401 (61%) patients were male. 471 (72%) patients were White. Aflibercept 8q12 and 8q16 demonstrated non-inferior BCVA gains to aflibercept 2q8 (BCVA mean change from baseline 8·8 letters [SD 9·0] in the 8q12 group, 7·9 letters [8·4] in the 8q16 group, and 9·2 letters [9·0] in the 2q8 group). The difference in least squares means was -0·57 letters (95% CI -2·26 to 1·13, p value for non-inferiority <0·0001) between 8q12 and 2q8 and -1·44 letters (-3·27 to 0·39, p value for non-inferiority 0·0031) between aflibercept 8q16 and 2q8. Proportions of patients with ocular adverse events in the study eye were similar across groups (8q12 n=104 [32%], 8q16 n=48 [29%], and 2q8 n=46 [28%])., Interpretation: Aflibercept 8 mg demonstrated efficacy and safety with extended dosing intervals and could decrease treatment burden in patients with DMO., Funding: Regeneron Pharmaceuticals and Bayer., Competing Interests: Declaration of interests DMB serves as a scientific adviser for Regeneron/Bayer and Genentech/Roche and as a member of the Regeneron Combination Products Steering Committee. DSB has served as a consultant for Adverum, Allergan, Bayer, Genentech, Graybug, Novartis, Regeneron Pharmaceuticals, REGENXBIO, and Roche. DVD is a consultant to Allergan, AsclepiX, Boehringer Ingelheim, Clearside, Genentech, Kodiak Sciences, and Regeneron Pharmaceuticals and has received research funding from AsclepiX, Boehringer Ingelheim, Genentech, and Regeneron Pharmaceuticals. CCW is a consultant for 4DMT, AbbVie, Adverum, Aerie, AGTC, Alcon, Annexon, Apellis, Arrowhead, Bausch + Lomb, Boehringer Ingelheim, Cholgene, Clearside, Curacle, EyePoint, Genentech, Gyroscope, IACTA, Iveric Bio, Janssen, Kato, Kiora, Kodiak Sciences, Kriya, Merck, Nanoscope, NGM, Novartis, Ocular Therapeutix, OcuTerra, ONL, Opthea, Oxular, Palatin, PerceiveBio, Perfuse, Ray, RecensMedical, Regeneron Pharmaceuticals, REGENXBIO, Roche, and Stealth and has received research support from 4DMT, Adverum, AffaMed, Alexion, Alimera, Alkahest, Allgenesis, Amgen, Annexin, Annexon, Apellis, AsclepiX, Bayer, Boehringer Ingelheim, Clearside, Curacle, EyePoint, Gemini, Genentech, GlaxoSmithKline, Gyroscope, IONIS, iRENIX, Iveric Bio, Kodiak Sciences, LMRI, Nanoscope, Neurotech, NGM, Novartis, Ocular Therapeutix, Ocuphire, OcuTerra, Opthea, Ophthotech, Oxurion, Oxular, Oyster Point, PerceiveBio, Regeneron Pharmaceuticals, REGENXBIO, Roche, and UNITY. TSa is a consultant for Bayer, Boehringer Ingelheim, Chugai/Roche, Novartis, and Senju. ASe is a consultant for Syneos Health and Novartis; has served as an adviser for Roche; and has contributed to the industry-sponsored international multicentre studies for Allergan, Amgen, Bayer, Formycon, Hexal, Iveric Bio, Kodiak Sciences, Oculis, Opthea, Novartis, Qilu Pharma, Regeneron Pharmaceuticals, Roche, and Sam Chun Dang Pharma. AJB, RV, KWC, KR, RR, YC, WS, DV, RB, and BH are employees and stockholders of Regeneron Pharmaceuticals. SL, US-O, TSc, ASc, and XZ are employees of Bayer. GDY is the founding scientist, President, and Chief Scientific Officer of Regeneron Pharmaceuticals. SS is an adviser and contributes to the industry-sponsored international multicentre studies for AbbVie, Bayer, Boehringer Ingelheim, Novartis, Optos, and Roche and has received consultancy fees from Allergan, Apellis, Bayer, Biogen, Boehringer Ingelheim, Eyebiotech, Novartis Pharma, Optos, and Roche. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Purpose: Advancements in retinal imaging have augmented our understanding of the pathology and structure-function relationships of retinal disease. No single diagnostic test is sufficient; rather, diagnostic and management strategies increasingly involve the synthesis of multiple imaging modalities. Methods: This literature review and editorial offer practical clinical guidelines for how the retina specialist can use multimodal imaging to manage retinal conditions. Results: Various imaging modalities offer information on different aspects of retinal structure and function. For example, optical coherence tomography (OCT) and B-scan ultrasonography can provide insights into the microstructural anatomy; fluorescein angiography (FA), indocyanine green angiography (ICGA), and OCT angiography (OCTA) can reveal vascular integrity and perfusion status; and near-infrared reflectance and fundus autofluorescence (FAF) can characterize molecular components within tissues. Managing retinal vascular diseases often includes fundus photography, OCT, OCTA, and FA to evaluate for macular edema, retinal ischemia, and the secondary complications of neovascularization (NV). OCT and FAF play a key role in diagnosing and treating maculopathies. FA, OCTA, and ICGA can help identify macular NV, posterior uveitis, and choroidal venous insufficiency, which guides treatment strategies. Finally, OCT and B-scan ultrasonography can help with preoperative planning and prognostication in vitreoretinal surgical conditions. Conclusions: Today, the retina specialist has access to numerous retinal imaging modalities that can augment the clinical examination to help diagnose and manage retinal conditions. Understanding the capabilities and limitations of each modality is critical to maximizing its clinical utility., Competing Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Dr. Berrocal has financial interests in Aerie Pharmaceuticals, ProQR therapeutics, Oculus Surgical, Alcon, Allergan, Bayer, DORC, Phoenix Clinical, Vizunex Medical Systems, Zeiss, and Novartis. Dr. Modi is a consultant to Alimera, Alcon, Allergan/Abbvie, Bausch + Lomb, DORC, EyePoint, Genentech, Iveric Bio, Regeneron, Thea, and Zeiss. Dr. Wykoff receives consulting fees/honoraria for ongoing services provided as a consultant to 4DMT, AbbVie, Adverum, Aerie, AGTC, Alcon, Annexon, Apellis, Arrowhead, Bausch + Lomb, Boehringer Ingelheim, Cholgene, Clearside, Curacle, EyePoint, Foresite, Frontera, Genentech, Iveric Bio, Janssen, Kato, Kiora, Kodiak, Kriya, Merck, Nanoscope, NGM, Notal Vision, Novartis, Ocular Therapeutix, OcuTerra, ONL, Opthea, Oxular, Palatin, PerceiveBio, Perfuse, Ray, RecensMedical, Regeneron, RegenXBio, Resonance, Roche, SciNeuro, Stealth, Surrozen, Suzhou Raymon, THEA, TissueGen, and Valo; received grants paid to his institution for ongoing research support as a principal investigator for trials sponsored by 4DMT, Adverum, AffaMed, Alexion, Alimera, Alkahest, Allgenesis, Amgen, Annexin, Annexon, Apellis, Asclepix, Bayer, Boehringer Ingelheim, Chengdu Kanghong, Clearside, Curacle, EyePoint, Gemini, Genentech, GlaxoSmithKline, Gyroscope, IONIS, iRENIX, Iveric Bio, Kodiak, LMRI, Nanoscope, Neurotech, NGM, Novartis, Ocular Therapeutix, Ocuphire, OcuTerra, Ophthotech, Opthea, Oxurion, Oxular, Oyster Point, PerceiveBio, Regeneron, RegenXBio, Roche, SamChunDang Pharm, Sandoz, UNITY, Verily, and Xbrane; and has stock options (not owner) from ongoing relationships as a consultant from the following private for-profit entities: ONL, PolyPhotonix, RecensMedical, TissueGen, Visgenx, and Vitranu. None of the other authors declared potential conflicts of interest with respect to the research, authorship, and/or publication of the article., (© The Author(s) 2024.)

Topic: To compare the efficacy and safety of subthreshold macular laser to conventional focal laser photocoagulation for the treatment of vision loss secondary to diabetic macular edema (DME)., Clinical Relevance: Macular laser remains an important and cost effective treatment option for vision loss secondary to DME. Although anti-VEGF therapy is often first-line, macular laser is of utility in low-resource or remote settings, for patients at risk of loss to follow-up, and for DME not meeting country-specific reimbursement criteria for anti-VEGF therapy. Subthreshold laser is a modality that does not produce clinical or histologic evidence of thermal damage, thereby potentially limiting the common complications of conventional laser., Methods: Ovid MEDLINE, EMBASE, and CENTRAL databases were searched for randomized controlled trials (RCTs) from inception to September 28, 2022. Meta-analyses were performed using random-effects modeling. Data were collected at 12 and 24 months for best-corrected visual acuity (BCVA), central retinal thickness, diabetic retinopathy severity scale, rate of adverse events, rate of enrolled patients not completing treatment, rate of patients receiving retreatment, and quality-of-life measures. The risk of bias and certainty of evidence were assessed using Cochrane's Risk-of-Bias version 2 and the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) frameworks, respectively. Subgroup analysis was performed between subthreshold laser modalities and evaluated with Instrument to assess the Credibility of Effect Modification Analyses tool., Results: Fourteen RCTs comprising 514 eyes receiving conventional laser and 574 eyes receiving subthreshold laser were included. Subthreshold laser likely results in no difference to BCVA (moderate GRADE certainty) compared with conventional laser. Conventional laser demonstrated a small, statistically significant improvement in central retinal thickness (low GRADE certainty); however, the magnitude of this improvement is unlikely to be clinically important. There may not be a difference in the rate of adverse events (low GRADE certainty) at 12 months when comparing subthreshold laser to conventional laser for DME., Conclusion: Randomized controlled trial literature to date suggests subthreshold laser to be as effective as conventional laser in the treatment of DME. Increased follow-up duration is needed to observe any long-term safety benefit from reduced retinal damage., Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article., (Copyright © 2023 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: Retinal non-perfusion (RNP) is fundamental to disease onset and progression in diabetic retinopathy (DR). Whether anti-vascular endothelial growth factor (anti-VEGF) therapy can modify RNP progression is unclear. This investigation quantified the impact of anti-VEGF therapy on RNP progression compared with laser or sham at 12 months., Methods: A systematic review and meta-analysis of randomised controlled trials (RCTs) were performed; Ovid MEDLINE, EMBASE and CENTRAL were searched from inception to 4th March 2022. The change in any continuous measure of RNP at 12 months and 24 months was the primary and secondary outcomes, respectively. Outcomes were reported utilising standardised mean differences (SMD). The Cochrane Risk of Bias Tool version-2 and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) guidelines informed risk of bias and certainty of evidence assessments., Results: Six RCTs (1296 eyes) and three RCTs (1131 eyes) were included at 12 and 24 months, respectively. Meta-analysis demonstrated that RNP progression may be slowed with anti-VEGF therapy compared with laser/sham at 12 months (SMD: -0.17; 95% confidence interval [CI]: -0.29, -0.06; p = 0.003; I 2  = 0; GRADE rating: LOW) and 24-months (SMD: -0.21; 95% CI: -0.37, -0.05; p = 0.009; I 2  = 28%; GRADE rating: LOW). The certainty of evidence was downgraded due to indirectness and due to imprecision., Conclusion: Anti-VEGF treatment may slightly impact the pathophysiologic process of progressive RNP in DR. The dosing regimen and the absence of diabetic macular edema may impact this potential effect. Future trials are needed to increase the precision of the effect and inform the association between RNP progression and clinically important events., Prospero Registration: CRD42022314418., (© 2023 The Authors. Acta Ophthalmologica published by John Wiley & Sons Ltd on behalf of Acta Ophthalmologica Scandinavica Foundation.)

Free-floating, pigmented vitreous cysts were documented in two patients. In a 15-year-old girl with intermittent symptoms, a 2.4-mm cyst was observed; origin was attributed to prior trauma, and clinical observation was pursued. In a 35-year-old woman with progressive symptoms, a 11.5-mm cyst was observed; origin was attributed to a history of multiple ocular surgical interventions, and surgical excision by pars plana vitrectomy was performed. [ Ophthalmic Surg Lasers Imaging Retina 2024;55:55-58.] .