Search

Gahyung Ryu,1,2 Donghyoun Noh,1,2 Guihyun Moon,3 Min Sagong1,2 1Department of Ophthalmology, Yeungnam University College of Medicine, Daegu, Republic of Korea; 2Yeungnam Eye Center, Yeungnam University Hospital, Daegu, Republic of Korea; 3Bayer Korea Ltd, Seoul, Republic of KoreaCorrespondence: Min SagongDepartment of Ophthalmology, Yeungnam University College of Medicine, 170 Hyunchungro, Nam-gu, Daegu, 42415, Republic of KoreaTel +82-53-620-3443Fax +82-53-626-5936Email msagong@yu.ac.krPurpose: To investigate the efficacy and safety of intravitreal aflibercept (IVT-AFL) in Asian patients with neovascular age-related macular degeneration (nAMD) in a real-world clinical setting.Patients and Methods: In this analysis of a prospective, regulatory, postmarketing surveillance study for IVT-AFL, 3115 patients with nAMD were included and followed for 8 months. The mean changes in best-corrected visual acuity (BCVA) and central retinal thickness (CRT) were analyzed using last observation carried forward method. A post hoc subgroup analysis and a multivariate logistic regression analysis were also performed to assess factors related to treatment outcomes.Results: Mean BCVA improved from 0.62 to 0.51 logarithm of minimum angle resolution and mean CRT decreased from 383.3 to 289.7 μm, with a mean of 3.4 injections during the 8-month follow-up. In the subgroup analysis, patients who had received 3 initial monthly doses had significantly better anatomical improvements than those treated as needed. Patients with confirmed polypoidal choroidal vasculopathy (PCV) had significantly better anatomical improvements and better visual recovery than those with other types of nAMD. The multivariate regression analysis demonstrated that age, injection number, PCV, and baseline BCVA were significantly associated with higher odds of gaining 3 lines at 8 months, and sex, injection number, PCV, and baseline CRT were associated with CRT ≤ 250 μm at 8 months. No new safety findings were identified.Conclusion: IVT-AFL was effective and well tolerated in a real-world setting with a large number of Asian patients with nAMD. Number of injections and PCV were important determinants for improved treatment outcomes.Keywords: aflibercept, Asian, neovascular age-related macular degeneration, polypoidal choroidal vasculopathy, postmarketing surveillance, real-world

Min Sagong,1 Se Joon Woo,2 Youkyung Lee3 On behalf of the LUMINOUS™ study investigators from South Korea1Department of Ophthalmology, Yeungnam University College of Medicine, Daegu, Korea; 2Department of Ophthalmology, Seoul National University Bundang Hospital, Seongnam, Korea; 3Novartis Korea Ltd., Seoul, KoreaCorrespondence: Se Joon WooDepartment of Ophthalmology, Seoul National University Bundang Hospital, 173– 82 Gumi-ro, Bundang-gu, Seongnam-si, Gyeonggi-do, 13620, South KoreaTel +82-31-787-7377Fax +82-31-787-4057Email sejoon1@snu.ac.krPurpose: To evaluate the real-world effectiveness, treatment patterns, and safety of ranibizumab in Korean patients with neovascular age-related macular degeneration (nAMD).Methods: LUMINOUS™ is a 5-year, global, prospective, observational, open-label study. Adults aged ≥ 18 years who were either treatment-naïve or prior-treated were enrolled and treated with ranibizumab 0.5 mg as per the local label. Outcome measures included mean (± standard deviation [SD]) changes from baseline in visual acuity (VA) and central retinal thickness (CRT), and rate of ocular and non-ocular adverse events (AEs).Results: Overall, 367 Korean patients with nAMD (152 treatment-naïve and 215 prior-treated) were enrolled. The mean (SD) VA changes from baseline at 1-year were +10.1 (± 21.77; P=0.0005) and +1.4 (± 15.17; P=0.2142) Early Treatment Diabetic Retinopathy Study letters, with mean numbers of injections of 5.2 and 3.4 in the treatment-naïve and prior-treated groups, respectively. VA gains were greater in patients with lower baseline VA, who received a loading dose, and with polypoidal choroidal vasculopathy (PCV). Multivariate logistic regression analyses demonstrated younger age, worse baseline VA, and those who received loading dose being associated with higher odds of any gain in VA at 1 year (P< 0.05). Mean (SD) CRT changes from baseline were – 126.7 (± 174.90) μm (P< 0.0001) and +10.8 (± 89.62) μm (P=0.5833) in the treatment-naïve and prior-treated groups, respectively, with greater reductions observed in patients with PCV. Ocular and non-ocular AEs were reported in 8.4% (n=31) and 10.1% (n=37) of patients, respectively.Conclusion: The LUMINOUS study confirms real-world effectiveness and safety of ranibizumab in Korean patients with nAMD; factors including age, baseline VA, and loading-dose were associated with VA gain at one-year post-treatment.Keywords: neovascular age-related macular degeneration, polypoidal choroidal vasculopathy, ranibizumab, real-world

Introduction: The aim of this study was to investigate the predictive factors for persistent disease activity following anti-vascular endothelial growth factors (anti-VEGF) and their long-term effects in patients to be treated for neovascular age-related macular degeneration (nAMD) under real-world conditions., Methods: Retrospective data analysis of the PROOF study, a multi-center real-world retrospective chart review conducted across Korea in patients with nAMD included treatment-naive patients with nAMD who received first anti-VEGF (ranibizumab, bevacizumab, or aflibercept) between January 2017 and March 2019 was performed. All 600 patients (cohort 1) had a minimum follow-up of 12 months of which 453 patients (cohort 2) were followed-up for 24 months from baseline., Results: At month 12 after anti-VEGF therapy, 58.10% (95% confidence interval [CI]: 54.09, 62.12) of patients and at month 24, 66.02% of patients continued to have persistent retinal fluid. At both months 12 and 24, predictive factors for persistent disease activity were fibrovascular pigment epithelial detachments (PED) (P = 0.0494) and retinal fluid at month 3 after loading phase (P = 0.0082). The mean changes in visual acuity were + 6.2, + 10.1, and + 13.3 letters and in the central subfield thickness were - 79.1 µm, - 96.3 µm, and - 134.4 µm at 12 months from baseline, in the bevacizumab, aflibercept, and ranibizumab groups, respectively., Conclusions: The presence of retinal fluid after loading phase and fibrovascular PED were predictors of persistent disease activity after at least 1 year of anti-VEGF treatment., (© 2024. The Author(s).)

Construction of a robust artificial solid-electrolyte interphase (SEI) layer has proposed an effective strategy to overcome the instability of the lithium (Li). However, existing artificial SEI layers inadequately controlled ion distribution, leading to dendritic growth and penetration. Furthermore, the environmental impact of the manufacturing process and materials of the artificial layer is often overlooked. In this work, a chemically and physically reinforced membrane (C-Li@P) composed of the biocompatible Li + coordinated carboxymethyl guar gum (CMGG) and polyacrylamide (PAM) polymers serves as an artificial SEI membrane for dendrite-free Li. This membrane with hollow channels not only directs ion flux along the interspace of fibers, fostering uniform Li plating but also induces a desirable interface chemistry. Consequently, artificial SEI membrane-covered Li exhibits stable electrochemical plating/stripping reactions, surpassing the cycle life of ≈750% of bare Li. It demonstrates exceptional capacity retention of ≈93.9%, ≈88.1%, and ≈79.18% in full cells paired with LiNi 0.8 Mn 0.1 Co 0.1 O 2 (NMC811), LiNi 0.6 Mn 0.2 Co 0.2 O 2 (NMC622) and S cathodes, respectively over 200 cycles at 1 C rate. Additionally, the water-based green manufacturing and biodegradability of the membrane demonstrated the sustainable development and disposal of electrodes. This work provides a comprehensive framework for the design of an artificial layer chemically and physically regulating dendritic growth., (© 2024 The Author(s). Advanced Materials published by Wiley‐VCH GmbH.)

Treatment with atezolizumab and bevacizumab is the first-line therapy for unresectable hepatocellular carcinoma. Although immune checkpoint inhibitors are novel and effective treatments, they can induce immune-related adverse events. However, neurological immune-related adverse events have rarely been reported. We report the case of a man in his 40s with hepatocellular carcinoma who developed life-threatening encephalitis after atezolizumab plus bevacizumab was administered. The patient presented with fever, headache, altered mentality, and general epileptic seizures, ten days after administration. Cerebrospinal fluid analysis showed elevated white blood cells and elevated protein levels, but revealed no infection or malignancy. Brain magnetic resonance imaging showed diffuse leptomeningeal enhancement in both the cerebrum and cerebellum. As immune checkpoint inhibitor-induced encephalitis was strongly suspected, steroid pulse therapy was initiated and neurological symptoms quickly improved. The patient was discharged after 66 days of hospitalization, and administration of sorafenib and radiotherapy was started for the hepatocellular carcinoma on an outpatient basis. This case demonstrates the importance of recognizing neurological immune-related adverse events following atezolizumab and bevacizumab treatment for early intervention. We discuss this case in comparison to available literature and previous two cases of Atezolizumab- and bevacizumab- induced encephalitis in hepatocellular carcinoma., (© 2024. The Author(s).)

It has been reported that the retinal vessel and macular region of the retina are displaced after macular hole (MH) surgery. However, there is no detailed information for correlations between retinal and choroidal displacements. We obtained optical coherence tomography angiography (OCTA) and en-face optical coherence tomography (OCT) images from 24 eyes to measure the retinal and choroidal vascular displacement before and after surgery. These images were merged into infrared images using blood vessel patterns. The same vascular bifurcation points were automatically selected for each follow-up image, and the displacements of the bifurcation points were analyzed as a vector unit for prespecified grid regions in a semi-automated fashion. The results showed displacements of the choroidal intermediate vessels and retinal vessels following MH surgery (p = 0.002, p < 0.001). The topographic changes showed inferior, nasal, and centripetal displacement of the retina and inferiorly displaced choroid. The ILM peeling size and basal MH size were significantly associated with the retinal displacement (p < 0.001 and p = 0.010). Additionally, changes in the amount of the choroidal displacement were significantly correlated with that of the retinal displacements (p = 0.002). Clinicians should keep in mind that there might be topographic discrepancies of the displacement between retina and choroid when analyzing them following surgery., (© 2024. The Author(s).)

The development of intravitreally injected biologic medicines (biologics) acting against vascular endothelial growth factor (VEGF) substantially improved the clinical outcomes of patients with common VEGF-driven retinal diseases. The relatively high cost of branded agents, however, represents a financial burden for most healthcare systems and patients, likely resulting in impaired access to treatment and poorer clinical outcomes for some patients. Biosimilar medicines (biosimilars) are clinically equivalent, potentially economic alternatives to reference products. Biosimilars approved by leading health authorities have been demonstrated to be similar to the reference product in a comprehensive comparability exercise, generating the totality of evidence necessary to support analytical, pre-clinical, and clinical biosimilarity. Anti-VEGF biosimilars have been entering the field of ophthalmology in the US since 2022. We review regulatory and scientific concepts of biosimilars, the biosimilar development landscape in ophthalmology, with a specific focus on anti-VEGF biosimilars, and discuss opportunities and challenges facing the uptake of biosimilars., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr Neil M Bressler reported receiving grants from Samsung Bioepis to Johns Hopkins University and receiving grants from Bayer, Biogen, Boehringer Ingelheim, F. Hoffman-LaRoche, Genentech, and Regeneron and having a patent to System and Method for Automated Detection of Age-Related Macular Degeneration and Other Retinal Abnormalities issued. Dr Peter Kaiser reported being a consultant for Allergan, Allgenesis, Bayer, Bausch and Lomb, Biogen Idec, Boehringer Ingelheim, Carl Zeiss Meditec, Coherus, Genentech/Roche, Innovent, Kanghong, Kodiak, Novartis, Ocular Therapeutix, Regeneron, RegenxBio, and Samsung Bioepis. Dr Kyu Hyung Park reported receiving lecture fee and being a consultant for Bayer, Novartis, Roche and Samsung Bioepis. Dr Se Joon Woo reported being a consultant for Samsung Bioepis, Janssen, Novartis, Curacle, Novelty Nobility, Sometech, Rznomics; being an equity owner of Retimark and Panolos Bioscience; receiving grants from Samsung Bioepis, Novelty Nobility, Pharmabcine, Novartis, Alteogen, Geneuintech, and Curacle; and receiving lecture fees from Novartis, Bayer, Allergan, Abbvie, Retimark, and Alcon outside the submitted work. Dr Min Sagong reported being a consultant for and receiving grant support from Samsung Bioepis, Novartis, Bayer, Roche, Allergan/Abbvie, Celltrion, Alteogen, Alcon and Curacle, and receiving lecture fee from Novartis, Bayer, Roche, and Allergan/Abbvie. Dr Mario Bradvica obtained honoraria for presentations by Novartis and Abbvie. He is part of the advisory board of Novartis and obtained grants for clinical trials from Iveric Bio (former Optotech), Novartis, Roche, Ophthea, and Samsung Bioepis. Mercy Yeeun Kim and Seungkee Kim are reported being employees of Samsung Bioepis. Dr SriniVas R Sadda reported receiving honoria as a consultant for 4DMT, Abbvie/Allergan, Alexion, Amgen, Apelis, Astellas, Bayer, Biogen, Boerhinger Ingelheim, Catalyst, Centervue, Roche/Genentech, Gyroscope, Heidelberg, IvericBio, Jannsen, Merck, Nanoscope, Novartis, Optos, Oxurion, Osyterpoint, Eyepoint, Pfizer, Regeneron, Samsung Bioepis, and Vertex Pharmaceuticals. He has also received honoraria for talks given at symposia sponsored by Roche, Novartis, Apellis, Heidelberg, Optos, and Nidek. He has received research funding from Carl Zeiss Meditec and he has received research instruments from Optos, Nidek, Centervue, Topcon, Heidelberg, and Carl Zeiss Meditec. Dr Diana Do and Dr Quan Dong Nguyen declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To demonstrate the therapeutic similarity of CT-P42 compared with reference aflibercept (Eylea) in adult patients with diabetic macular edema (DME)., Design: Randomized, active-controlled, double-masked, phase III clinical trial PARTICIPANTS: Patients with a diagnosis of either type 1 or 2 diabetes mellitus with DME involving the center of the macula., Methods: Patients were randomized (1:1) to receive either CT-P42 or reference aflibercept (2 mg/0.05 ml) by intravitreal injection every 4 weeks (5 doses), then every 8 weeks (4 doses), in the main study period. Results up to week 24 are reported herein., Main Outcome Measures: The primary end point was mean change from baseline at week 8 in best-corrected visual acuity (BCVA) using the ETDRS chart. Equivalence between CT-P42 and reference aflibercept was to be concluded if the 2-sided 95% confidence interval (CI) (global assumptions) and 2-sided 90% CI (United States Food and Drug Administration [FDA] assumptions) for the treatment difference fell entirely within the equivalence margin of ±3 letters, as assessed in the full analysis set., Results: Overall, 348 patients were randomized (CT-P42: 173; reference aflibercept: 175). Best-corrected visual acuity improved from baseline to week 8 in both groups, with a least squares mean (standard error) improvement of 9.43 (0.798) and 8.85 (0.775) letters in the CT-P42 and reference aflibercept groups, respectively. The estimated between-group treatment difference was 0.58 letters, with the CIs within the predefined equivalence margin of ±3 letters (95% CI, -0.73 to 1.88 [global]; 90% CI, -0.52 to 1.67 [FDA]). Through week 24, other efficacy results for the 2 groups, in terms of change in BCVA and retinal central subfield thickness, as well as ETDRS Diabetic Retinopathy Severity Scale score, supported therapeutic similarity. Pharmacokinetics, usability, safety (including the proportions of patients experiencing ≥1 treatment-emergent adverse event [CT-P42: 50.3%; reference aflibercept: 53.7%]), and immunogenicity were also comparable between groups., Conclusions: This study in patients with DME demonstrated equivalence between CT-P42 and reference aflibercept (2 mg/0.05 ml) in terms of efficacy, with similar pharmacokinetic, usability, safety, and immunogenicity profiles., 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.)

Ischemic colitis (IC) and sarcopenia are associated with aging and multiple comorbidities. We aimed to investigate the prevalence and predictive role of sarcopenia in patients with IC. We retrospectively analyzed 225 hospitalized patients (median age, 72 years; women, 67.1%; severe IC, 34.2%) who were diagnosed with IC between January 2007 and February 2022. Sarcopenia was defined as the skeletal muscle index at the third lumbar vertebra determined by computed tomography. It was present in 49.3% (n = 111) of the patients and was significantly associated with severe IC compared to those without sarcopenia (48.6% vs. 20.2%, P < 0.001). Sarcopenia was associated with extended hospitalization (median: 8 vs. 6 days, P < 0.001) and fasting periods (4 vs. 3 days, P = 0.004), as well as prolonged antibiotic use (9 vs. 7 days, P = 0.039). Sarcopenia was linked to a higher risk of surgery or mortality (9.0% vs. 0%, P = 0.001) and independently predicted this outcome (odds ratio [OR], 11.17; 95% confidence interval [CI], 1.24‒1467.65, P = 0.027). It was prevalent among hospitalized patients with IC, potentially indicating severe IC and a worse prognosis. This underscores the importance of meticulous monitoring, immediate medical intervention, and timely surgical consideration., (© 2024. The Author(s).)

Background: The aim of this study is to report short-term outcomes after the shortening of the treatment interval to 4 weeks with a treat-and-extend (TAE) regimen (Si4w) of aflibercept in patients with refractory neovascular age-related macular degeneration (nAMD). Methods: This retrospective study included 34 patients given aflibercept with a TAE regimen of a minimum of a 4-week interval when they had a limited response to bimonthly aflibercept. The best-corrected visual acuity (BCVA) and central macular thickness (CMT) were compared before and after Si4w. The resolution of subretinal and intraretinal fluid before and after Si4w was also examined. The risk factors associated with persistent fluid were analyzed. Results: The average treatment duration until initiation of Si4w was 57.82 ± 28.59 months, with an average of 23.64 ± 12.40 injections administered. The BCVA was not significantly improved after Si4w. The CMT decreased significantly from 427.91 ± 125.74 μm to 336.38 ± 121.67 μm at the third visit ( p < 0.001). Eighteen eyes (52.9%) showed complete resolution, and twenty-three eyes (67.6%) experienced complete resolution at least once during the three visits. The duration of fluid before Si4w was significantly associated with complete resolution ( p = 0.011). Conclusions: Si4w of aflibercept showed satisfactory anatomical outcomes with complete resolution of fluid in patients with a limited response to bimonthly aflibercept injections, and should be considered as a useful treatment option.

Purpose: To investigate the long-term efficacy and safety of intravitreal brolucizumab (BRZ) injections in patients with typical neovascular age-related macular degeneration (typical nAMD) and polypoidal choroidal vasculopathy (PCV)., Methods: This multicentre retrospective study included 401 eyes of 398 patients with nAMD who received BRZ injection(s), with a follow-up duration of ≥12 months. Changes in best-corrected visual acuity (BCVA), retinal fluid evaluation and central subfield thickness (CST) on optical coherence tomography were assessed. The efficacy of BRZ was compared between typical nAMD and PCV groups., Results: Analyses were conducted with 280 eyes of 278 patients with typical nAMD and 121 eyes of 120 patients with PCV (mean age, 71.1 ± 8.6 years). 29 eyes (7.2%) were treatment naïve. The mean follow-up period was 15.3 ± 2.8 months; the mean number of BRZ injections within 1 year was 4.5 ± 1.7. BCVA was maintained during the follow-up period, and CST significantly improved from the first injection month and was maintained for 12 months in both the typical nAMD and PCV groups. The dry macula proportion increased from 2.7% at baseline to 56.1% at 1 month and 42.9% at 12 months. Among the 18 eyes that underwent indocyanine green angiography both before and after treatment, 10 (55.6%) showed polyp regression. Overall, the incidence of intraocular inflammation (IOI), retinal vasculitis and occlusive retinal vasculitis was 9.4% (38 eyes), 1.2% (5 eyes) and 0.5% (2 eyes), respectively. IOI occurred from the first to the sixth injections, with an average IOI onset of 28.5 ± 1.4 days. All eyes achieved IOI resolution, although the two eyes with occlusive retinal vasculitis showed a severe visual decline after IOI resolution., Conclusion: Brolucizumab was effective in maintaining BCVA and managing fluid in eyes with nAMD for up to 1 year, exhibiting a high polyp regression rate. However, the not uncommon incidence of IOI and the severe visual decline caused by the rare occlusive retinal vasculitis following BRZ treatment underscore the importance of careful monitoring and timely management., (© 2024 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Background/aims: To evaluate efficacy, safety, pharmacokinetics (PK) and immunogenicity of SB15 versus reference aflibercept (AFL), and switching from AFL to SB15 in neovascular age-related macular degeneration (nAMD)., Design: Prospective, double-masked, randomised, phase 3 trial., Methods: Participants with nAMD were randomised 1:1 to receive SB15 (N=224 participants) or AFL (N=225). At week 32, participants either continued on SB15 (SB15/SB15, N=219) or AFL (AFL/AFL, N=108), or switched from AFL to SB15 (AFL/SB15, N=111). This manuscript reports 1-year and switching results of secondary efficacy endpoints such as changes from baseline to week 56 in best-corrected visual acuity (BCVA), central subfield thickness (CST, from internal limiting membrane (ILM) to retinal pigment epithelium), and total retinal thickness (TRT, from ILM to Bruch's membrane). Additional endpoints included safety, PK and immunogenicity., Results: Efficacy results were comparable between groups. The least squares mean (LSmean) change in BCVA from baseline to week 56 was 7.4 letters for SB15/SB15 and 7.0 letters for AFL/AFL (difference (95% CI)=0.4 (-2.5 to 3.2)). The LSmean changes from baseline to week 56 in CST and TRT were -119.2 µm and -132.4 µm for SB15/SB15 and -126.6 µm and -136.3 µm for AFL/AFL, respectively (CST: difference (95% CI)=7.4 µm (-6.11 to 20.96); TRT: difference (95% CI)=3.9 µm (-18.35 to 26.10)). Switched and non-switched participants showed similar LSmean changes in BCVA from baseline to week 56 (AFL/SB15, 7.9 letters vs AFL/AFL, 7.8 letters; difference (95% CI)=0.0 (-2.8 to 2.8)). Safety, PK and immunogenicity were comparable between groups., Conclusions: Efficacy, safety, PK and immunogenicity were comparable between SB15 and AFL and between switched and non-switched participants., Competing Interests: Competing interests: WC, IO and HJ are employed by Samsung Bioepis. Samsung Bioepis funded medical writing support and article processing charges. Additional potential conflicts of interest are listed below. SJW obtained consulting fees from Samsung Bioepis, Janssen, Novartis, Curacle, Novelty Nobility, Sometech, Rznomics and Pharmabcine, grants from Samsung Bioepis, Novelty Nobility, Novartis, Alteogen, Roche, Geneunitech, Bayer, Bio Bank Healing, and Curacle, and payments for lectures from Novartis, Bayer, and Allergan-Abbvie. He serves as equity owner of Retimark and Panolos Bioscience. SRS obtained consulting fees from Apellis, Amgen, Abbvie/Allergan, Samsung Bioepis, Biogen, Boerhinger Ingelheim, Iveric, Novartis, Roche, Bayer, Regeneron, Pfizer, Astellas, Nanoscope, Jannsen, Centervue, Optos and Heidelberg, and honoraria for lectures from Novartis, Roche, Optos, and Heidelberg. He is part of the Data Safety Monitoring/Advisory Board of Regeneron and holds leadership/fiduciary functions in ARVO and Macula Society. MB obtained honoraria for presentations by Novartis and Abbvie. He is part of the advisory board of Novartis and obtained grants for clinical trials from Iveric Bio (former Optotech), Novartis, Roche, Ophthea and Samsung Bioepis. AV obtained consulting fees and honoraria for lectures from Novartis, Roche, Pfizer, Bausch & Lomb, Zeiss, and Alcon. He also obtained support for meeting attendances by Novartis, Pfizer, Bausch & Lomb, Roche, Zeiss, Alcon, Iveric Bio, Amgen, Chengdu, Mylan, Panoptica, Formycon, Thrombogenics, Regeneron and Clearside. He is part of the Data Safety Monitoring/Advisory Board of Zeiss, Bayer, Novartis, Pfizer, and Roche. MS obtained grants from Allergan/Abbvie, Bayer and Novartis, consulting fees from Samsung Bioepis, Bayer, Novartis, Allergan/Abbvie, Roche, Alcon and Curacle, honoraria for lectures from Samsung Bioepis, Bayer, Novartis, Allergan/Abbvie, Roche, Alcon and Johnson & Johnson, and support for meeting attendances from Bayer, Allergan/Abbvie and Novartis. Min Sagong is part of the Data Safety Monitoring/Advisory board of Bayer, Novartis, and Allergan/Abbvie. JS obtained consulting fees from Abbvie and support for meeting attendances from Bayer. MV obtained consulting fees from Abbvie and Roche and support for meeting attendances from Bayer. EW obtained honoraria for lectures from Bayer, Roche, Alfa Sigma, Allergan, Zeiss and Thea, and is part of the advisory board of Allergan. SP obtained grants from Aerie, Aerpio, Allergan, Allgenesis, Apellis, Boehringer Ingelheim, Chengdu Kanghong, Clearside, EyePoint, Genentech-Roche, Ionis Pharmaceuticals, IVERIC Bio, KalVista, Kodiak Sciences, Mylan, Novartis, Oculis, Opthea, Ora, Oxurion, Regeneron, Samsung, SmileBiotek, Stealth Biotherapeutics, ThromboGenics, Xbrane Biopharma, consulting fees from AiViva, Allergan, Allgenesis, Genentech-Roche, Kala, Kodiak Sciences, Oxugenix, and RegenxBio, and support for travel expenses from EyePoint. He is part of the Data Safety Monitoring/Advisory Board of Allergan, Allgenesis Biotherapeutics, Genentech-Roche, Kodiak Sciences, and Iveric Bio and serves as equity owner and chief medical officer for Allgenesis Biotherapeutics. WC received consulting fees from Samsung Bioepis and payments for lectures from Bayer, Novartis and Chong Kun Dang., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Since the 2000s, the Y439 lineage of H9N2 avian influenza virus (AIV) has been the predominant strain circulating in poultry in Korea; however, in 2020, the Y280 lineage emerged and spread rapidly nationwide, causing large economic losses. To prevent further spread and circulation of such viruses, rapid detection and diagnosis through active surveillance programs are crucial. Here, we developed a novel H9 rRT-PCR assay that can detect a broad range of H9Nx viruses in situations in which multiple lineages of H9 AIVs are co-circulating. We then evaluated its efficacy using a large number of clinical samples. The assay, named the Uni Kor-H9 assay, showed high sensitivity for Y280 lineage viruses, as well as for the Y439 lineage originating in Korean poultry and wild birds. In addition, the assay showed no cross-reactivity with other subtypes of AIV or other avian pathogens. Furthermore, the Uni Kor-H9 assay was more sensitive, and had higher detection rates, than reference H9 rRT-PCR methods when tested against a panel of domestically isolated H9 AIVs. In conclusion, the novel Uni Kor-H9 assay enables more rapid and efficient diagnosis than the "traditional" method of virus isolation followed by subtyping RT-PCR. Application of the new H9 rRT-PCR assay to AI active surveillance programs will help to control and manage Korean H9 AIVs more efficiently., (© 2023. The Author(s), under exclusive licence to Microbiological Society of Korea.)

We investigated predictors of visual outcomes and injection interval in macular edema (ME) secondary to branch retinal vein occlusion (BRVO) treated with a treat-and-extend (TAE) regimen. All 48 patients in a multicenter study were followed for 52 weeks and received three monthly intravitreal aflibercept injections before the TAE regimen, with treatment intervals adjusted by 4 weeks, up to a maximum of 16 weeks. Various laboratory biomarkers and optical coherence tomography parameters were evaluated. Patients were classified into the extension failure group if they had ≥ 1 treatment interval decreased due to an increase in the central macular thickness compared to the previous visit and 18 patients were assigned to this group. In multivariate logistic analyses, presence of microaneurysms and prominent middle limiting membrane (p-MLM) sign, increased initial external limiting membrane (ELM) disruption, and higher total cholesterol were correlated with inhibiting a sustained extension in the injection interval (P = 0.015, P = 0.032, P = 0.037, P = 0.009, respectively). Therefore, in the patients with ME secondary to BRVO with these risk factors, early consideration of frequent injection may improve treatment outcome., (© 2023. The Author(s).)

Importance: Aflibercept biosimilars can expand available treatment options in retinal diseases and have the potential to improve patient access to safe and effective therapy., Objective: To establish equivalence in efficacy and similarity in safety, pharmacokinetics, and immunogenicity of SB15 and reference aflibercept (AFL) in neovascular age-related macular degeneration (nAMD)., Design, Setting, and Participants: This was a randomized double-masked parallel group phase 3 trial conducted at 56 centers in 10 countries from June 2020 to March 2022, including follow-up through 56 weeks. Of 549 screened participants, 449 participants 50 years and older with treatment-naive nAMD were included and randomly assigned to SB15 (n = 224) or AFL (n = 225). Key exclusion criteria included considerable scarring, fibrosis, atrophy, and hemorrhage. This report includes results up to the end of the parallel group period at week 32. Of the 449 randomized participants, 438 (97.6%) completed week 32 follow-up., Intervention: Participants were randomized 1:1 to receive 2 mg of SB15 or AFL every 4 weeks for the first 12 weeks (3 injections), followed by dosing every 8 weeks up to week 48, with final assessments at week 56., Main Outcomes and Measures: The primary end point was the change in best-corrected visual acuity (BCVA) from baseline to week 8 with predefined equivalence margins of -3 letters to 3 letters. Other key end points were changes in BCVA and central subfield thickness up to week 32, safety, pharmacokinetics, and immunogenicity., Results: The mean (SD) age among the 449 included participants was 74.0 (8.1) years, and 250 participants (55.7%) were female. Baseline demographic characteristics and most disease characteristics were comparable between treatment groups. The least squares mean change in BCVA from baseline to week 8 in the SB15 group was equivalent to that in the AFL group (6.7 letters vs 6.6 letters, respectively; difference, 0.1 letters; 95% CI, -1.3 to 1.4). Comparable efficacy between treatment groups was maintained up to week 32 (least squares mean change from baseline in BCVA: SB15, 7.6 letters vs AFL, 6.5 letters; least squares mean change from baseline in central subfield thickness: SB15, -110.4 μm vs AFL, -115.7 μm). No clinically relevant differences were observed in the incidence of treatment-emergent adverse events (TEAEs) (SB15, 107/224 [47.8%] vs AFL, 98/224 [43.8%]) and ocular TEAEs in the study eye (SB15, 41/224 [18.3%] vs AFL, 28/224 [12.5%]). The serum concentration profiles and cumulative incidences of overall antidrug antibody positive participants were comparable., Conclusions and Relevance: In this phase 3 randomized clinical trial, SB15 and AFL showed equivalent efficacy and comparable safety, pharmacokinetics, and immunogenicity in participants with nAMD., Trial Registration: ClinicalTrials.gov Identifier: NCT04450329.

High pathogenicity avian influenza (HPAI) viruses of clade 2.3.4.4 H5Nx have been circulating in poultry and wild birds worldwide since 2014. In South Korea, after the first clade 2.3.4.4b H5N1 HPAI viruses were isolated from wild birds in October 2021, additional HPAIV outbreaks occurred in poultry farms until April 2022. In this study, we genetically characterized clade 2.3.4.4b H5N1 HPAIV isolates in 2021-2022 and examined the pathogenicity and transmissibility of A/mandarin duck/Korea/WA585/2021 (H5N1) (WA585/21) in chickens and ducks. Clade 2.3.4.4b H5N1 HPAI viruses caused 47 outbreaks in poultry farms and were also detected in multiple wild birds. Phylogenetic analysis of HA and NA genes indicated that Korean H5N1 HPAI isolates were closely related to Eurasian viruses isolated in 2021-2022. Four distinct genotypes of H5N1 HPAI viruses were identified in poultry, and the majority were also found in wild birds. WA585/21 inoculated chickens showed virulent pathogenicity with high mortality and transmission. Meanwhile, ducks infected with the virus showed no mortality but exhibited high rates of transmission and longer viral shedding than chickens, suggesting that they may play an important role as silent carriers. In conclusion, consideration of both genetic and pathogenic traits of H5N1 HPAI viruses is required for effective viral control.

An efficient synthetic approach for chiral malonates was established via enantioselective phase transfer catalysis. The α-alkylation of 2,2-diphenylethyl tert-butyl α-methylmalonates with (S,S)-3,4,5-trifluorophenyl-NAS bromide as a phase-transfer catalyst under phase-transfer catalytic conditions successfully produced corresponding α-methyl-α-alkylmalonates; these compounds are versatile chiral building blocks containing a quaternary carbon center in high chemical yields (up to 99%) with excellent enantioselectivities (up to 98% ee). α,α-Dialkylmalonates were selectively hydrolyzed to the corresponding chiral malonic monoacids under basic (KOH/MeOH) and acidic conditions (TFA/CH 2 Cl 2 ), showing the practicality of the method., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Guo, Oh, Sagong, Yang, Lee and Park.)

Worldwide, high pathogenic avian influenza viruses belonging to clades 2.3.4.4 and 2.3.2.1 have been circulating in both poultry and wild birds. Since 2018, Korea has built a national antigen bank to ensure preparedness in an emergency. In this study, we developed a bivalent vaccine candidate containing antigens derived from two reassortant KA435/2.3.2.1d and H35/2.3.4.4b strains for Korean national antigen bank. We evaluated its immunogenicity and protective efficacy in specific pathogen free chickens. The two vaccine strains, rgKA435-H9N2 PB2/2.3.2.1d and rgH35/2.3.4.4b, both of which were generated successfully by reverse genetics, were highly immunogenic (titres of haemagglutination inhibition: 8.3 and 8.4 log 2 , respectively) and showed good protective efficacy (100 and 147 50% protective dose, respectively) against lethal challenge with wild-type virus when delivered as a 1:1 mixture. Notably, the vaccine provided complete protection against viral shedding at a full dose (512 HAU) and a 1/10 dose (51.2 HAU), with no clinical signs, after challenge with H35/2.3.4.4b. The bivalent vaccine developed in this study may reduce the cost of vaccine production and could be used as a H5 subtype avian influenza vaccine candidate against two clades simultaneously., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Polypoidal choroidal vasculopathy (PCV) is characterized by choroidal vascular abnormalities including polypoidal lesion and branching vascular networks. Not only choroidal structural changes, but also choroidal hyperpermeability and congestion are also thought to be involved in pathogenesis of PCV. We investigated choroidal vascular brightness intensity (CVB) using ultra-widefield indocyanine green angiography (UWF-ICGA) images and analyzed its association with clinical features in patients with PCV. In this study, 33 eyes with PCV and 27 eyes of age-matched controls were included. CVB was measured by extracting the enhanced pixels of choroidal vessels after the reference brightness across the images was adjusted to be uniform. Associations between choroidal vascular features and the clinical features of PCV were also determined. The mean CVB was higher in PCV than control eyes, regardless of the segmented region (all p < 0.001). CVB was also higher at the posterior pole than at the periphery, and the inferior quadrants were brighter than the superior quadrants in both the PCV and control group (all p < 0.05). In affected eyes, CVB was higher than in unaffected fellow eyes at the posterior pole, whereas there was no difference at the periphery. Posterior pole CVB correlated significantly with subfoveal choroidal thickness (r = 0.502, p = 0.005), polyp number (r = 0.366 p = 0.030), and the greatest linear dimension (r = 0.680, p = 0.040). Greatest linear dimension was positively correlated with CVB at posterior pole (p = 0.040), whereas SFCT or CVD in all regions didn't show the significant correlation. The UWF ICGA results showed an increase in CVB at the inferior quadrants and posterior pole, suggesting venous outflow congestion in PCV eyes. CVB might provide more substantial information on the phenotype than other choroidal vascular features., (© 2023. The Author(s).)

For the early detection of avian influenza virus (AIV), molecular diagnostic methods such as real-time RT-PCR (rRT-PCR) are the first choice in terms of accuracy and speed in many countries. A laboratory's capability to perform this diagnostic method needs to be measured through external and independent assessment to ensure that the method is validated within the laboratory and in interlaboratory comparison. The Animal and Plant Quarantine Agency of Korea has implemented five rounds of proficiency testing (PT) for rRT-PCR targeting local veterinary service laboratories involved in the AIV national surveillance program from 2020 to 2022. In each round, a portion composed of six or more samples was selected from the entire PT panel consisting of H5, H7, and H9 viruses isolated in Korea and distributed to each participant, and at least one pair of samples was commonly included in each panel for interlaboratory comparison. During the five rounds of PT, a few incorrect and outlying results were detected that required immediate inspection or corrective actions. However, in the quantitative measurement of Ct values, the average standard deviation or coefficient of variation decreased as multiple PT rounds progressed, and a positive correlation between consecutive rounds of PT was observed since 2021. The better consistency or stability in the experimental performance appeared to contribute to the more harmonized results in the latest PTs, and it is assumed that the positive reaction of participants to the challenges of quantitative assessment reports showing their status intuitively might work. We need to continue operating the PT program for local laboratories because they play crucial roles at the front line of the national avian influenza surveillance program, and frequent changes in the human resources or environment for diagnosis in those laboratories are inevitable.

Importance: Until now, other than complex neurologic tests, there have been no readily accessible and reliable indicators of neurologic dysfunction among patients with Parkinson disease (PD). This study was conducted to determine the role of fundus photography as a noninvasive and readily available tool for assessing neurologic dysfunction among patients with PD using deep learning methods., Objective: To develop an algorithm that can predict Hoehn and Yahr (H-Y) scale and Unified Parkinson's Disease Rating Scale part III (UPDRS-III) score using fundus photography among patients with PD., Design, Settings, and Participants: This was a prospective decision analytical model conducted at a single tertiary-care hospital. The fundus photographs of participants with PD and participants with non-PD atypical motor abnormalities who visited the neurology department of Kangbuk Samsung Hospital from October 7, 2020, to April 30, 2021, were analyzed in this study. A convolutional neural network was developed to predict both the H-Y scale and UPDRS-III score based on fundus photography findings and participants' demographic characteristics., Main Outcomes and Measures: The area under the receiver operating characteristic curve (AUROC) was calculated for sensitivity and specificity analyses for both the internal and external validation data sets., Results: A total of 615 participants were included in the study: 266 had PD (43.3%; mean [SD] age, 70.8 [8.3] years; 134 male individuals [50.4%]), and 349 had non-PD atypical motor abnormalities (56.7%; mean [SD] age, 70.7 [7.9] years; 236 female individuals [67.6%]). For the internal validation data set, the sensitivity was 83.23% (95% CI, 82.07%-84.38%) and 82.61% (95% CI, 81.38%-83.83%) for the H-Y scale and UPDRS-III score, respectively. The specificity was 66.81% (95% CI, 64.97%-68.65%) and 65.75% (95% CI, 62.56%-68.94%) for the H-Y scale and UPDRS-III score, respectively. For the external validation data set, the sensitivity and specificity were 70.73% (95% CI, 66.30%-75.16%) and 66.66% (95% CI, 50.76%-82.25%), respectively. Lastly, the calculated AUROC and accuracy were 0.67 (95% CI, 0.55-0.79) and 70.45% (95% CI, 66.85%-74.04%), respectively., Conclusions and Relevance: This decision analytical model reveals amalgamative insights into the neurologic dysfunction among PD patients by providing information on how to apply a deep learning method to evaluate the association between the retina and brain. Study data may help clarify recent research findings regarding dopamine pathologic cascades between the retina and brain among patients with PD; however, further research is needed to expand the clinical implication of this algorithm.

Prior to the identification of low pathogenic avian influenza H9N2 viruses belonging to the Y280 lineage in 2020, Y439 lineage viruses had been circulating in the Republic of Korea since 1996. Here, we developed a whole inactivated vaccine (vac564) by multiple passage of Y439 lineage viruses and then evaluated immunogenicity and protective efficacy in specific-pathogen-free chickens. We found that LBM564 could be produced at high yield in eggs (10 8.4 EID 50 /0.1 mL; 1024 hemagglutinin units) and was immunogenic (8.0 ± 1.2 log 2 ) in chickens. The vaccine showed 100% inhibition of virus in the cecal tonsil with no viral shedding detected in either oropharyngeal or cloacal swabs after challenge with homologous virus. However, it did not induce effective protection against challenge with heterologous virus. An imported commercial G1 lineage vaccine inhibited viral replication against Y280 and Y439 lineage viruses in major tissues, although viral shedding in oropharyngeal and cloacal swabs was observed up until 5 dpi after exposure to both challenge viruses. These results suggest that a single vaccination with vac564 could elicit immune responses, showing it to be capable of protecting chickens against the Y439 lineage virus. Thus, our results suggest the need to prepare suitable vaccines for use against newly emerging and re-emerging H9N2 viruses.

Although many studies demonstrated the differences of clinical features, natural course, and response to treatment between typical age-related macular degeneration (AMD) and polypoidal choroidal vasculopathy (PCV), differential microRNAs (miRNAs) expression in the aqueous humor (AH) between them has not been reported yet. We investigated the roles of miRNAs in the AH of patients with typical AMD and PCV using next-generation sequencing (NGS) and quantitative PCR (qPCR). Target genes and predicted pathways of miRNAs were investigated via pathway enrichment analysis using the Kyoto Encyclopedia of Genes and Genomes database. A total of 161 miRNAs from eyes with typical AMD and 185 miRNAs from eyes with PCV were differentially expressed. 33 miRNAs were commonly upregulated, and 77 miRNAs were commonly downregulated in both typical AMD and PCV groups. Among them, hsa-miR-140-5p, hsa-miR-374c-3p, and hsa-miR-200a-5p were differentially expressed and were predicted to regulate proteoglycans in cancer, p53 signaling pathway, Hippo signaling pathway, and adherens junction. The differential expression profiles and target gene regulation networks of AH miRNAs may contribute to the development of different pathological phenotypes in typical AMD and PCV. The results of this study provide novel insights into the pathogenesis, associated prognostic biomarkers, and therapeutic targets in AMD and PCV., (© 2023. The Author(s).)

Introduction: The aim of the study was to determine the short-term real-world safety and efficacy of intravitreal brolucizumab injections in Korean patients with neovascular age-related macular degeneration (nAMD)., Methods: This multicenter retrospective study involved 294 eyes (treatment naïve 20 eye [6.8%] and nontreatment naïve 274 eyes [93.2%]) of 290 patients from 13 hospitals or retinal centers in South Korea. Patients with nAMD who received brolucizumab injection(s) between April 1 and November 30, 2021, with a follow-up ≥1 month, were included. Primary outcomes were safety, incidence of intraocular inflammation (IOI), and potential risk factors. The secondary outcome was efficacy, i.e., change in best-corrected visual acuity (BCVA) and optical coherence tomography-measured macular thickness and retinal fluid., Results: The mean age was 71.63 ± 8.66. The follow-up period was 2.38 ± 0.79 months. The mean number of brolucizumab injections during the follow-up was 1.52 ± 0.58. The overall incidence of IOI was 13.9% (n = 41 eyes). Most IOI cases were of anterior uveitis (8.8%, 26 eyes), followed by retinal vasculitis (2.4%, seven eyes) and occlusive retinal vasculitis (0.3%, one eye). Most eyes showed IOI resolution (n = 40, 97.5%) and BCVA restoration (n = 39, 95.1%) with or without corticosteroid treatment during the follow-up. Age, sex, IOI history, or other anti-vascular endothelial growth factor injection histories were not associated with the occurrence of IOI. However, only thin subfoveal choroidal thickness (SFCT) was associated with the occurrence of IOI (odds ratio = 0.995, p = 0.020). BCVA at 1 month improved from baseline (baseline 0.518 ± 0.356 vs. 1 month 0.503 ± 0.383, p = 0.023), but the improvement was not maintained. Anatomical improvement was significant after 3 months., Conclusion: In Korean patients with nAMD, the incidence of IOI following brolucizumab injections was 13.9%. IOI was well-controlled with or without steroid treatment. Most IOI eyes (95.1%) were restored to the level of vision before. IOI occurrence and occlusive vasculitis was rare. In the short term, brolucizumab injection effectively improved vision at 1 month and dried retinal fluid for 3 months., (© 2023 S. Karger AG, Basel.)

Purpose: To evaluate plasma antiretinal autoantibody (ARA) profiling and diagnostic efficacy for autoimmune retinopathy (AIR)., Design: A multicenter, diagnostic evaluation study., Methods: Forty-nine patients with a clinical diagnosis of AIR, disease controls including 20 patients with retinitis pigmentosa (RP), and 30 normal controls were included. Plasma samples from patients were analyzed for the presence of 6 ARAs, including recoverin, α-enolase, carbonic anhydrase II, heat shock protein 60, aldolase C, and cone-rod homeobox/cone-rod retinal dystrophy 2 using western blotting., Results: Autoantibody detection rates against cone-rod homeobox/cone-rod retinal dystrophy 2, heat shock protein 60, and aldolase C in AIR were 67.3%, 40.8%, and 42.9%, respectively, which were higher than those in RP and normal controls (P < .001, P < .001, and P = .007, respectively), but recoverin, α-enolase, and carbonic anhydrase II were not different from other control groups (P = .117, P = .774, and P = .467, respectively). Among ARAs, antirecoverin antibody was the most specific, as it was found in 3 (6.1%) patients with AIR and none of the control groups. As the number of detected ARAs increased, the probability of AIR increased (odds ratio: 1.913; P < .001; 95% confidence interval: 1.456-2.785). The positive number of ARAs was significantly higher when photoreceptor disruption was observed on optical coherence tomography, or severe dysfunction was observed in electroretinography (P = .022 and P = .029, respectively)., Conclusions: The profiles of ARAs in the AIR group were different from those in the RP and normal controls. The higher number of positive ARAs suggests a higher possibility of AIR diagnosis. ARAs should be used as adjunct tools for the clinical diagnosis of AIR., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The H9N2 avian influenza (AI) has become endemic in poultry in many countries since the 1990s, which has caused considerable economic losses in the poultry industry. Considering the long history of the low pathogenicity H9N2 AI in many countries, once H9N2 AI is introduced, it is more difficult to eradicate than high pathogenicity AI. Various preventive measures and strategies, including vaccination and active national surveillance, have been used to control the Y439 lineage of H9N2 AI in South Korea, but it took a long time for the H9N2 virus to disappear from the fields. By contrast, the novel Y280 lineage of H9N2 AI was introduced in June 2020 and has spread nationwide. This study reviews the history, genetic and pathogenic characteristics, and control strategies for Korean H9N2 AI. This review may provide some clues for establishing control strategies for endemic AIV and a newly introduced Y280 lineage of H9N2 AI in South Korea., Competing Interests: The authors declare no conflicts of interest., (© 2023 The Korean Society of Veterinary Science.)