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Phospholipase D1 (PLD1) contributes to cancer development and progression through its effects on cell proliferation, survival, invasion, metastasis, angiogenesis, drug resistance, and modulation of the tumor microenvironment. Its central role in these processes makes it a promising target for novel cancer treatments aimed at inhibiting its activity and disrupting the signaling pathways it regulates. In this study, we aimed to investigate the effect of PLD1 inhibition on gastric cancer cell growth using a novel peptide inhibitor, TAT-TVTSP. PLD1, which plays a role in cancer progression, catalyzes the conversion of phosphatidylcholine into choline and phosphatidic acid through hydrolysis. To effectively target PLD1 in cells, we engineered TAT-TVTSP by fusing a PLD1-inhibitory peptide (TVTSP) with a cell-penetrating peptide (TAT). We observed that TAT-TVTSP effectively inhibited PLD1 activity in AGS gastric cancer cells. Moreover, TAT-TVTSP significantly inhibited the mammalian target of the rapamycin signaling pathway, including the phosphorylation of key downstream targets such as S6K1, AKT, S473, glycogen synthase kinase-3b, and forkhead box O1. TAT-TVTSP did not induce cell death, but it triggered cell cycle arrest by activating p21 and p27 via AKT phosphorylation. Functional assays revealed that TAT-TVTSP significantly impaired the colony-forming ability of AGS cells, thus inhibiting cell proliferation. Transwell and wound-healing assays revealed that this peptide disrupted the cellular behaviors critical to cancer progression, such as migration and invasion. In vivo, TAT-TVTSP significantly reduced tumor growth in the xenograft model of gastric cancer without any toxicity. Overall, our results suggest that TAT-TVTSP is a novel therapeutic agent for PLD1-mediated cancers., Competing Interests: DECLARATION OF COMPETING INTERESTS 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 © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: This retrospective case series aimed to assess the concordance between clinical diagnoses of punctate inner choroidopathy and multifocal choroiditis and panuveitis (MCP) using the 2021 Standardization of Uveitis Nomenclature Working Group criteria., Methods: Using the medical records of the patients, the authors reevaluated 100 eyes of 75 patients with idiopathic multifocal chorioretinal inflammatory lesions based on Standardization of Uveitis Nomenclature criteria and compared the result with the clinical diagnosis., Results: Of 100 eyes, 29 eyes (29%) were diagnosed as punctate inner choroidopathy and 15 eyes (15%) were diagnosed as MCP using Standardization of Uveitis Nomenclature criteria, and 56 (56%) eyes could not be diagnosed as either. Clinically diagnosed punctate inner choroidopathy eyes were significantly more myopic than the clinically diagnosed MCP eyes (mean spherical equivalent -6.65 ± 4.63 vs. -3.85 ± 2.31, P = 0.01). Sixteen eyes with vitreous inflammation were all clinically diagnosed as MCP, but four (25%) could not be diagnosed as MCP using Standardization of Uveitis Nomenclature criteria., Conclusion: The existing diagnostic criteria showed limitations in capturing all clinical cases of punctate inner choroidopathy or MCP, and adding or revising criteria on features such as vitreous inflammation or myopia could be considered to enhance diagnostic accuracy.

Purpose: Little is known about the major risk factors for submacular hemorrhage (SMH). This study aimed to evaluate the factors associated with SMH in patients with neovascular age-related macular degeneration (nAMD) and polypoidal choroidal vasculopathy (PCV) receiving three consecutive loading doses of intravitreal aflibercept or ranibizumab injections., Methods: This retrospective cross-sectional study included 48 patients diagnosed with wAMD and PCV who completed three loading doses under a treat-and-extend regimen. Patients were divided into the SMH group (n=24) and the non-SMH group (age- and sex-matched without SMH). Intravitreal injections, agents, and optical coherence tomography (OCT) features were compared., Results: In the SMH group, SMH occurred approximately 3.29 years after post-nAMD diagnosis. The non-SMH group received more intravitreal injections of aflibercept and brolucizumab during the follow-up period after the initial loading phase. The SMH group exhibited a higher prevalence of serous/hemorrhagic pigment epithelial detachments (PEDs) at the last visit before SMH occurrence compared to the non-SMH group. Patients with a PED increase in the past two visits showed a higher tendency in the SMH group. No other OCT features significantly correlated with SMH development., Conclusions: The presence of serous/hemorrhagic PEDs may indicate a higher risk of SMH, and eyes with these features should be closely monitored to prevent sudden and devastating visual loss caused by SMH.

Purpose: To investigate the clinical characteristics, imaging features, and predictive factors for spontaneous separation in patients with idiopathic or secondary ERM., Methods: The overall cohort was divided into two subgroups: idiopathic ERM (28 eyes, 56%) and secondary ERM (22 eyes, 44%). Electronic records and multimodal imaging were reviewed., Results: Among the 50 eyes included in this study, the self-separation of ERM occurred over a mean duration of 28.1 ± 25.3 months (median: 25.4 months). Compared with the secondary ERM group, the idiopathic group had a shorter interval to separation (idiopathic vs. secondary, 23.4 vs. 34.1 months, respectively; P = .01) and better vision at diagnosis (logMAR 0.094 vs. 0.224; P = .009) and after separation (logMAR 0.097 vs. 0.188; P = .01). Overall, in both subgroups, spontaneous ERM separation appeared to have been induced by posterior vitreous detachment (PVD) (P < .001). Multivariate analysis revealed that the self-separation interval (odds ratio [OR] 0.936) and IRF (OR 0.049) were significantly associated with complete ERM separation (all P < .05). Additionally, secondary ERM (OR 15.224) and lower initial best-corrected visual acuity (OR 267.589) were significantly associated with improvements in vision after self-separation (all P < .05)., Conclusion: The self-separation of ERM appears to be induced by PVD development in most eyes. Owing to the possibility of complete spontaneous separation, surgical membrane peeling may be delayed by up to 28 months in eyes without PVD, regardless of whether the cause is idiopathic or secondary. Patients with secondary ERM may experience favorable visual improvement after self-separation despite having poor vision at diagnosis and IRF on OCT., Key Messages: What is known • An epiretinal membrane (ERM), the most prevalent retinal disease in adults, is less understood regarding clinical factors and the accurate mechanism of spontaneous separation. What is new • The separation of ERM appears to be induced by PVD development in most eyes. • Favorable vision outcomes were associated with secondary ERMs and lower initial visual acuity. • Complete ERM separation was associated with a shorter self-resolution interval and the absence of intraretinal fluid (IRF) in OCT imaging., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: To investigate predictive factors for redislocation in patients with recurrent intraocular lens (IOL) dislocation after secondary scleral-fixated IOL (SF IOL) surgery., Setting: 2 tertiary referral hospitals., Design: Retrospective case series., Methods: Patients undergoing SF IOL surgery were grouped into redislocation and no-redislocation groups. Medical records of consecutive patients who underwent SF IOL surgery between June 2014 and December 2019 at 2 tertiary referral centers were reviewed. Data regarding patient demographics, treatment factors, anatomical and functional outcomes, and postoperative complications were recorded., Results: 237 eyes of 225 patients (169 [75.1%] men) were included. The redislocation group was more likely to have a younger mean age at the initial SF IOL surgery (redislocation vs no-redislocation, 55.4 vs 62.0 years, respectively; P = .008), have a prior history of a previous suture break (23 eyes, 52.3% vs 1 eye, 0.5%; P < .001), and have undergone the initial SF IOL surgery using <1 mm-sized side-port incisions (17 eyes, 38.6% vs 32 eyes, 16.5%; P = .002) than was the no-redislocation group. In addition, the redislocation group had a higher occurrence of complications ( P < .001). Multivariate regression revealed that younger age, left eye involvement, aphakic status before the surgery, unremarkable primary IOL dislocation cause, need for ocular hypertension treatment and glaucoma surgery, and no large incision during the initial surgery were significantly (all P < .05) associated with redislocation., Conclusions: Younger age, left eye involvement, postoperative complications such as ocular hypertension and glaucoma, and techniques without large incisions increase the risk of redislocation. Conversely, lower risk factors include unremarkable surgery causes and a history of aphakic conditions., (Copyright © 2024 Published by Wolters Kluwer on behalf of ASCRS and ESCRS.)

Background: Posterior chamber intraocular lens (IOL) dislocation is a common complication of cataract surgery. Dislocated IOLs often require surgical intervention due to the potentially severe risks of leaving this condition untreated. If a patient with extremely low corneal endothelial cell density (ECD) presents with IOL dislocation, the surgeon faces a crucial dilemma of choosing the most optimal surgical treatment option. We sought to investigate the efficacy and safety of retropupillary iris claw intraocular lens (R-IOL) implantation in patients with IOL dislocation and extremely low (< 1000 cells/mm 2 ) ECD., Methods: We retrospectively reviewed the medical records of nine patients (all men) whose pre-operative ECD was < 1000 cells/mm 2 and who underwent R-IOL implantation due to intraocular subluxation or total dislocation into the vitreous cavity between 2014 and 2020. We evaluated corneal endothelial function and visual outcomes after surgery., Results: Nine patients were included in this study. The mean age at diagnosis was 64.89 ± 7.15 years (range 57-76 years), and the follow-up duration was 37.93 ± 23.72 months (range 18.07-89.07 months). No patients developed bullous keratopathy during follow-up. Compared to the initial ECD, corneal thickness (CT), coefficient variation of cell area (CV) and percentage of hexagonal cells (HEX), there was no statistically significant decrease in the ECD, CV, and HEX at last follow-up (P = 0.944, 0.778, 0.445, 0.443). There was significant improvement in the mean uncorrected distance visual acuity (UDVA) at the last follow-up (average 0.13 logMAR, 20/27 Snellen) compared to the pre-operative mean UDVA (average 1.09 logMAR, 20/250 Snellen) (P < 0.01)., Conclusions: R-IOL implantation did not result in a statistically significant decline in corneal endothelial function in patients with preoperatively low ECD, and it significantly improved the mean UDVA postoperatively. R-IOL implantation appears to be a safe and effective treatment modality for intraocular lens dislocation in patients with low ECD (< 1000 cells/mm²); however, long-term follow-up studies are warranted to corroborate these findings., (© 2024. The Author(s).)

Purpose: This study aimed to determine the incidence and visual outcomes of pachychoroid neovasculopathy (PNV) in patients initially diagnosed with central serous chorioretinopathy (CSC)., Methods: In this study, 144 patients aged 20 to 55 years with treatment-naive chronic CSC, defined as the persistence of subretinal fluid (SRF) for ≥6 months, were retrospectively enrolled. Patients with PNV at the initial evaluation were categorized as group 1, whereas those who developed new-onset PNV during follow-up were categorized as group 2. Patients without PNV until the end of the follow-up were categorized as group 3., Results: Over a mean follow-up period of 49.9 ± 39.9 months, new-onset PNV was diagnosed in 11.8% of patients with CSC. The time taken to reach the initial resolution was longest in group 1 (group 1, 11.13 ± 10.70 months; group 2, 8.14 ± 7.90 months; group 3, 7.32 ± 9.55 months), although these differences were not statistically significant. The numbers of injections needed to achieve initial resolution were 3.76 ± 5.90, 1.64 ± 2.06, and 1.74 ± 4.33 in groups 1, 2, and 3, respectively, with no significant differences. SRF recurrence was recorded in seven patients (29.2%) in group 1, nine (64.3%) in group 2, and 28 (26.7%) in group 3. The recurrence rates were significantly higher in group 2 than those in group 1 or 3. At the end of the follow-up period, significant improvements in best-corrected visual acuity were achieved in groups 1 and 3, compared with baseline, but not in group 2., Conclusions: Patients with chronic CSC with new-onset PNV exhibited higher SRF recurrence and worse visual outcomes compared to those with initial PNV or those with chronic CSC without PNV. Our study emphasizes the importance of routine screening for prompt diagnoses of new-onset PNV in individuals with chronic CSC.

Despite of the substantial potential of human-derived retinal organoids, the degeneration of retinal ganglion cells (RGCs) during maturation limits their utility in assessing the functionality of later-born retinal cell subtypes. Additionally, conventional analyses primarily rely on fluorescent emissions, which limits the detection of actual cell functionality while risking damage to the 3D cytoarchitecture of organoids. Here, an electrophysiological analysis is presented to monitor RGC development in early to mid-stage retinal organoids, and compare distinct features with fully-mature mouse retina. This approach utilizes high-resolution 3D printing of liquid-metal microelectrodes, enabling precise targeting of specific inner retinal layers within organoids. The adaptable distribution and softness of these microelectrodes facilitate the spatiotemporal recording of inner retinal signals. This study not only demonstrates the functional properties of RGCs in retinal organoid development but also provides insights into their synaptic connectivity, reminiscent of fetal native retinas. Further comparison with fully-mature mouse retina in vivo verifies the organoid features, highlighting the potential of early-stage retinal organoids in biomedical research., (© 2024 The Author(s). Advanced Materials published by Wiley‐VCH GmbH.)

X-linked juvenile retinoschisis (XLRS) is a hereditary retinal degeneration affecting young males caused by mutations in the retinoschisin ( RS1 ) gene. We generated human induced pluripotent stem cells (hiPSCs) from XLRS patients and established three-dimensional retinal organoids (ROs) for disease investigation. This disease model recapitulates the characteristics of XLRS, exhibiting defects in RS1 protein production and photoreceptor cell development. XLRS ROs also revealed dysregulation of Na/K-ATPase due to RS1 deficiency and increased ERK signaling pathway activity. Transcriptomic analyses of XLRS ROs showed decreased expression of retinal cells, particularly photoreceptor cells. Furthermore, relevant recovery of the XLRS phenotype was observed when co-cultured with control ROs derived from healthy subject during the early stages of differentiation. In conclusion, our in vitro XLRS RO model presents a valuable tool for elucidating the pathophysiological mechanisms underlying XLRS, offering insights into disease progression. Additionally, this model serves as a robust platform for the development and optimization of targeted therapeutic strategies, potentially improving treatment outcomes for patients with XLRS.

Purpose: We studied Korean patients with Eales' disease to document clinical features, long-term outcomes, and explore its association with TB, given South Korea's high TB burden., Methods: We retrospectively reviewed medical records of Eales' disease patients for clinical characteristics, long-term outcomes, and its association with TB., Results: Among 106 eyes, the average age of diagnosis was 39.28 years, with 82.7% male and 58.7% having unilateral involvement. Patients who underwent vitrectomy showed greater long-term improvement in visual acuity ( P  = .047), while those with glaucoma filtration surgery showed less improvement ( P  = .008). Having glaucoma through disease progression was associated with poor visual outcomes (odds ratio=15.556, P  < .02). 27 out of 39 patients (69.23%) who underwent IGRA screening tested positive for TB., Conclusions: In Korean patients with Eales' disease, we observed male predominance, unilateral presentation, older age of onset, and a link with TB. Timely diagnosis and management should be considered to maintain good vision in patients with Eales' disease.

Purpose: This study sought to compare the long-term outcomes of surgeries for retinal detachment (RD) secondary to viral or parasitic infectious retinitis., Methods: A total of 47 eyes that received pars plana vitrectomy with or without scleral buckling due to RD secondary to polymerase chain reaction-proven viral (cytomegalovirus, varicella zoster virus, and herpes zoster virus) or parasitic (toxoplasma and toxocara) retinitis from October 1, 2006, to June 30, 2023, in a single medical center were retrospectively enrolled., Results: Mean follow-up period was 59.03 ± 55.24 months in viral retinitis and 34.80 ± 33.78 months in parasitic retinitis after primary reattachment surgery. During follow-up, nine eyes (24.3%) with viral retinitis and five eyes (50.0%) with parasitic retinitis developed retinal redetachment. Visual acuity success at final follow-up was achieved in 19 eyes (51.4%) with viral retinitis and six eyes (60.0%) with parasitic retinitis (p = 0.64). The incidence of retinal redetachment during the 1st postoperative year was significantly higher in parasitic retinitis compared with viral retinitis (crude incidence, 0.21 vs. 0.85; p = 0.02). Hazard ratio analysis adjusted for age and sex showed 4.58-fold (95% confidence interval, 1.22-17.27; p = 0.03) increased risk of retinal redetachment in parasitic retinitis compared with viral retinitis during the 1st postoperative year. Tamponade with silicone oil and preoperative diagnostic vitrectomy were associated with significantly decreased risk of retinal redetachment in patients with parasitic retinitis., Conclusions: Compared with RD secondary to viral retinitis, RD secondary to parasitic retinitis showed higher incidence of retinal redetachment during the 1st postoperative year. Tamponade with silicone oil and preoperative diagnostic vitrectomy were associated with significantly decreased risk of retinal redetachment in patients with parasitic retinitis.

Electronic retinal prostheses for stimulating retinal neurons are promising for vision restoration. However, the rigid electrodes of conventional retinal implants can inflict damage on the soft retina tissue. They also have limited selectivity due to their poor proximity to target cells in the degenerative retina. Here we present a soft artificial retina (thickness, 10 μm) where flexible ultrathin photosensitive transistors are integrated with three-dimensional stimulation electrodes of eutectic gallium-indium alloy. Platinum nanoclusters locally coated only on the tip of these three-dimensional liquid-metal electrodes show advantages in reducing the impedance of the stimulation electrodes. These microelectrodes can enhance the proximity to the target retinal ganglion cells and provide effective charge injections (72.84 mC cm -2 ) to elicit neural responses in the retina. Their low Young's modulus (234 kPa), owing to their liquid form, can minimize damage to the retina. Furthermore, we used an unsupervised machine learning approach to effectively identify the evoked spikes to grade neural activities within the retinal ganglion cells. Results from in vivo experiments on a retinal degeneration mouse model reveal that the spatiotemporal distribution of neural responses on their retina can be mapped under selective localized illumination areas of light, suggesting the restoration of their vision., (© 2024. The Author(s).)

Importance: Despite advances in next-generation sequencing (NGS), a significant proportion of patients with inherited retinal disease (IRD) remain undiagnosed after initial genetic testing. Exome sequencing (ES) reanalysis in the clinical setting has been suggested as one method for improving diagnosis of IRD., Objective: To investigate the association of clinician-led reanalysis of ES data, which incorporates updated clinical information and comprehensive bioinformatic analysis, with the diagnostic yield in a cohort of patients with IRDs in Korea., Design, Setting, and Participants: This was a multicenter prospective cohort study involving 264 unrelated patients with IRDs, conducted in Korea between March 2018 and February 2020. Comprehensive ophthalmologic examinations and ES analyses were performed, and ES data were reanalyzed by an IRD specialist for single nucleotide variants, copy number variants, mobile element insertions, and mitochondrial variants. Data were analyzed from March to July 2023., Main Outcomes and Measures: Diagnostic rate of conventional bioinformatic analysis and clinician-driven ES reanalysis., Results: A total of 264 participants (151 [57.2%] male; mean [SD] age at genetic testing, 33.6 [18.9] years) were enrolled, including 129 patients (48.9%) with retinitis pigmentosa and 26 patients (9.8%) with Stargardt disease or macular dystrophy. Initial bioinformatic analysis diagnosed 166 patients (62.9%). Clinician-driven reanalysis identified the molecular cause of diseases in an additional 22 patients, corresponding to an 8.3-percentage point increase in diagnostic rate. Key factors associated with new molecular diagnoses included clinical phenotype updates (4 patients) and detection of previously overlooked variation, such as structural variants (9 patients), mitochondrial variants (3 patients), filtered or not captured variants (4 patients), and noncanonical splicing variants (2 patients). Among the 22 patients, variants in 7 patients (31.8%) were observed in the initial analysis but not reported to patients, while those in the remaining 15 patients (68.2%) were newly detected by the ES reanalysis., Conclusions and Relevance: In this cohort study, clinician-centered reanalysis of ES data was associated with improved molecular diagnostic yields in patients with IRD. This approach is important for uncovering missed genetic causes of retinal disease.

Purpose: We establish an accurate and rapid diagnostic method for pathogen detection in infectious uveitis using nanopore metagenomic next-generation sequencing (NGS)., Methods: In eight patients with suspected infectious uveitis, we prospectively compared the accuracy and time taken for pathogen identification between conventional diagnostic methods, such as cultures and PCR, and nanopore metagenomic NGS., Results: All causative pathogens were identified using nanopore sequencing, while only five of the eight patients were confirmed positive for a specific pathogen using conventional methods. The overall sample-to-answer turnaround time of nanopore sequencing was much shorter than that of conventional methods in the bacterial and fungal infection (mean, 17 h vs. 4d, respectively; P = .028). The pathogens could be detected even when the quantity or quality of DNA was not optimal., Conclusion: Nanopore metagenomic NGS is a promising diagnostic tool that can rapidly and accurately identify the causative pathogen in infectious uveitis.

Purpose: Pathogenic variants in North Carolina macular dystrophy (NCMD) have rarely been reported in the East Asian population. Herein, we reported novel variants of NCMD in 2 Korean families., Methods: The regions associated with NCMD were analyzed with genome sequencing, and variants were filtered based on the minor allele frequency (0.5%) and heterozygosity. Non-coding variants were functionally annotated using multiple computational tools., Results: We identified two rare novel variants, chr6:g.99,598,914T>C (hg38; V17) and chr6:g.99,598,926G>A (hg38; V18) upstream of PRDM13 in families A and B, respectively. In Family 1, Grade 2 NCMD and a best-corrected visual acuity of 20/25 and 20/200 in the right and left eyes, respectively, were observed. In Family B, all affected individuals had Grade 1 NCMD with characteristic confluent drusen at the fovea and a best-corrected visual acuity of 20/20 in both eyes. These two variants are 10-22 bp downstream of the reported V10 variant within the DNase1 hypersensitivity site. This site is associated with progressive bifocal chorioretinal atrophy and congenital posterior polar chorioretinal hypertrophy and lies in the putative enhancer site of PRDM13 ., Conclusion: We identified two novel NCMD variants in the Korean population and further validated the regulatory role of the DNase1 hypersensitivity site upstream of  PRDM13 ., (Copyright © 2024 Molecular Vision.)

The solute carrier family 35 F2 (SLC35F2) belongs to membrane-bound carrier proteins that are associated with multiple cancers. The main factor that determines cancer progression is the expression level of SLC35F2. Thus, identifying the E3 ligase that controls SLC35F2 protein abundance in cancer cells is critical. Here, we identified βTrCP1 interacting with and reducing the SLC35F2 protein level. βTrCP1 signals SLC35F2 protein ubiquitination and reduces SLC35F2 protein half-life. The mRNA expression pattern between βTrCP1 and SLC35F2 across a panel of cancer cell lines showed a negative correlation. Additionally, the depletion of βTrCP1 accumulated SLC35F2 protein and promoted SLC35F2-mediated cell growth, migration, invasion, and colony formation ability in HeLa cells. Overall, we demonstrate that βTrCP1 acts as a tumor suppressor by controlling SLC35F2 protein abundance in cancer cells. The depletion of βTrCP1 promotes SLC35F2-mediated carcinogenesis. Thus, we envision that βTrCP1 may be a potential target for cancer therapeutics., Competing Interests: Declaration of competing interest The authors have no competing interests regarding the content of this manuscript to declare., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Coats' disease is an idiopathic retinal vascular disorder, known to usually occur unilaterally; however, recent studies have highlighted vascular abnormalities in the fellow unaffected eyes. This retrospective study investigated the peripheral vascular features and macular vascular structure of unaffected fellow eyes in patients with unilateral Coats' disease using multimodal imaging tools. We analysed images of patients, including bilateral ultra-widefield imaging, fluorescein angiography (FA), ultra-widefield FA, or standard fundus photography. Available bilateral optical coherence tomography angiography (OCT-A) images were used for macular vascular structure analysis. OCT-A parameters, including foveal avascular zone (FAZ), perfusion index, and vessel density (VD) in the superficial and deep capillary plexuses (SCP, DCP), were calculated using Image J software. The mean age at diagnosis was 34.5 ± 17.9 years. The mean final best-corrected visual acuity of the affected eyes was logMAR 0.78 ± 0.79, while that of the fellow eyes was logMAR 0.04 ± 0.12. Ten fellow eyes had microaneurysms (47.6%), two had tortuous vessel abnormalities (9.5%), and 11(52.4%) had abnormal vascular findings on FA. Although there was a trend towards larger DCP FAZ (1.201 ± 0.086 vs. 1.072 ± 0.226), and lower DCP VD (8.593 ± 1.583 vs. 10.827 ± 3.392) in the affected eyes as measured by the Cirrus machine, the difference was not statistically significant between affected and fellow eyes when measured using the Zeiss Cirrus machine (P = 0.686, P = 0.343, respectively). However, when measured with the Spectralis machine, DCP FAZ was larger in affected eyes (0.828 ± 0.426 vs. 0.254 ± 0.092, P = 0.002) and DCP VD was lower in affected eyes (6.901 ± 2.634 vs. 17.451 ± 7.207, P = 0.002) compared to the fellow eyes, while other parameters showed no significant variations. These findings indicate that there may be subtle vascular abnormalities primarily located in the peripheral regions of the unaffected fellow eyes in patients with unilateral Coats' disease, while the macular microvasculature remains unaffected., (© 2023. The Author(s).)

Purpose: To determine the diagnostic potential of next-generation sequencing (NGS) in vitreous samples, analyze genotype-phenotype characteristics, and compare NGS of matched vitreous and brain samples in patients with associated central nervous system lymphoma (CNSL)., Methods: A total of 32 patients suspected of vitreoretinal lymphoma (VRL) who underwent diagnostic vitrectomy and NGS were included in this retrospective observational case-series. Fresh vitreous specimens from diagnostic vitrectomy of VRL-suspected patients underwent NGS using a custom panel targeting 747 candidate genes for lymphoma. They also underwent malignancy cytology, interleukin (IL)-10/IL-6, immunoglobulin heavy chain (IGH)/immunoglobulin kappa light chain (IGK) monoclonality testing. MYD88 L265P mutation was examined from anterior chamber tap samples. The diagnosis of VRL was made based on typical clinical characteristics for VRL, as well as malignant cytology, IGH/IGK clonality, or IL-10/IL-6 > 1. Sensitivity and specificity of NGS were compared with conventional diagnostic tests. Brain tissues suspected of lymphoma were collected by stereotactic biopsy and underwent NGS. Genetic variations detected in NGS of vitreous and brain tissue specimens were compared., Results: The sensitivity values for cytology, IL-10/IL-6 > 1, clonality assays for IGH and IGK, MYD88 L265P detection in anterior chamber tap samples, and vitreous NGS were 0.23, 0.83, 0.68, 0.79, 0.67, and 0.85, with specificity values of 1.00, 0.83, 0.50, 0.25, 0.83, and 0.83, respectively. The sensitivity (0.85) of vitreous NGS was the highest compared to other conventional diagnostic tests for VRL. The most common mutations were MYD88 (91%), CDKN2A (36%), PIM1 (32%), IGLL5 (27%), and ETV6 (23%). Although several gene alterations demonstrated heterogeneity between the brain and eyes, some common mutational profiles were observed in matched vitreous and brain samples., Conclusions: Overall, NGS of the vitreous demonstrated high sensitivity among conventional diagnostic tests. VRL and CNSL appeared to have both shared and distinct genetic variations, which may suggest site-specific variations from a common origin.

In this study, bacterial ghosts (BGs) were generated from Weissella koreensis LKS42 (WKorGs) and Pediococcus pentosacues KA94 (PPGs) by chemically inducing lysis using substances such as hydrochloric acid (HCl), sulfuric acid (H2SO4), nitric acid (HNO3), acetic acid (CH3COOH), sodium hydroxide (NaOH), potassium hydroxide (KOH), sodium carbonate (Na2CO3), n-butanol, and C6H8O7. HCl-induced WKorGs and PPGs exhibited complete removal of DNA and displayed transverse membrane dissolution tunnel structures under scanning electron microscopy (SEM). Cell viability assays showed high viability of RAW 264.7 cells exposed to HCl-induced WKorGs and PPGs. Additionally, treatment with HCl-induced WKorGs and PPGs elevated mRNA levels of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α, iNOS) and the anti-inflammatory cytokine IL-10 in RAW 264.7 cells. These findings suggest that HCl-induced WKorGs and PPGs have the potential to be used as inactivated bacterial immunostimulants, highlighting their promising applications in immunization and immunotherapy., Competing Interests: Declaration of competing interest The authors declare that they have no competing financial interests or personal relationships that may have influenced the work reported in this study., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: To evaluate the characteristics of bacillary layer detachment (BALAD) in acute Vogt-Koyanagi-Harada (VKH) disease and determine its prognostic value., Methods: Seventy patients with acute VKH disease with a minimum follow-up of 6 months were studied. The primary outcomes were clinical characteristics associated with BALAD, including features on multimodal imaging at baseline and follow-up. The secondary outcomes included best-corrected visual acuity and VKH with recurrence features., Results: Of 70 eyes (36 patients), 41 (58.6%) showed BALAD. The mean baseline best-corrected visual acuity and mean best-corrected visual acuity after resolution of serous retinal detachment were significantly lower in the BALAD group than in the no-BALAD group (0.90 ± 0.49 vs. 0.35 ± 0.35 log minimum angle of resolution, P < 0.001 and 0.39 ± 0.27 vs. 0.20 ± 0.20 log minimum angle of resolution, P = 0.020). The loss of ellipsoid zone integrity at baseline, proportion of serous retinal detachment, duration of serous retinal detachment, loss of ellipsoid zone integrity at 1 month, and subfoveal choroidal thickness at baseline were significantly higher in the BALAD group ( P = 0.017, P = 0.006, P = 0.023, P = 0.002, and P = 0.046, respectively). The mean best-corrected visual acuity and subfoveal choroidal thickness did not differ between the two groups at 6 months ( P = 0.380 and P = 0.180, respectively). Bacillary layer detachment at baseline was found to be a significant prognostic factor for VKH with recurrence features ( P = 0.007)., Conclusion: Vogt-Koyanagi-Harada with BALAD featured more severe clinical characteristics than VKH without BALAD during the acute phase. Patients with baseline BALAD require more vigilant monitoring as they are more likely to show recurrence features within the first 6 months.

Purpose: To investigate the clinical features, natural course, and genetic characteristics of Koreans with rhodopsin-associated retinitis pigmentosa ( RHO -associated RP). Design: We conducted a retrospective, multicenter, observational cohort study. Participants: We reviewed the medical records of 42 patients with RHO -associated RP of 36 families who visited 4 hospitals in Korea. Methods: Patients with molecular confirmation of pathogenic variants of the RHO gene were included. The patients were divided into two subgroups: the generalized and sector RP groups. A central visual field of the better-seeing eye of <10° or a best-corrected visual acuity of the better-seeing eye <20/40 indicated the progression to late-stage RP. Results: The mean age at which symptoms first appeared was 26.3 ± 17.9 years (range: 8-78 years), and the mean follow-up period was 80.9 ± 68.7 months (range: 6-268 months). At the last follow-up visit, the generalized RP group showed a significantly higher rate of visual field impairment progression to late-stage RP than that of the sector RP group (22 of 35 [62.9%] vs. 0 of 7 [0.0%], p = 0.003). No cases in the sector RP group progressed to generalized RP. Best-corrected visual acuity deterioration to late-stage RP was observed only in the generalized RP group (13 of 35 patients; 37.1%), whereas no deterioration was observed in the sector RP group. We identified 16 known and three novel RHO mutations, including two missense mutations (p.T108P and p.G121R) and one deletion mutation (p.P347&#95;A348del). The pathogenic variants were most frequently detected in exon 1 (14 of 36 [38.9%]). The most common pathogenic variants were p.P347L and T17M (5 of 36 [13.9%] families). Among 42 patients of 36 families, 35 patients of 29 families (80.6%) presented with the generalized RP phenotype, and seven patients of seven families (19.4%) presented with the sector RP phenotype. Three variants (p.T17M, p.G101E, and p.E181K) presented with both the generalized and sector RP phenotypes. Conclusion: This multicenter cohort study provided information on the clinical and genetic features of RHO -associated RP in Koreans. It is clinically important to expand the genetic spectrum and understand genotype-phenotype correlations to ultimately facilitate the development of gene therapy., 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 Jung, Kwak, Joo, Lee, Park, Kim, Lee, Byeon, Lee, Han, Lee, Yoon and Woo.)

This paper presents pose tracking experiments using a supermicrosurgical robot designed to consider teleoperation with multiple surgeons. Currently, existing supermicrosurgical robots assist only the primary surgeon. However, both primary and assistant surgeons need a high-precision motion for critical tasks that can easily damage microtissue. To assist multiple surgeons in supermicrosurgery with a surgical robot, dynamic collision avoidance becomes a critical issue due to the operation in a narrow surgical site. As a milestone to overcome this issue, we first developed a pose tracking algorithm by analyzing the inverse kinematics based on null-space control and a weighting matrix. Moreover, we also developed a control framework based on fully open-source software to run the pose tracking algorithm. Finally, we validated the proposed pose tracking algorithm by performing line tracing and rubber ring transferring experiments.

Rationale: Although regional metastasis to the lymph nodes is common in advanced oral cancer, extensive local invasion into surrounding structures such as the mandible, skin and soft tissue of the neck, and masticator space is relatively rare. Sometimes surgical treatment cannot be performed and only palliative chemotherapy and radiation therapy are offered to preserve the quality of life of patients with advanced oral cancer. Nevertheless, the surgical resection of tumors remains the most effective treatment. This study presents a case of aggressive mouth floor cancer in which extensive composite defects on the mouth floor, oral mucosa, mandible, skin and soft tissue of the neck caused by tumor resection were reconstructed., Patient Concerns: A 66-year-old man and a 65-year-old man with no significant personal or family history visited our clinic due to a large and multiple masses on the floor of the mouth and both sides of the neck., Diagnosis: Histopathological evaluation of the biopsy specimen revealed squamous cell carcinoma., Interventions: A fibula osteocutaneous free flap and customized titanium plate were used for the intraoral lining. Mandibular reconstruction was performed using a 3D-printed bone model, and an anterolateral thigh free flap was used to resurface the anterior of the neck., Outcomes: Reconstruction using this method was successful, and excellent functional and aesthetic outcomes were achieved without cancer recurrence., Lessons: This study show that the reconstruction of extensive composite defects of the oral mucosa, mandible, and neck soft tissue following surgical resection of mouth floor cancer can be performed in a single-stage operation. Through a single-stage reconstruction, both excellent functional aspects without cancer recurrence and satisfactory aesthetic outcomes can be obtained., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Huntington's disease (HD) is caused by a CAG repeat expansion in the huntingtin (HTT) gene. CRISPR-Cas9 nuclease causes double-strand breaks (DSBs) in the targeted DNA that induces toxicity, whereas CRISPR interference (CRISPRi) using dead Cas9 (dCas9) suppresses the target gene expression without DSBs. Delivery of dCas9-sgRNA targeting CAG repeat region does not damage the targeted DNA in HEK293T cells containing CAG repeats. When this study investigates whether CRISPRi can suppress mutant HTT (mHTT), CRISPRi results in reduced expression of mHTT with relative preservation of the wild-type HTT in human HD fibroblasts. Although both dCas9 and Cas9 treatments reduce mHTT by sgRNA targeting the CAG repeat region, CRISPRi delays behavioral deterioration and protects striatal neurons against cell death in HD mice. Collectively, CRISPRi can delay disease progression by suppressing mHtt, suggesting DNA DSB-free CRISPRi is a potential therapy for HD that can compensate for the shortcoming of CRISPR-Cas9 nuclease., (© 2023. The Author(s).)

The adoption of Li 2 CuO 2 has drawn interest as a Li-excess cathode additive for compensating irreversible Li + loss in anodes during cycling, which would move forward high-energy-density lithium-ion batteries (LIBs). Li 2 CuO 2 provides a high irreversible capacity (>200 mAh g -1 ) in the first cycle and an operating voltage comparable with commercial cathode materials, but its practical use is still restricted by the structural instability and spontaneous oxygen (O 2 ) evolution, resulting in poor overall cycling performance. It is thus crucial to reinforce the structure of Li 2 CuO 2 to make it more reliable as a cathode additive for charge compensation. Pursuing the structural stability of Li 2 CuO 2 , herein, we demonstrate cosubstitution by heteroatoms, such as nickel (Ni) and manganese (Mn), for improving the structural stability and electrochemical performance of Li 2 CuO 2 . Such an approach effectively enhances the reversibility of Li 2 CuO 2 by suppressing continuous structural degradation and O 2 gas evolution during cycling. Our findings provide new conceptual pathways for developing advanced cathode additives for high-energy LIBs.

The CRISPR/Cas9 system easily edits target genes in various organisms and is used to treat human diseases. In most therapeutic CRISPR studies, ubiquitously expressed promoters, such as CMV, CAG, and EF1α, are used; however, gene editing is sometimes necessary only in specific cell types relevant to the disease. Therefore, we aimed to develop a retinal pigment epithelium (RPE)-specific CRISPR/Cas9 system. We developed a CRISPR/Cas9 system that operates only in retinal pigment epithelium (RPE) by expressing Cas9 under the RPE-specific vitelliform macular dystrophy 2 promoter (pVMD2). This RPE-specific CRISPR/pVMD2-Cas9 system was tested in human retinal organoid and mouse model. We confirmed that this system works specifically in the RPE of human retinal organoids and mouse retina. In addition, the RPE-specific Vegfa ablation using the novel CRISPR-pVMD2-Cas9 system caused regression of choroidal neovascularization (CNV) without unwanted knock-out in the neural retina in laser-induced CNV mice, which is a widely used animal model of neovascular age-related macular degeneration. RPE-specific Vegfa knock-out (KO) and ubiquitous Vegfa KO were comparable in the efficient regression of CNV. The promoter substituted, cell type-specific CRISPR/Cas9 systems can be used in specific 'target cell' therapy, which edits genes while reducing unwanted off- 'target cell' effects., (© 2023. The Author(s).)

Aims: To retrospectively compare the therapeutic effect of modified double-dose photodynamic therapy (PDT) with standard-dose PDT in patients with circumscribed choroidal haemangioma (CCH)., Methods: Thirty-nine patients with CCH were categorised in two groups by PDT type. The standard-dose group (n=12) was treated with 6 mg/m 2 verteporfin and a 689 nm laser for 83 s. The modified double-dose group (n=27) received one vial of verteporfin (15 mg), and the dose was calculated for each patient based on body surface area, then irradiance time was adjusted according to calculated verteporfin dose to achieve a 'double'-dose effect. Treatment outcomes (foveal centre thickness, subretinal fluid, tumour thickness and diameter) were measured at baseline and 1 year post-treatment; subretinal fluid levels were also measured at 1, 3 and 6 months post-treatment., Results: No differences in baseline characteristics were found between the two groups. The modified double-dose group showed a greater reduction in tumour thickness (45.3% vs 20.6%, p=0.013) and tumour volume (60.0% vs 30.0%, p=0.006) at 1 year post-treatment. Recurred or non-complete resolution patients in the standard-dose group tended to show much increased subretinal fluid than those in the modified double-dose group at 1-year post-treatment., Conclusion: Modified double-dose PDT is an effective and safe protocol for symptomatic CCH management, greater tumour regression and potentially better resolution of subretinal fluid compared with standard PDT., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

We present a novel genome-wide off-target prediction method named Extru-seq and compare it with cell-based (GUIDE-seq), in vitro (Digenome-seq), and in silico methods using promiscuous guide RNAs with large numbers of valid off-target sites. Extru-seq demonstrates a high validation rate and retention of information about the intracellular environment, both beneficial characteristics of cell-based methods. Extru-seq also shows a low miss rate and could easily be performed in clinically relevant cell types with little optimization, which are major positive features of the in vitro methods. In summary, Extru-seq shows beneficial features of cell-based and in vitro methods., (© 2023. The Author(s).)

Purpose: To determine potential factors associated with the long-term visual prognoses in patients with choroidal osteoma undergoing anti-vascular endothelial growth factor (VEGF) treatment., Design: Retrospective case series., Methods: Patients diagnosed at tertiary high-volume hospitals between January 2000 and December 2020 were evaluated. The primary outcome measure was visual acuity at 5-year follow-up. The secondary outcome measures included factors associated with favorable vision, defined as loss of <1 line and >20/200 vision., Results: Of 38 eyes from 36 patients (22 female, 61%; mean age 38 years) with choroidal osteoma, 23 eyes (61%) received anti-VEGF treatment (bevacizumab 1.25mg/0.05 cc, monthly or treat-and-extend) and 65% completed the 5 years of follow-up. All treated eyes had associated chorioretinal comorbidities (subretinal fluid 91%; choroidal neovascularization 74%; subretinal hemorrhage 30%). Although there was significant vision loss by 5 years (P = .002), 12 eyes (44%) had favorable outcomes. Only tumor thickness was significantly associated with unfavorable visual outcomes (OR 917.1, 95% CI 1.0-5687.7; P = .049). The optimal cut-off point predictive of visual outcomes was 1.4 mm, and tumor thickness ≥ 1.4 mm was associated with unfavorable vision (OR 27.0, 95% CI 2.0-368.4; P = .013)., Conclusions: Among patients with choroidal osteoma undergoing anti-VEGF therapy, a particular patient subset presented with divergent outcomes with very poor vision. Tumor thickness appeared to be the differentiating factor and is thus a potential prognostic indicator for long-term visual prognoses., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Choroidal nevus is a precursor of choroidal melanoma. Multimodal imaging has become vital in predicting the malignant transformation of choroidal nevi. This single-center, retrospective study analyzed clinical characteristics and multimodal imaging findings of 168 choroidal nevi (164 patients) of the Korean population. The mean age at presentation was 50 ± 15 (range, 13−85) (women, n = 88 [53.7%]). Choroidal nevi (melanotic, n = 164 [97.6%]; postequatorial, n = 160 [95.2%]) were densely located between the optic disc and foveola (65.5%). The mean maximum linear basal diameter on fundus photography and thickness on optical coherence tomography were 2.97 ± 1.51 mm and 521 ± 297 μm, respectively. On ultrasonography, the mean thickness was 0.87 ± 0.60 mm. Choroidal nevi in women were associated with a higher maximum linear basal diameter (3.23 ± 1.65 vs. 2.68 ± 1.21 mm; p = 0.033) and age at diagnosis (52 ± 14 vs. 47 ± 16 years; p = 0.046) than those in men. Choroidal nevi with associated subretinal fluid (23.2%) presented with larger basal diameter (p = 0.049) and thickness on B-scan and optical coherence tomography (p < 0.001), but a younger age at diagnosis (p < 0.001) than those of dry nevi. This multimodal imaging study of choroidal nevi revealed some distinct characteristics, including topographic distribution, sex-related differences, and a younger age at diagnosis of nevi with fluid.

(1) Background: To determine the diagnostic value of vitreous cytology in patients with vitreoretinal lymphoma (VRL) and evaluate its diagnostic accuracy relative to that of other diagnostic tests. (2) Methods: In total, 38 eyes from 38 patients with VRL who underwent diagnostic vitrectomy and were followed up for at least 6 months were analyzed. The clinical manifestations and VRL diagnostic rates for all diagnostic tests were determined. (3) Results: The presence of vitreous cells/opacity was the most common ophthalmic finding (97.4%), followed by sub-retinal pigment epithelial infiltration (65.8%) and retinal hemorrhage (21.1%). The VRL diagnostic rates were 89.3% for interleukin (IL)-10 levels > 50 pg/mL; 82.1% for IL-10/IL-6 ratios > 1; 60.0% and 63.3% for immunoglobulin heavy chain and kappa light chain clonality assays, respectively; and 44.4% for vitreous cytology. The VRL diagnostic rate for vitreous cytology was significantly lower in the steroid pretreatment group than in the non-steroid pretreatment group (p = 0.007). (4) Conclusions: The VRL detection rate for vitreous cytology was lower than that for the other tests, especially in patients who received steroid pretreatment. These findings suggest that even if vitreous cytology findings are negative, other tests and characteristic fundus findings should be evaluated to confirm VRL diagnosis.

Purpose: To assess the clinical features, treatment factors, and long-term visual and anatomical outcomes of optic disc pit maculopathy (ODPM) in Korean patients., Methods: Consecutive patients diagnosed between January 2000 and September 2020 were retrospectively reviewed. The primary outcome was best-corrected visual acuity (BCVA) and anatomical changes (determined by macular thickness reduction and fluid resorption). Secondary outcomes included factors associated with poor visual outcomes (> 3-line decrease or < 20/200 vision)., Results: Of the 24 eyes (24 patients, mean age, 42.8 years) in this study, two peak incidence groups were noted: children younger than 14 years (six patients; mean age, 9.7 years) and middle-aged adults (18 patients; 53.8 years). There were no significant differences between groups in terms of clinical features, treatment, and outcomes (P > 0.05). The primary treatment involved immediate (7 eyes) or delayed (9) vitrectomy, laser only (2), or observation only (6). Good (50%) or partial (33%) anatomical response was noted in most cases at the final follow-up (P > 0.05). However, regression analyses showed that poor visual outcomes were associated with low preoperative BCVA (OR, 8.73; 95%CI, 1.34-56.85; P = 0.023) and delayed vitrectomy (OR, 13.00; 95%CI, 1.70-99.38; P = 0.013), while presence of intraretinal fluid in the inner and outer layers reduced the risk (OR, 0.086; 95%CI, 0.01-0.88; P = 0.039)., Conclusion: Patients with ODPM may have two peak incidence groups with similar clinical features and treatment outcomes, supporting the idea of heterogeneous mechanisms triggering fluid accumulation. Although the primary treatment choice may not impact long-term anatomical outcomes, delayed vitrectomy may be associated with poorer visual outcomes., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Bone homeostasis is regulated by constant remodeling through osteogenesis by osteoblasts and osteolysis by osteoclasts and osteoporosis can be provoked when this balance is broken. Present pharmaceutical treatments for osteoporosis have harmful side effects and thus, our goal was to develop therapeutics from intrisincally safe natural products. Fucoidan is a polysaccharide extracted from many species of brown seaweed, with valuable pharmaceutical activities. To intensify the effect of fucoidan on bone homeostasis, we hydrolyzed fucoidan using AMG, Pectinex and Viscozyme. Of these, fucoidan biotransformed by Pectinex (Fu/Pec) powerfully inhibited the induction of tartrate-resistant acid phosphatase (TRAP) activity in osteoclasts differentiated from bone marrow macrophages (BMMs) by the receptor for activation of nuclear factor-κB ligand (RANKL). To investigate potential of lower molecular weight fucoidan it was separated into >300 kDa, 50-300 kDa, and <50 kDa Fu/Pec fractions by ultrafiltration system. The effects of these fractions on TRAP and alkaline phosphatase (ALP) activities were then examined in differentiated osteoclasts and MC3T3-E1 osteoblasts, respectively. Interestingly, 50-300 kDa Fu/Pec suppressed RANKL-induced osteoclasts differentiation from BMMs but did not synergistically enhance osteoblasts differentiation induced by osteogenic agents. In addition, this fraction inhibited the expressions of NFATc1, TRAP, OSCAR, and RANK, which are all key transcriptional factors involved in osteoclast differentiation, and those of Src, c-Fos and Mitf, as determined by RT-PCR. In conclusion, enzymatically low-molecularized 50-300 kDa Fu/Pec suppressed TRAP by downregulating RANKL-related signaling, contributing to the inhibition of osteoclasts differentiation, and represented a potential means of inducing bone remodeling in the background of osteoporosis.

Objective: To describe the clinical course and anatomic features of focal scleral nodules (FSNs) based on their clinical characteristics and multimodal imaging findings and analyze their potential associations with the patient's age., Design: Single-center, retrospective, observational case series., Subjects: Twenty-three lesions of 23 patients with FSN., Methods: Clinical characteristics were analyzed, and multimodal imaging was performed, including color fundus photography, OCT, fundus autofluorescence imaging, near-infrared imaging, B-scan ultrasonography, fluorescein and indocyanine green angiography, and OCT angiography of FSNs., Main Outcome Measures: Qualitative features, including the slope of anterior curvature (curvature of the dome shape is less than nodular curvature, which is less than volcanic curvature; i.e., volcanic curvature has the steepest slope), retinal pigment epithelium (RPE) status, and fluid compartments, were analyzed. Quantitative measurements, including maximum linear basal diameter, maximum horizontal length at the choroidoscleral border, maximum vertical length (V max ) from the choroidoscleral border, and choroidal thickness, were analyzed., Results: The mean age at presentation was 44 ± 17 years (range, 4-68 years), and the mean follow-up duration was 32.2 ± 29.5 months. On OCT, all lesions were confined to the sclera. Patients with volcanic or nodular anterior curvature were younger than those with the dome-shaped phenotype (35 ± 19 years vs. 52 ± 9 years, respectively; Mann-Whitney U test; P = 0.015). The Spearman rank correlation analysis displayed a significant correlation between age at diagnosis and V max (r = -0.466; P = 0.025). The Wilcoxon matched paired t test for the patients demonstrated a significant decrease in V max at the final follow-up visit (initial, 555 ± 228 μm vs. final, 517 ± 202 μm, respectively; P = 0.028). We observed subretinal fluid, intraretinal fluid, pigment epithelial detachment, and severe outer retinal atrophy in a relatively older population with sustained nodular or volcanic anterior curvature (age, 52 ± 7 years; range, 43-60 years). One lesion diagnosed in a patient aged 4 years demonstrated spontaneous regression., Conclusions: Young patients tended to have protruded lesions (high V max ) with nodular or volcanic anterior curvature. Older patients manifested the dome-shaped phenotype, and those with sustained nodular or volcanic curvature tended to develop fluid compartments or atrophic changes of the overlying RPE and retina because of possible chronic mechanical compression. Thus, there could be a significant association between FSN phenotype and age., (Copyright © 2022 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: We aim to report noncoding pathogenic variants in patients with FRMD7-related infantile nystagmus (FIN)., Methods: Genome sequencing (n = 2 families) and reanalysis of targeted panel next generation sequencing (n = 2 families) was performed in genetically unsolved cases of suspected FIN. Previous sequence analysis showed no pathogenic coding variants in genes associated with infantile nystagmus. SpliceAI, SpliceRover, and Alamut consensus programs were used to annotate noncoding variants. Minigene splicing assay was performed to confirm aberrant splicing. In silico analysis of exonic splicing enhancer and silencer was also performed., Results: FRMD7 intronic variants were identified based on genome sequencing and targeted next-generation sequencing analysis. These included c.285-12A>G (pedigree 1), c.284+63T>A (pedigrees 2 and 3), and c. 383-1368A>G (pedigree 4). All variants were absent in gnomAD, and the both c.285-12A>G and c.284+63T>A variants were predicted to enhance new splicing acceptor gains with SpliceAI, SpliceRover, and Alamut consensus approaches. However, the c.383-1368 A>G variant only had a significant impact score on the SpliceRover program. The c.383-1368A>G variant was predicted to promote pseudoexon inclusion by binding of exonic splicing enhancer. Aberrant exonizations were validated through minigene constructs, and all variants were segregated in the families., Conclusions: Deep learning-based annotation of noncoding variants facilitates the discovery of hidden genetic variations in patients with FIN. This study provides evidence of effectiveness of combined deep learning-based splicing tools to identify hidden pathogenic variants in previously unsolved patients with infantile nystagmus., Translational Relevance: These results demonstrate robust analysis using two deep learning splicing predictions and in vitro functional study can lead to finding hidden genetic variations in unsolved patients.

Purpose: To investigate the clinical features and treatment outcomes of patients with choroidal tuberculoma., Methods: In this retrospective, observational case series, the medical records of five patients with choroidal tuberculoma who were followed up at a university hospital for at least 6 months were analyzed., Results: Of five patients, one was male and four were female. The overall mean age was 38.0 ± 9.4 years (mean follow-up: 41.2 ± 33.8 months). Tuberculin skin test was performed in three patients, and it was positive in two of them. Interferon-gamma assay was performed in two patients and was positive in all two. Three patients had systemic tuberculosis involving the lung or other organs. Five patients were treated with antitubercular therapy for a period of 9.6 ± 8.6 months. Systemic corticosteroid treatment was performed in 3 patients, with a period of 3.5 ± 0.7 months. One patient with a recurrent vascularized tuberculoma was successfully treated with single intravitreal bevacizumab injection., Conclusion: Choroidal tuberculoma can develop without evidence of systemic tuberculosis and can recur despite antitubercular treatment. High index of suspicion is important in early detection, and management of choroidal tuberculoma. In cases of suspected choroidal tuberculoma, positive results on immunological tests would be sufficient to initiate antitubercular therapy even if radiological evidence of systemic tuberculosis is not found. Antitubercular therapy combined with systemic corticosteroids provided favorable results. Intravitreal injection of anti-vascular endothelial growth factor may be considered for highly vascularized choroidal tuberculoma., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: This study aims to report complications, treatments, and visual prognosis of choroidal osteoma., Methods: We retrospectively reviewed electronic medical records and multimodal images of 41 patients with choroidal osteoma., Results: Visually significant complications included choroidal neovascularization (CNV) in 21 (47.7%) eyes and subretinal fluid (SRF) without CNV in 14 (31.8%) eyes. The most common treatment was intravitreal anti-vascular endothelial growth factor (VEGF) injection: 13 (61.9%) eyes with CNV received an average of 6.3 injections, and 6 (42.9%) eyes with SRF but without CNV received 1.8 injections. As the first-line treatment, intravitreal anti-VEGF injection induced complete or partial remission in 93.4% of eyes with CNV and 57.1% of eyes with SRF. The probability of legally low vision estimated at 3 and at 5 years was 29.1% and 34.2%, respectively. The presence of CNV and outer retinal tubulation (ORT) was independent risk factors for vision loss (adjusted odds ratio, 8.08 and 6.94, respectively)., Conclusions: The development of CNV and ORT was strong risk factors for visual impairment. Due to the frequent recurrence of complications and poor visual prognosis, regular check-ups and appropriate treatment choices are warranted., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: To evaluate the therapeutic effects and safety of oral spironolactone (SPRL) in patients with central serous chorioretinopathy (CSC)., Materials and Methods: The medical records and imaging data of patients diagnosed with CSC and treated with SPRL were retrospectively reviewed. Central macular thickness (CMT), subretinal fluid (SRF) height, subfoveal choroidal thickness (SFCT), and best-corrected visual acuity (BCVA) at baseline, at 1, 3, and 6 months, and at the last visit after the treatment were analyzed., Results: In total, 103 patients with 107 eyes were included. The mean age of the patients was 51.5±9.3 years, and 77 (72.0%) were male. The mean follow-up duration was 48.6±40.2 weeks. The mean duration of oral SPRL therapy was 15.5±13.4 weeks. CMT, SRF height, and SFCT improved significantly at 1, 3, and 6 months after SPRL therapy and at the last follow-up. BCVA, however, showed no significant change at any time point. The rate of complete resolution of SRF at 1 month was higher in those with chronic CSC than in those with acute CSC (21.1% vs. 6.0%, respectively). Recurrence occurred in 14 (13.1%) eyes after the complete resolution of SRF. Older age ( p =0.001), a greater number of previous intravitreal bevacizumab injections ( p =0.006), and poor initial visual acuity ( p =0.048) were associated with recurrence. No permanent adverse effects were observed., Conclusion: Oral SPRL showed therapeutic benefits in patients with CSC in terms of SRF resolution, but relatively frequent recurrence was observed, especially in older patients., Competing Interests: The authors have no potential conflicts of interest to disclose., (© Copyright: Yonsei University College of Medicine 2022.)

We investigated the incidence and risk factors of late age-related macular degeneration (AMD) in the fellow eye (FE) without significant drusen of patients with unilateral exudative macular neovascularization (MNV). In this retrospective study, 241 eligible patients who were followed-up for more than 3 years were enrolled. We analyzed the incidence and hazard ratios (HRs) of late AMD in the FE according to demographic and ophthalmologic variables. Hypopigmentation on color fundus photography (CFP) corresponds to shallow irregular RPE elevation (SIRE), so-called "double-layer sign" and/or "attenuation or disruption of RPE and/or ellipsoid zone" on OCT. The 5-year incidence of FE exudative MNV conversion was 8.6%. The 5-year incidence of FE exudative MNV of large hypopigmentation (≥ 0.5 disc area; DA) and small hypopigmentation (< 0.5 DA) on CFP, and SIRE (≥ 1000 µm) and small RPE elevation (< 1000 µm) on OCT were 36.2%, 14.2%, 55.0%, and 15.6%, respectively. The multivariate Cox proportional hazard model revealed that large hypopigmentation, small hypopigmentation, SIRE, and small RPE elevation showed HRs of 23.230, 8.037, 132.589, and 41.823 for FE exudative MNV occurrence, respectively. Hypopigmentation on CFP and SIRE on OCT could represent the same lesion. Even small hypopigmentation and small RPE elevation were significant risk factors for progression to exudative MNV., (© 2022. The Author(s).)

Introduction: Globally, more people are spending time on the Internet and gaming since the outbreak of the Coronavirus Disease 2019 (COVID-19). Consequently, concerns about developing behavioral addiction of adolescents have been raised. Such risk could be greater for adolescents in South Korea where the majority of adolescents have access to the Internet and own a smartphone. In fact, statistics indicate that Korean youths are spending significantly more time on the Internet and gaming during the COVID-19 pandemic. Previous studies on the patterns of time spent on the Internet and Internet gaming show inconsistent results. The aim of this study is to investigate the latent profiles of the Internet and Internet game usage among adolescents in South Korea. Method: Data from a national survey on elementary and middle school students across South Korea were used. The sample consists of 3,149 respondents, and 2,984 responses were analyzed after removing missing responses. Latent profile analysis was performed to investigate the number of latent profiles for the Internet and Internet game usage time. To validate the profiles, differences in problematic gaming behavior, sex, and neuroticism were examined. Results: Seven profiles were found: Casual User, Moderate User, Smartphone User, Internet User, PC Internet Gamer, Heavy User, and Excessive User. Validation of the profiles indicated differences in problematic gaming behavior, sex, and neuroticism among selected profiles. Conclusion: This study presented different profiles of the Internet and Internet game usage among adolescents in South Korea. Profiles with higher game usage time scored higher in problematic game use compared to other profiles. Males were more likely to be in the profiles with high gaming time, and females were more likely to be in Internet and Smartphone User profiles. The results indicate that Internet and Internet gaming usage patterns could be classified by the type of device used and the content of the Internet., 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 © 2021 Kim, Lee and Nam.)

Uveal melanoma(UM) is the most common primary intraocular malignancy in adults. However, the incidence of UM in Asia is 10 to 20 times less than in Western populations. Therefore, for the first time, we report our whole exome sequencing (WES) data analysis to discover differences in the molecular features of Asian and Western UM, and to determine the disparities between the primary tumor before brachytherapy and enucleated samples after brachytherapy. WES of 19 samples (13 primary tumors, 5 enucleation samples after brachytherapy, and 1 liver metastasis) from 13 patients diagnosed with UM and treated between 2007 and 2019 at the Yonsei University Health System (YUHS) were analyzed using bioinformatics pipelines. We identified significantly altered genes in Asian UM and changes in mutational profiles before and after brachytherapy using various algorithms. GNAQ, BAP1, GNA11, SF3B1 and CYSLTR2 were significantly mutated in Asian UM, which is similar that reported frequently in previous Western-based UM studies. There were also similar copy number alterations (M3, 1p loss, 6p gain, 8q gain) in both groups. In paired comparisons of the same patients, DICER1 and LRP1B were distinctly mutated only in tumor samples obtained after brachytherapy using rare-variant association tests (P = 0.01, 0.01, respectively). The mutational profiles of Asian UM were generally similar to the data from previous Western-based studies. DICER1 and LRP1B were newly mutated genes with statistical significance in the regrowth samples after brachytherapy compared to the primary tumors, which may be related to resistance to brachytherapy., (© 2021. The Author(s).)

Since the outbreak of the COVID-19 pandemic, the heightened risk of school closures and mental disorders has made adolescents particularly vulnerable to developing internet gaming disorder (IGD). There have been reports of increased time spent playing games on the internet among adolescents during the pandemic, and the risk of developing IGD may be higher for adolescents in South Korea as the majority of them play games on the internet. However, to the best of our knowledge, no studies have examined the impact of the pandemic on adolescents' internet gaming behavior in South Korea. This study aimed to explore the different profiles of addictive internet gaming behavior among adolescents before and after the outbreak of the COVID-19 pandemic and examine how the pandemic influenced addictive internet gaming usage and time spent playing games on the internet. Nationally representative survey data from the Ministry of Gender Equality and Family with 3040 and 2906 responses from 2018 and 2020, respectively, were analyzed. Using seven factors of a maladaptive gaming usage scale (tolerance, withdrawal, excessive usage, control impairment, compulsive usage, neglecting daily activity, and gaming despite negative consequence), a four-profile model was selected in both 2018 and 2020 for latent profile analysis: 'casual' gamer, 'moderate' gamer, 'potential-risk' gamer and 'addictive' gamer. The results from the two-way ANCOVA showed significant interaction between the cohorts (2018 cohort vs. 2020 cohort) and the four profiles on addictive internet gaming usage (F = 119.747, p < 0.001, η 2 = 0.05), including time spent playing internet games on a PC (F = 22.893, p < 0.001, η 2 = 0.013), and time spent playing games on a mobile phone (F = 3.245, p < 0.05, η 2 = 0.02). The results indicated that the increase of addictive internet gaming usage and gameplay time differed by profile. The results imply that the increase in gameplay time was higher for profiles with higher scores in addictive internet gaming usage for internet games played on a PC while the relationship was not obvious for games played on a mobile phone. Despite the statistical significance, there was only 1.2% to 4.9% of mean difference in addictive internet gaming usage between the 2018 and 2020 cohorts, which implies little clinical significance. While adolescents of the four profiles showed no significant signs of increased addictive internet gaming usage, the addictive gamer profile demonstrated a significant increase in game time after COVID-19.

Mobile element insertions (MEIs) typically exceed the read lengths of short-read sequencing technologies and are therefore frequently missed. Recently, a founder Alu insertion in exon 4 of RP1 has been detected in Japanese patients with macular dystrophy by PCR and gel electrophoresis. We aimed to develop a grep search program for the detection of the Alu insertion in exon 4 of RP1 using unprocessed short reads. Among 494 unrelated Korean patients with inherited eye diseases, 273 patients with specific retinal phenotypes who were previously genotyped by targeted panel or whole exome sequencing were selected. Five probands had a single heterozygous truncating RP1 variant, and one of their unaffected parents also carry this variant. To find a hidden genetic variant, whole genome sequencing was performed in two patients, and it revealed AluY c.4052&#95;4053ins328/p.(Tyr1352Alafs*9) insertion in RP1 exon 4. This AluY insertion was additionally identified in other 3 families, which was confirmed by PCR and gel electrophoresis. We developed simplified grep search program to detect this AluY insertion in RP1 exon 4. The simple grep search revealed a median variant allele frequency of 0.282 (interquartile range, 0.232-0.383), with no false-positive results using 120 control samples. The MEI in RP1 exon 4 was a common founder mutation in Korean, occurring in 1.8% of our cohort. The RP1-Alu grep program efficiently detected the AluY insertion, without the preprocessing of raw data or complex installation processes.

Purpose: To report a case of a patient whose MYD88 mutation disappeared from the aqueous humor following treatment with intravitreal methotrexate., Methods: A retrospective review of clinical, histopathological and imaging records., Results: A 49-year-old woman presented with bilateral primary vitreoretinal lymphoma confirmed by molecular and next-generation sequencing studies on vitreous biopsy samples. Initially, the MYD88 L265P mutation was detected in aqueous samples of both eyes. Serial testing for MYD88 L265P mutations performed on aqueous samples collected at the time of the weekly intravitreal methotrexate injections showed the mutation ceased to be detected after four weekly injections in the non-vitrectomized right eye and after two weekly injections in the vitrectomized left eye. Clinical improvement accompanied the negativization of the mutation in both eyes., Conclusion: We present a case that demonstrates the possible utilization of serial testing for the MYD88 L265P mutation as a tool for monitoring disease course in vitreoretinal lymphoma.

Background: The early detection of uveitis associated with systemic inflammatory disease in children is important for proper treatment and prognosis. However, the diagnosis may be delayed because of difficulties in childhood examinations and early minor systemic symptoms. The objective of our study was to identify the pattern of childhood uveitis and investigate the frequency and clinical features of rheumatic diseases in pediatric patients with uveitis., Methods: This retrospective observational study reviewed the medical records of children (age ≤ 18 years) with uveitis at a Korean tertiary hospital between January 2005 and December 2018. Data collected included the age at onset of uveitis, sex, anatomic location of ocular inflammation, comorbid disease (including systemic inflammatory disease), ocular complications, relevant laboratory data, and treatment. Fisher's exact test was used to compare categorical variables and the Mann-Whitney U test was used to compare continuous variables. A p-value of < 0.05 was considered statistically significant., Results: A total of 155 pediatric patients with uveitis were included in this study. The median age at diagnosis was 13.0 years (interquartile range, 9.5-16.0 years). The male-to-female ratio was 1.09. The process was unilateral in 51.6% of children. Anterior uveitis, panuveitis, intermediate uveitis, and posterior uveitis represented 51.6, 26.5, 6.5, and 1.9% of the cases, respectively. Idiopathic uveitis (65.2%) was the most frequent type of uveitis. Systemic rheumatic disease associations were responsible for 28.4% of the cases, among which juvenile idiopathic arthritis (JIA) was the most frequent cause (14.8%). Human leukocyte antigen (HLA)-B27 and antinuclear antibody (ANA) positive rates were significantly higher in patients with JIA than in those with idiopathic uveitis (p = 0.006 and p = 0.007, respectively)., Conclusions: Approximately one-third of children with uveitis in Korea have a systemic rheumatic disease, of which JIA accounts for the majority of cases. HLA-B27 and ANA can serve as risk factors for JIA-associated uveitis.

The PAX6 is essential for ocular morphogenesis and is known to be highly sensitive to changes in gene expression, where neither over- nor under-expression ensures normal ocular development. Two unrelated probands with classical aniridia who were previously considered "PAX6-negative", were studied by whole-genome sequencing. Through the use of multiple in silico deep learning-based algorithms, we identified two novel putative causal mutations, c.-133&#95;-132del in the 5' untranslated region (5'-UTR) and c.-52 + 5G>A in an intron upstream of the PAX6 gene. The luciferase activity was significantly increased and VAX2 binding was disrupted with the former 5'-UTR variant compared with wild-type sequence, which resulted in a striking overexpression of PAX6. The minigene assay showed that the c.-52 + 5G>A mutation caused defective splicing, which resulted in the formation of truncated transcripts.