Search

Conjunctival goblet cells (CGCs) are specialized epithelial cells playing key roles for ocular surface homeostasis, and their examination is important for diagnosing ocular surface diseases. Despite recent advancements in high-contrast CGC imaging for non-invasive examination, significant challenges remain for human applications. High-speed large-area imaging over the curved ocular surface is needed to assess statistically meaningful CGCs in the extensive human conjunctiva. To address this challenge, we developed a novel surface detection method and an integrated microscopy system for human use. With both a long detection range of 2 mm and a high update rate of 50 Hz, the surface detection method enabled real-time surface tracking during large-area imaging. The integrated microscopy could complete 5 × 2 patch imaging in approximately 10 s. CGC density analysis showed significantly reduced uncertainties with large-area imaging. This is the first demonstration of non-contact large-area cellular examination in humans, and this new development holds promise for non-invasive CGC examination and accurate diagnosis of ocular surface diseases., 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 © 2024. Published by Elsevier B.V.)

Background: The purpose of the study was to evaluate the relationship between prediction errors (PEs) and ocular biometric variables in cataract surgery using nine intraocular lens (IOL) formulas with an explainable machine learning model., Methods: We retrospectively analyzed the medical records of consecutive patients who underwent standard cataract surgery with a Tecnis 1-piece IOL (ZCB00) at a single center. We calculated predicted refraction using the following IOL formulas: Barrett Universal II (BUII), Cooke K6, EVO V2.0, Haigis, Hoffer QST, Holladay 1, Kane, SRK/T, and PEARL-DGS. We used a LightGBM-based machine learning model to evaluate the explanatory power of ocular biometric variables for PEs and assessed the relationship between PEs and ocular biometric variables using Shapley additive explanation (SHAP) values., Results: We included 1,430 eyes of 1,430 patients in the analysis. The SRK/T formula exhibited the highest R 2 value (0.231) in the test set among the machine-learning models. In contrast, the Kane formula exhibited the lowest R 2 value (0.021) in the test set, indicating that the model could explain only 2.1% of the PEs using ocular biometric variables. BUII, Cooke K6, EVO V2.0, Haigis, Hoffer QST, Holladay 1, PEARL-DGS formulas exhibited R 2 values of 0.046, 0.025, 0.037, 0.194, 0.106, 0.191, and 0.058, respectively. Lower R 2 values for the IOL formulas corresponded to smaller SHAP values., Conclusion: The explanatory power of currently used ocular biometric variables for PEs in new-generation formulas such as BUII, Cooke K6, EVO V2.0 and Kane is low, implying that these formulas are already optimized. Therefore, the introduction of new ocular biometric variables into IOL calculation formulas could potentially reduce PEs, enhancing the accuracy of surgical outcomes., Competing Interests: Declarations. Ethics approval and consent to participate: This study was approved by the Institutional Review Board of Seoul National University Hospital (IRB No. 2112-132-1284) and was conducted in accordance with the Declaration of Helsinki. The need for written informed consent was waived because of the retrospective design and the use of deidentified patient data. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests. Meeting presentation: 16th Joint Meeting of Korea-China-Japan Ophthalmologists, 2023., (© 2024. The Author(s).)

Purpose: This study aimed to investigate the effects of subconjunctival injection of aflibercept, a soluble protein decoy for VEGFR-1 and VEGFR-2, on corneal angiogenesis and VEGFR-expressing CD11b + cells in a mouse model of suture-induced corneal neovascularization., Methods: Corneal neovascularization was induced in BALB/c mice by placing three sutures on the cornea. Immediately after surgery, either 200 µg aflibercept (5 µL) or an equal volume of phosphate-buffered saline (PBS) was administered into the subconjunctival space. Seven days after later, corneal new vessels were quantified through clinical examination and measurement of the CD31-stained area in corneal flat mounts. The levels of pro-angiogenic and inflammatory markers in the cornea were evaluated using RT-qPCR. The percentages of VEGFR-2 + CD11b + cells and VEGFR-3 + CD11b + cells were analyzed in the cornea, blood, and draining cervical lymph nodes (DLNs) using flow cytometry., Results: Subconjunctival injection of aflibercept significantly reduced the growth of corneal new vessels compared to subconjunctival PBS injection. The mRNA levels of Cd31, vascular growth factors (Vegfc and Angpt1), and pro-angiogenic/inflammatory markers (Tek/Tie2, Mrc1, Mrc2, and Il6) in the cornea were downregulated by subconjunctival aflibercept. Also, the percentage of VEGFR-3 + CD11b + cells in the cornea, blood, and DLNs was decreased by aflibercept, whereas that of VEGFR-2 + CD11b + cells was unaffected., Conclusion: Subconjunctival aflibercept administration inhibits inflammatory angiogenesis in the cornea and reduces the numbers of cornea-infiltrating and circulating VEGFR-3 + CD11b + cells., Competing Interests: Declarations. Ethical approval: The experimental protocol was approved from the Institutional Animal Care and Use Committee of Seoul National University Hospital Biomedical Research Institute (Seoul, Korea) and followed the guidelines stated by ARVO for ophthalmic and vision research. Conflict of interest: The authors have no relevant financial or non-financial interests to disclose., (© 2024. The Author(s).)

Purpose: To evaluate the agreement of ocular biometry measured using a swept-source optical coherence (Casia 2) and a dual Scheimpflug (Galilei G6) tomography in keratoconus., Methods: This retrospective study included 102 eyes from 102 keratoconus patient examined using both devices. Parameters compared included flat (Kf) and steep (Ks) keratometry, astigmatism of anterior, posterior, and total keratometry, central (CCT) and thinnest (TCT) corneal thickness. To assess the agreement, intraclass coefficient (ICC) and Bland-Altman analysis with 95% limits of agreement (LoA) were used., Results: Anterior and total Ks and Kf showed moderate or good agreement with 95% limits of agreement (LoA) range over 9.75 D. Posterior Ks and Kf were lower in the Galilei G6 (all p < 0.001). Astigmatism showed moderate, poor, and moderate agreement for anterior, posterior, and total keratometry, respectively. CCT and TCT showed excellent agreement; however, the 95% LoA range was over 60 μm., Conclusion: The agreement between the two devices was not excellent for most parameters used to diagnose keratoconus and assess disease progression, and the differences were clinically significant. Therefore, the measurements from these two devices are not interchangeable for patients with keratoconus., (© 2024. The Author(s).)

Purpose: The aim of this study was to investigate the efficacy of RCI001 (RCI) in a mouse model of primary Sjögren syndrome., Methods: Eight 12-week-old NOD.B10-H2b mice were used in this study. All experimental animals were randomly divided into phosphate-buffered saline (PBS) and RCI groups in NOD.B10-H2b mice. The eyes of mice were topically treated with PBS or RCI twice a day for a week. Ocular surface staining (OSS) and tear secretion were compared between before and after treatment. The transcript levels of inflammatory cytokines and nicotinamide adenine dinucleotide phosphate oxidase (NOX) in the conjunctiva and cornea (CC) and lacrimal gland were assayed. In addition, immunofluorescence staining of the conjunctiva was assessed., Results: The RCI group showed significant clinical improvement in OSS and tear secretion after 1 week of treatment compared with the baseline (both P < 0.001) and showed better improvement in OSS and tear secretion than the PBS group after 1 week of treatment (both P < 0.05). The levels of IL-1β and IL-17 in CC and IL-6 in the lacrimal gland were also significantly reduced in the RCI group compared with the PBS group (each P < 0.05). Transcript levels of NOX2 and NOX4 were also significantly reduced in CC of the RCI group compared with those of the PBS group (P < 0.05). The RCI group also resulted in lower conjunctival expression of oxidative stress markers (4-hydroxy-2-nonenal, hexanoyl-lysine, and NOX4) than the PBS group., Conclusions: Topical RCI001 demonstrated excellent therapeutic efficacy in a mouse model of primary Sjögren syndrome by inhibiting inflammation and oxidative stress., Competing Interests: D. H. Kim invented a patent for the topical use of RCI001 as treatment of various ocular diseases (Republic of Korea: 10-1816277/United States: 10/675294). Y. H. Kim is the Chief Executive Officer of RudaCure, the company developing RCI001. The remaining authors have no conflicts of interest to disclose., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Mesenchymal stem/stromal cells (MSCs) maintain tissue homeostasis in response to microenvironmental perturbations. Toll-like receptors (TLRs) are key sensors for exogenous and endogenous signals produced during injury. In this study, we aimed to investigate whether TLRs affect the homeostatic functions of MSCs after injury. Methods: We examined the expression of TLR2, TLR3 and TLR4 in MSCs, and analyzed the functional significance of TLR2 activation using single-cell RNA sequencing. Additionally, we investigated the effects and mechanisms of TLR2 and its downstream activation in MSCs on the MSCs themselves, on monocytes/macrophages, and in a mouse model of sterile injury-induced inflammatory corneal angiogenesis. Results: MSCs expressed TLR2, which was upregulated by monocytes/macrophages. Activation of TLR2 in MSCs promoted their immunoregulatory and angiostatic functions in monocytes/macrophages and in mice with inflammatory corneal angiogenesis, whereas TLR2 inhibition attenuated these functions. Single-cell RNA sequencing revealed AKR1C1 , a gene encoding aldo-keto reductase family 1 member C1, as the most significantly inducible gene in MSCs upon TLR2 stimulation, though its stimulation did not affect cell compositions. AKR1C1 protected MSCs against ferroptosis, increased secretion of anti-inflammatory cytokines, and enhanced their ability to drive monocytes/macrophages towards immunoregulatory phenotypes, leading to the amelioration of inflammatory corneal neovascularization in mice. Conclusion: Our findings suggest that activation of TLR2-AKR1C1 signaling in MSCs serves as an important pathway for the survival and homeostatic activities of MSCs during injury., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Background: To evaluate the therapeutic effects of topical RCI001 (RCI) and compare its efficacy with that of 1% prednisolone acetate (PDE) and 5% Lifitegrast in a modified mixed dry eye disease (DED) model., Methods: The environmental DED model was induced in BALB/c mice in a dry chamber with scopolamine. The eyes of the mice were treated topically with phosphate buffered saline (PBS), PDE, Lifitegrast or RCI twice daily for 1 week. Ocular surface staining (OSS), tear secretion, inflammatory cytokines in the ocular surface and lacrimal gland, and immunofluorescence staining in the conjunctiva and cornea(CC) were assessed., Results: The RCI group demonstrated better improvement of OSS and tear secretion than the PBS group (OSS, PBS: 13.0 ± 1.6, RCI: 9.4 ± 3.0; tear secretion, PBS: 5.0 ± 0.4 mm, RCI: 7.0 ± 0.3 mm, each P < 0.001) and better clinical efficacy than PDE and Lifitegrast groups on Day 7 (improvement rate of OSS, RCI: 32.45%, Lifitegrast: 13.13%, PDE: 12.25%). The RCI group resulted in significantly lower expression of oxidative stress markers in the CC than the PBS group (4-HNE, NOX2, and NOX4 in the conjunctiva; NOX2 in the cornea, each P < 0.05). However, the PDE and Lifitegrast groups did not show significant differences compared with the PBS group. There were no significant differences of inflammatory cytokines in the ocular surface and lacrimal gland between all groups., Conclusion: Topical RCI001 showed excellent therapeutic effects in environmental DED models by stimulating tear secretion, modulating oxidative stress and improving corneal epithelial healing compared to 1% PDE and 5% Lifitegrast., (© 2024. The Author(s).)

Objectives: To identify patterns in inflammatory marker and vital sign responses in adult with suspected bloodstream infection (BSI) and define expected trends in normal recovery., Methods: We included patients ≥16 y from Oxford University Hospitals with a blood culture taken between 1-January-2016 and 28-June-2021. We used linear and latent class mixed models to estimate trajectories in C-reactive protein (CRP), white blood count, heart rate, respiratory rate and temperature and identify CRP response subgroups. Centile charts for expected CRP responses were constructed via the lambda-mu-sigma method., Results: In 88,348 suspected BSI episodes; 6908 (7.8%) were culture-positive with a probable pathogen, 4309 (4.9%) contained potential contaminants, and 77,131(87.3%) were culture-negative. CRP levels generally peaked 1-2 days after blood culture collection, with varying responses for different pathogens and infection sources (p < 0.0001). We identified five CRP trajectory subgroups: peak on day 1 (36,091; 46.3%) or 2 (4529; 5.8%), slow recovery (10,666; 13.7%), peak on day 6 (743; 1.0%), and low response (25,928; 33.3%). Centile reference charts tracking normal responses were constructed from those peaking on day 1/2., Conclusions: CRP and other infection response markers rise and recover differently depending on clinical syndrome and pathogen involved. However, centile reference charts, that account for these differences, can be used to track if patients are recovering line as expected and to help personalise infection., 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 © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objective: To investigate refractive outcomes and associated factors after sutureless flanged intrascleral fixation of intraocular lens (SFIF-IOL)., Methods: We retrospectively reviewed the medical records of consecutive patients who underwent SFIF-IOL at a single centre. The prediction error (PE; difference between the achieved and target refractive error) and absolute PE (APE) were analysed. Risk factors associated with refractive surprise, defined as APE > +0.5 D, were investigated using multivariable logistic regression analysis., Results: Ninety-one eyes were included. At the final follow-up, the mean PE and APE were +0.07 ± 0.88 and +0.68 ± 0.56 D, respectively. Refractive surprise was observed in 44 eyes (54.3%) and was associated with a shorter axial length (AL) [odds ratio, 0.825; 95% confidence interval, 0.688-0.991; P = 0.039]. APE showed a significant correlation with AL at the final visit (⍴ = -0.269, P = 0.010), and eyes with AL ≥ 26 mm had significantly lower APE than did those with AL of 24-26 mm (P = 0.021) and AL < 24 mm (P = 0.0059)., Conclusions: The refractive outcome after SFIF-IOL using manufacturer's A constant was favourable on average. Eyes with a longer AL were more likely to show a smaller deviation from the target refraction., (© 2023. The Author(s), under exclusive licence to The Royal College of Ophthalmologists.)

New Korean guidelines for the diagnosis and management of dry eye disease were developed based on literature reviews by the Korean Dry Eye Guideline Establishment Committee, a previous dry eye guideline by Korean Corneal Disease Study Group, a survey of Korean Dry Eye Society (KDES) members, and KDES consensus meetings. The new definition of dry eye was also proposed by KDES regular members. The new definition by the regular members of the KDES is as follows: "Dry eye is a disease of the ocular surface characterized by tear film abnormalities and ocular symptoms." The combination of ocular symptoms and an unstable tear film (tear breakup time &lt;7 seconds) was considered as essential components for the diagnosis of dry eye. Schirmer test and ocular surface staining were considered adjunctive diagnostic criteria. The treatment guidelines consisted of a simplified stepwise approach according to aqueous deficiency dominant, evaporation dominant, and altered tear distribution subtypes. New Korean guidelines can be used as a simple, valid, and accessible tool for the diagnosis and management of dry eye disease in clinical practice.

There is an increasing need for an objective grading system to evaluate the severity of dry eye disease (DED). In this study, a fully automated deep learning-based system for the assessment of DED severity was developed. Corneal fluorescein staining (CFS) images of DED patients from one hospital for system development (n = 1400) and from another hospital for external validation (n = 94) were collected. Three experts graded the CFS images using NEI scale, and the median value was used as ground truth. The system was developed in three steps: (1) corneal segmentation, (2) CFS candidate region classification, and (3) estimation of NEI grades by CFS density map generation. Also, two images taken on different days in 50 eyes (100 images) were compared to evaluate the probability of improvement or deterioration. The Dice coefficient of the segmentation model was 0.962. The correlation between the system and the ground truth data was 0.868 (p<0.001) and 0.863 (p<0.001) for the internal and external validation datasets, respectively. The agreement rate for improvement or deterioration was 88% (44/50). The fully automated deep learning-based grading system for DED severity can evaluate the CFS score with high accuracy and thus may have potential for clinical application., Competing Interests: NO authors have competing interests., (Copyright: © 2024 Kim et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

This paper examines the institutional mechanisms supporting the ethical oversight of human participant research conducted by the United Nations (UN). The UN has served an instrumental role in shaping international standards on research ethics, which invariably require ethical oversight of all research studies with human participants. The authors' experiences of conducting research collaboratively with UN agencies, in contrast, have led to concern that the UN frequently sponsors, or participates in, studies with human participants that have not received appropriate ethical oversight. It is argued that the institutional mechanisms in place to prevent research with human participants from being undertaken by the UN without ethical oversight do not, at present, extend substantively beyond the provision of guidelines and online training offered by a minority of UN bodies. The WHO and UNICEF are identified as notable exceptions, having implemented various measures to prevent health research with human participants from being undertaken without ethical oversight. Yet, it is highlighted that the WHO and UNICEF are not the only UN bodies that undertake health research with human participants and there are countless actors under the umbrella of the UN system that are regularly involved in non-health research with human participants. Arguments for the pursuit of the highest standard of ethical oversight by UN bodies are presented. Moving forward, the paper asks the question: is it time for the UN to set the standards for the oversight of ethical oversight?, Competing Interests: Competing interests: RJT and BC have previously conducted paid and unpaid research for United Nations agencies., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Graft detachment is a common and significant complication in Descemet membrane endothelial keratoplasty (DMEK). We investigated the risk factors of graft detachment requiring rebubbling after DMEK using imported pre-cut donor tissues. The medical records of 48 patients who underwent DMEK for Fuchs' endothelial dystrophy (FED) or bullous keratopathy (BK) at Seoul National University Hospital were retrospectively reviewed. Donor, recipient, and surgical factors were evaluated using univariate and multivariate logistic regression models. Graft detachment requiring rebubbling occurred in 17 (32.7%) eyes. The detachment group exhibited older recipient age ( p = 0.006), higher prevalence of diabetes ( p = 0.001), and a higher proportion of FED (65%, p = 0.003). Notably, the detachment group demonstrated a significantly lower postoperative 2-h intraocular pressure (IOP) ( p = 0.002) and a greater proportion of eyes with IOP <20 mmHg ( p < 0.001). Older recipient age (OR 1.08, 95% CI 1.02-1.17), diabetes (OR 23.8, 95% CI 2.61-217), FED surgical indication (OR 6.19, 95% CI 1.74-22.0), lower postoperative 2-h IOP (OR 1.21, 95% CI 1.06-1.38), and postoperative 2-h IOP <20 mmHg (OR 14.0, 95% CI 1.64-119) were associated with increased odds of graft detachment. According to multivariate logistic regression, lower postoperative 2-h IOP (OR 1.23, 95% CI 1.02-1.47) and postoperative 2-h IOP <20 mmHg (OR 25.1, 95% CI 1.05-602) increased the risk of graft detachment. Lower postoperative 2-h IOP, particularly below 20 mmHg, may increase the risk of graft detachment, and diabetes in recipients may pose a higher risk of graft detachment after DMEK., 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 © 2024 Kim, Yoon and Kim.)

Goblet cells (GCs) in the conjunctiva are specialized epithelial cells secreting mucins for the mucus layer of protective tear film and playing immune tolerance functions for ocular surface health. Because GC loss is observed in various ocular surface diseases, GC examination is important for precision diagnosis. Moxifloxacin-based fluorescence microscopy (MBFM) was recently developed for non-invasive high-contrast GC visualization. MBFM showed promise for GC examination by high-speed large-area imaging and a robust analysis method is needed to provide GC information. In this study, we developed a deep learning framework for GC image analysis, named dual-channel attention U-Net (DCAU-Net). Dual-channel convolution was used both to extract the overall image texture and to acquire the GC morphological characteristics. A global channel attention module was adopted by combining attention algorithms and channel-wise pooling. DCAU-Net showed 93.1% GC segmentation accuracy and 94.3% GC density estimation accuracy. Further application to both normal and ocular surface damage rabbit models revealed the spatial variations of both GC density and size in normal rabbits and the decreases of both GC density and size in damage rabbit models during recovery after acute damage. The GC analysis results were consistent with histology. Together with the non-invasive high-contrast imaging method, DCAU-Net would provide GC information for the diagnosis of ocular surface diseases., (© 2023. The Author(s).)

We compared the accuracy of three intraocular lens (IOL) calculation formulas in eyes with a shallow anterior chamber depth (ACD) and normal axial length (AXL) and control eyes. We retrospectively reviewed eyes with a shallow ACD (<2.5 mm from the corneal epithelium) with normal AXL (22.5≤AXL<24.0 mm) and controls (3.0≤ACD<3.5 mm and normal AXL). Prediction error (PE) and median absolute error (MedAE) were evaluated with SRK/T, Barrett Universal II (BUII), and Kane formulas after adjusting the mean PE to zero for all patients. Percentages of eyes achieving a PE within 0.25 to 1.00 D, and correlations between ACD, lens thickness (LT), and PE were analyzed. Thirty-five shallow ACD and 63 control eyes were included. PE in the shallow ACD group showed more hyperopic results with BUII and Kane but not with SRK/T compared to controls. Within the shallow ACD group, PE showed more hyperopic results in BUII and Kane compared to SRK/T. However, the standard deviation (SD) of PE among formulas was not different. In the shallow ACD group, SRK/T showed a higher percentage of PE within 0.25 D than BUII and Kane, but the percentages within 0.50 to 1.00 D were similar. PE was negatively correlated with ACD in BUII and Kane, and positively correlated with LT in all formulas. BUII and Kane may induce slight hyperopic shift in eyes with a shallow ACD and normal AXL. However, the performance of the three formulas was comparable in the shallow ACD group in terms of MedAE, the SD of PE, and the percentage of eyes achieving PE within 0.50 D., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Lee et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Purpose: Pseudognaphalium affine (P. affine), a medicinal plant, has long been used to treat various diseases due to its astringent and vulnerary effects. These therapeutic benefits are largely attributed to high contents of phytochemicals, such as flavonoids and polyphenols, that have anti-inflammatory and tissue-protective activities. Herein, we investigated the potential of dicaffeoylquinic acids (diCQAs), polyphenols from P. affine, as a novel treatment for dry eye disease (DED)., Methods: We isolated 1,5-, 3,4-, 3,5- and 4,5-diCQAs from the P. affine methanol extract, and tested the effects of diCQA isomers in cultures of human corneal epithelial cells (CECs) under desiccating hyperosmolar stress and in two mouse models for DED: desiccating environmental stress-induced DED and the NOD.B10-H2 b mouse model of ocular Sjögren's syndrome., Results: Initial screening showed that, among the diCQAs, 1,5-diCQA significantly inhibited apoptosis and enhanced viability in cultures of CECs under hyperosmolar stress. Moreover, 1,5-diCQA protected CECs by promoting proliferation and downregulating inflammatory activation. Subsequent studies with two mouse models of DED revealed that topical 1,5-diCQA administration dose-dependently decreased corneal epithelial defects and increased tear production while repressing inflammatory cytokines and T cell infiltration on the ocular surface and in the lacrimal gland. 1,5-diCQA was more effective in alleviating DED, as compared with two commercially-available dry eye treatments, 0.05% cyclosporine and 0.1% sodium hyaluronate eye drops., Conclusions: Together, our results demonstrate that 1,5-diCQA isolated from P. affine ameliorates DED through protection of corneal epithelial cells and suppression of inflammation, thus suggesting a novel DED therapeutic strategy based on natural compounds., Competing Interests: Declaration of competing interest C.H.Y., H.J., K.A., S.O., J.O., J.H.C and J.Y.O. are co-inventors on a published patent (10-2022-0027751). Otherwise, potential competing interests don't exist., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Pterygium is an abnormal growth of fibrous conjunctival tissue that invades the cornea, resulting in corneal distortion, astigmatism, and increased higher-order aberrations (HOAs). However, few studies have compared eyes with pterygium to normal fellow eyes when interpreting HOAs and there is no study that revealed the effect of the thickness or grading of the pterygium on the change of HOAs. Therefore, we evaluated the effects of nasal pterygium by comparing the normal fellow eye of 59 patients. The pterygium significantly increased with-the-rule corneal astigmatism and corneal irregularity. Trefoils, horizontal coma, and quatrefoils were significantly induced by the pterygium. The grading of the pterygium was not correlated with its characteristics except for the thickness. In multiple linear regression analysis, pterygium-induced corneal astigmatic/irregularity values and horizontal trefoil/quatrefoil were associated with the area of the pterygium. The length of the pterygium was an independent inducer of oblique trefoil/quatrefoil, while horizontal coma was independently associated with both its length and width. The thickness was not correlated with any optical parameters. Together, the results demonstrate that nasal pterygium significantly induces corneal astigmatism, irregularity and some HOAs. These pterygium-associated changes in optical parameters could be predicted by the length, width and area of the pterygium., (© 2023. The Author(s).)

Background: Mobile health platforms like smartphone apps that provide clinical guidelines are ubiquitous, yet their long-term impact on guideline adherence remains unclear. In 2016, an antibiotic guidelines app, called SCRIPT, was introduced in Auckland City Hospital, New Zealand, to provide local antibiotic guidelines to clinicians on their smartphones., Objective: We aimed to assess whether the provision of antibiotic guidelines in a smartphone app resulted in sustained changes in antibiotic guideline adherence by prescribers., Methods: We analyzed antibiotic guideline adherence rates during the first 24 hours of hospital admission in adults diagnosed with community-acquired pneumonia using an interrupted time-series study with 3 distinct periods post app implementation (ie, 3, 12, and 24 months)., Results: Adherence increased from 23% (46/200) at baseline to 31% (73/237) at 3 months and 34% (69/200) at 12 months, reducing to 31% (62/200) at 24 months post app implementation (P=.07 vs baseline). However, increased adherence was sustained in patients with pulmonary consolidation on x-ray (9/63, 14% at baseline; 23/77, 30% after 3 months; 32/92, 35% after 12 month; and 32/102, 31% after 24 months; P=.04 vs baseline)., Conclusions: An antibiotic guidelines app increased overall adherence, but this was not sustained. In patients with pulmonary consolidation, the increased adherence was sustained., (©Chang Ho Yoon, Imogen Nolan, Gayl Humphrey, Eamon J Duffy, Mark G Thomas, Stephen R Ritchie. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 02.05.2023.)

Purpose: To evaluate the characteristics of ocular biometric parameters in adult Korean patients with cataract., Setting: Department of Ophthalmology, Seoul National University Hospital, Seoul, South Korea., Design: Retrospective case series., Methods: Ocular biometric values of 5273 eyes of 5273 Korean patients undergoing cataract surgery measured with the IOLMaster 700 at the Seoul National University Hospital between November 2019 and December 2021 were reviewed., Results: A total of 5273 eyes of 5273 Korean patients were analyzed. The mean ± SD age was 66.1 ± 12.8 years, and 62% were female. Overall, age and ocular biometric parameters were correlated with each other. Particularly, age showed a negative correlation with anterior chamber depth (ACD; r = -0.357), axial length (AL; r = -0.344), and posterior keratometry (PK; r = -0.054) and a positive correlation with lens thickness (LT; r = 0.484), angle α ( r = 0.194), total keratometry (TK; r = 0.137), anterior keratometry (AK; r = 0.129), and angle κ ( r = 0.071). AL showed a positive correlation with ACD ( r = 0.503) and PK ( r = 0.339) and a negative correlation with AK ( r = -0.342), TK ( r = -0.334), LT ( r = -0.288), angle α ( r = -0.220), and angle κ ( r = -0.040). With age, anterior and total corneal astigmatism changed from with-the-rule (WTR) to against-the-rule (ATR) astigmatism. Posterior corneal astigmatism was ATR regardless of age; however, the magnitude decreased with age., Conclusions: Age showed a significant correlation in the order of LT, ACD, and AL. With age, angle α and κ increased, and total corneal astigmatism changes from WTR to ATR, which is mainly affected by changes in anterior corneal astigmatism. AL showed a significant correlation in the order of ACD, AK, PK, and TK. These data are pertinent for improving the result after cataract surgery, especially when using premium intraocular lenses., (Copyright © 2023 Published by Wolters Kluwer on behalf of ASCRS and ESCRS.)

Purpose: To validate the international chronic ocular graft-versus-host disease (GVHD) diagnostic criteria (ICCGVHD) compared to the National Institute of Health diagnostic criteria 2014 (NIH2014) for chronic ocular GVHD., Methods: Between 2013 and 2019, the study enrolled 233 patients with or without chronic ocular GVHD combined with the presence or absence of systemic chronic GVHD in an internationally prospective multicenter and observational cohort from 9 institutions. All patients were evaluated for four clinical parameters of ICCGVHD., Results: The relation between the ICCGVHD score (0-11) and NIH2014 eye score (0-4) was relatively high (r = 0.708, 95% CI: 0.637-0.767, p < 0.001). The sensitivity and specificity of ICCGVHD for NIH 2014 for 233 patients were 94.3% (95% CI: 89.6%-98.1%) and 71.7% (95% CI: 63.0-79.5%), respectively (cutoff value of the ICCGVHD score = 6). The positive predictive value was 77.1% (95% CI: 71.1%-82.1%), and the negative predictive value was 87.0% (95% CI:81.6-92.5%). For the patients with systemic GVHD (n = 171), the sensitivity and specificity were 94.2% and 67.2%, respectively (ICCGVHD-score cutoff value = 6). By receiver operating characteristic (ROC) curve analysis, the area under the curve (AUC) was 0.903 (95% CI: 0.859-0.948). For patients without systemic GVHD (n = 62), the sensitivity and specificity were 100% and 76.7%, respectively (ICCGVHD-score cutoff value = 6). The AUC was 0.891 (95% CI 0.673-1.000)., Conclusions: Good sensitivity, specificity, predictive value and correlation were found between ICCGVHD and NIH2014. ICCGVHD scores ≥6 can be useful to diagnose ocular GVHD with or without systemic GVHD for clinical research., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose: To investigate the incidence, characteristics, risk factors, and treatment outcomes for infectious keratitis in patients with ocular Sjögren's syndrome (SS)., Methods: We performed a retrospective chart review of patients who had been followed up for ocular SS in Seoul National University Hospital from 2010 to 2020 and identified cases where infectious keratitis developed. The incidence, demographical and clinical characteristics, risk factors, microbiological profiles, and treatment outcome were investigated, some of which were compared with infectious keratitis cases in the non-SS group., Results: Out of 929 patients with ocular SS, infectious keratitis occurred in 18 eyes (1.94%). All 18 patients were female in the ocular SS group, while 48 out of 100 infectious keratitis patients (48%) were female in the non-SS group (p < 0.01). The mean age at diagnosis of infectious keratitis was 66.1 years in the ocular SS group, which was not different from the non-SS group (57.2 years, p = 0.12). Of risk factors analyzed, the use of therapeutic contact lens was more frequently used in the ocular SS patients, compared to the non-SS patients (67% vs. 11%, p < 0.01). Culture-positivity rate was 50% in the ocular SS group. All culture-proven cases were bacterial infection, one of which was bacterial-fungal coinfection. Infection resolved in all eyes after the mean 29 days of medical treatment, except one that additionally required penetrating keratoplasty with vitrectomy. The visual acuity improved in 15 eyes (83%) after resolution. Infectious keratitis recurred in three patients (17%) during the mean 55.7 months of follow-up., Conclusions: The incidence of infectious keratitis was 1.94% in patients with ocular SS. Most were bacterial infections and resolved by medical treatment. Therapeutic and visual outcomes were favorable, but recurrence occurred in 17%.

We argue why interpretability should have primacy alongside empiricism for several reasons: first, if machine learning (ML) models are beginning to render some of the high-risk healthcare decisions instead of clinicians, these models pose a novel medicolegal and ethical frontier that is incompletely addressed by current methods of appraising medical interventions like pharmacological therapies; second, a number of judicial precedents underpinning medical liability and negligence are compromised when 'autonomous' ML recommendations are considered to be en par with human instruction in specific contexts; third, explainable algorithms may be more amenable to the ascertainment and minimisation of biases, with repercussions for racial equity as well as scientific reproducibility and generalisability. We conclude with some reasons for the ineludible importance of interpretability, such as the establishment of trust, in overcoming perhaps the most difficult challenge ML will face in a high-stakes environment like healthcare: professional and public acceptance., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Background: Reported bacteraemia outcomes following inactive empirical antibiotics (based on in vitro testing) are conflicting, potentially reflecting heterogeneity in causative species, MIC breakpoints defining resistance/susceptibility, and times to rescue therapy., Methods: We investigated adult inpatients with Escherichia coli bacteraemia at Oxford University Hospitals, UK, from 4 February 2014 to 30 June 2021 who were receiving empirical amoxicillin/clavulanate with/without other antibiotics. We used Cox regression to analyse 30 day all-cause mortality by in vitro amoxicillin/clavulanate susceptibility (activity) using the EUCAST resistance breakpoint (>8/2 mg/L), categorical MIC, and a higher resistance breakpoint (>32/2 mg/L), adjusting for other antibiotic activity and confounders including comorbidities, vital signs and blood tests., Results: A total of 1720 E. coli bacteraemias (1626 patients) were treated with empirical amoxicillin/clavulanate. Thirty-day mortality was 193/1400 (14%) for any active baseline therapy and 52/320 (16%) for inactive baseline therapy (P = 0.17). With EUCAST breakpoints, there was no evidence that mortality differed for inactive versus active amoxicillin/clavulanate [adjusted HR (aHR) = 1.27 (95% CI 0.83-1.93); P = 0.28], nor of an association with active aminoglycoside (P = 0.93) or other active antibiotics (P = 0.18). Considering categorical amoxicillin/clavulanate MIC, MICs > 32/2 mg/L were associated with mortality [aHR = 1.85 versus MIC = 2/2 mg/L (95% CI 0.99-3.73); P = 0.054]. A higher resistance breakpoint (>32/2 mg/L) was independently associated with higher mortality [aHR = 1.82 (95% CI 1.07-3.10); P = 0.027], as were MICs > 32/2 mg/L with active empirical aminoglycosides [aHR = 2.34 (95% CI 1.40-3.89); P = 0.001], but not MICs > 32/2 mg/L with active non-aminoglycoside antibiotic(s) [aHR = 0.87 (95% CI 0.40-1.89); P = 0.72]., Conclusions: We found no evidence that EUCAST-defined amoxicillin/clavulanate resistance was associated with increased mortality, but a higher resistance breakpoint (MIC > 32/2 mg/L) was. Additional active baseline non-aminoglycoside antibiotics attenuated amoxicillin/clavulanate resistance-associated mortality, but aminoglycosides did not. Granular phenotyping and comparison with clinical outcomes may improve AMR breakpoints., (© The Author(s) 2022. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)

To investigate the effect of fucosyltransferase (FUT) 1-mediated fucosylation on meibomian glands (MG), we first confirmed that FUT1 and its fucosylated products were expressed in the eyelid, conjunctiva and skin in wild-type (WT) mice, whereas their mRNA and protein levels were downregulated in Fut1 knock-out (KO) mice. We then evaluated age-dependent changes in the total and acinar areas of MG, meibocyte differentiation, lipid synthesis, and eyelid inflammation and oxidative stress in Fut1 KO and WT mice. Results show that both the total and acinar areas of MG were smaller in Fut1 KO mice than in WT mice in all evaluated age groups. Meibocyte differentiation, lipid-producing capacities and the enzyme levels responsible for lipid synthesis were reduced in Fut1 KO mice, compared to WT controls. The levels of pro-inflammatory cytokines and oxidative-stress-related markers were elevated in the eyelids and MG of FUT1 KO mice. These findings demonstrate the physiologic function of FUT1-mediated fucosylation in MG development and function, and indicate its potential role in ocular surface homeostasis.

Conjunctival goblet cells (CGCs) are mucin-secreting cells in the eye and play essential roles for ocular surface homeostasis. Since various ocular surface pathologies are related to CGC dysfunction, CGC examination is important for the evaluation of ocular surface conditions. Recently we introduced moxifloxacin-based fluorescence microscopy (MBFM) for non-invasive CGC imaging. However, the imaging speed was up to 1 frame per second (fps) and needed to be improved for clinical applications. In this study, we developed a high-speed moxifloxacin-based, extended depth-of-field (EDOF) microscopy system that operates at a maximum imaging speed of 15 fps. The system used a deformable mirror for the high-speed axial sweeping of focal plane during single-frame acquisitions. The acquired images contained both in-focus and out-of-focus information, and deconvolution was used to filter the in-focus information. The system had a DOF of 800 [Formula: see text], field-of-view of 1.2 mm ×1.2 mm, and resolution of [Formula: see text]. Its performance was demonstrated by real-time, breathing-motion-insensitive CGC imaging of mouse and rabbit models, in vivo. High-speed EDOF microscopy has potentials for non-invasive, real-time CGC examinations of human subjects.

Long diagnostic wait times hinder international efforts to address antibiotic resistance in M. tuberculosis. Pathogen whole genome sequencing, coupled with statistical and machine learning models, offers a promising solution. However, generalizability and clinical adoption have been limited by a lack of interpretability, especially in deep learning methods. Here, we present two deep convolutional neural networks that predict antibiotic resistance phenotypes of M. tuberculosis isolates: a multi-drug CNN (MD-CNN), that predicts resistance to 13 antibiotics based on 18 genomic loci, with AUCs 82.6-99.5% and higher sensitivity than state-of-the-art methods; and a set of 13 single-drug CNNs (SD-CNN) with AUCs 80.1-97.1% and higher specificity than the previous state-of-the-art. Using saliency methods to evaluate the contribution of input sequence features to the SD-CNN predictions, we identify 18 sites in the genome not previously associated with resistance. The CNN models permit functional variant discovery, biologically meaningful interpretation, and clinical applicability., (© 2022. The Author(s).)

Objective: We investigated whether (1) imported pre-cut tissue is feasible for Descemet membrane endothelial keratoplasty (DMEK) in eyes of Asian patients, (2) the clinical outcome is comparable between the endothelium-in and endothelium-out methods, and (3) the corneal edema-induced anterior curvature changes may have an effect on the refractive error., Methods: The medical records of 32 DMEK patients who underwent either the endothelium-out or endothelium-in method using imported pre-cut grafts with a 3-day pre-cut-to-use time were retrospectively analyzed. Fuchs' endothelial dystrophy (37.5%) and bullous keratopathy (62.5%) cases were included. The main clinical outcome measures were graft survival, best corrected visual acuity (BCVA), endothelial cell density (ECD), corneal thickness (CT), and complications. Correlation of the anterior curvature changes with refractive error was analyzed in the DMEK with cataract surgery group., Results: The overall survival rate was 71.9%. Final graft failures were caused by rejection, glaucoma, and infection. Visual acuities improved by 89.3%. BCVA better than 20/40 and 20/20 was found in 75% and 28.6% of patients, respectively. The ECDs at 3 months and 1 year were 1400 and 1083 cells/mm2, respectively. The mean survival time, ECD, BCVA, CT, and complication rates were not different between the endothelium-in and endothelium-out methods. A hyperopic shift by +0.42 D was not related to the anterior curvature changes., Conclusion: Imported pre-cut tissues with a ≤ 3-day pre-cut-to-use time are feasible for DMEK in the treatment of corneal endothelial edema in eyes of Asian patients, and both endothelium-in and endothelium-out methods appear to be comparatively effective. Edema-induced anterior curvature change may not affect the refractive shift., Competing Interests: The authors have declared that no competing interests exist.

Microbiota promotes or inhibits the pathogenesis of a range of immune-mediated disorders. Although recent studies have elucidated the role of gut microbiota in ocular disease, the effect of ocular microbiota remains unclear. Herein, we explored the role of ocular commensal bacteria in non-infectious corneal inflammation and angiogenesis in a mouse model of suture-induced corneal neovascularization. Results revealed that the ocular surface harbored a microbial community consisting mainly of Actinobacteria, Firmicutes and Proteobacteria. Elimination of the ocular commensal bacteria by oral broad-spectrum antibiotics or topical fluoroquinolone significantly suppressed corneal inflammation and neovascularization. Disease amelioration was associated with reduced numbers of CD11b + Ly6C + and CD11b + Ly6G + myeloid cells, not Foxp3 + regulatory T cells, in the spleen, blood, and draining lymph nodes. Therapeutic concentrations of fluoroquinolone, however, did not directly affect immune cells or vascular endothelial cells. In addition, data from a clinical study showed that antibiotic treatment in combination with corticosteroids, as compared with corticosteroid monotherapy, induced faster remission of corneal inflammation and new vessels in pediatric patients with non-infectious marginal keratitis. Altogether, our findings demonstrate a pathogenic role of ocular microbiota in non-infectious inflammatory disorders leading to sight-threatening corneal neovascularization, and suggest a therapeutic potential of targeting commensal microbes in treating ocular inflammation., (© 2022. The Author(s), under exclusive licence to Society for Mucosal Immunology.)

Background: Stevens-Johnson syndrome (SJS) is an abnormal immune-response causing extensive exfoliation of the mucocutaneous tissue including conjunctiva. While several factors are associated with the alteration of conjunctival microbiota, the conjunctiva of SJS patients are found to harbor a different microbiota compared to healthy subjects. We investigated the conjunctival microbiota of Korean SJS patients, and identified factors associated with the conjunctival microbiota and its positive culture., Methods: Medical records were retrospectively reviewed in 30 chronic SJS patients who had undergone conjunctival swab culture sampling. Demographic factors, chronic ocular surface complications score (COCS), tear break-up time (TBUT), tear secretion, tear matrix metalloproteinase 9 (MMP9), and results of conjunctival swab culture were assessed., Results: Positive culture was seen in 58.1%. Gram positive bacteria was most commonly isolated, among which Coagulase-negative Staphylococci (45.5%) and Corynebacterium species (40.9%) were predominantly observed. Tear MMP9 positivity was observed significantly more in the positive culture group (100%) compared to the negative culture group (70%) (P = 0.041). Topical cyclosporine and corticosteroid were not associated with repetitive positive cultures. No significant differences in COCS, TBUT, and tear secretion were found between culture-positive and culture-negative groups., Conclusion: Our study suggests that tear MMP9 positivity may be related with the presence of an abnormal ocular surface microbiota in chronic SJS patients., (© 2022. The Author(s).)

Although pig-to-non-human primate (NHP) corneal xenotransplantation has shown long-term graft survival, xenogeneic antigen-related immune responses are still stronger than allogeneic antigen-associated responses. Therefore, there is an unmet need to investigate major rejection pathways in corneal xenotransplantation, even with immunosuppression. This study aimed to identify biomarkers in aqueous humor for predicting rejection and to investigate rejection-related pathways in grafts from NHPs transplanted with porcine corneas following the administration of steroids combined with tacrolimus/rituximab. NHPs who had received corneas from wild-type (WT) or α-1,3-galactosyltransferase gene-knockout (GTKO) pigs were divided into groups with or without rejection according to clinical examinations. Liquid chromatography-mass spectrometry (LC-MS) was used to analyze the proteomes of corneal tissues or aqueous humor. The biological functions of differentially expressed proteins (DEPs) were assessed using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) for pathways and protein-protein interaction network analysis. Among the 66 DEPs in aqueous humor, complement proteins (C3, C5, and C9) and cholesterol metabolic proteins (APOA1 and APOA2) were related to xenogeneic rejection as biomarkers, and alternative pathways of the complement system seemed to be important in xenogeneic graft rejection. Among the 416 DEPs of the cornea, NF-κB1 and proteosomes (PSMD7, PSMA5, and PSMD3) seemed to be related to xenogeneic graft rejection. Additionally, oxidative phosphorylation and leukocyte activation-related pathways are involved in rejection. Overall, our proteomic approach highlights the important role of NF-κB1, proteosomes, oxidative phosphorylation, and leukocyte activation-related inflammation in the cornea and the relevance of complement pathways of the aqueous humor as a predictive biomarker of xenogeneic rejection., 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 © 2022 Oh, Yoon, Ryu, Kim and Kim.)

A clinical decision support system (CDSS) informs or generates medical recommendations for healthcare practitioners. An alert is the most common way for a CDSS to interact with practitioners. Research about alerts in CDSS has proliferated over the past ten years. The research trend is ongoing with new emerging terms and focus. Bibliometric analysis is ideal for researchers to understand the research trend and future directions. Influential articles, institutes, countries, authors, and commonly used keywords were analyzed to grasp a comprehensive view on our topic, alerts in CDSS. Articles published between 2011 and 2021 were extracted from the Web of Science database. There were 728 articles included for bibliometric analysis, among which 24 papers were selected for content analysis. Our analysis shows that the research direction has shifted from patient safety to system utility, implying the importance of alert usability to be clinically impactful. Finally, we conclude with future research directions such as the optimization of alert mechanisms and comprehensiveness to enhance alert appropriateness and to reduce alert fatigue.

Background: Dextrose prolotherapy (DPT) is considered to be a type of regenerative therapy and is widely used in various musculoskeletal disorders. Plantar fasciitis is a common cause of heel pain that affects the quality of life of many people. We aimed to evaluate the effectiveness and safety of DPT for plantar fasciitis., Methods: PubMed, Embase, and the Cochrane Library were searched from their respective inception dates to June 2021. Only randomized controlled trials comparing DPT and other interventions for plantar fasciitis were included in this review. Standardized mean differences (SMDs) with 95% confidence intervals were calculated for comparison. The outcome measurements included visual analog score, numeric rating scale, Foot Function index, Revised Foot Function index, American Orthopedic Foot and Ankle Score, and plantar fascia thickness. Post-treatment duration was classified as short-term (1-2 months), medium-term (3 months), or long-term (6 months)., Results: Six studies with 388 adult patients diagnosed with plantar fasciitis were included for the meta-analysis. In terms of pain scores improvement, DPT was superior to placebo or exercise in the short-term (SMD: -1.163, 95%CI: -2.17 to -0.156) and the medium-term (SMD: -1.394, 95%CI: -2.702 to -0.085). DPT was inferior to corticosteroid injection in the short-term (SMD: 0.781, 95%CI: 0.41 to 1.152). For functional improvement, DPT was superior to placebo or exercise in the short-term (SMD: -1.51, 95%CI: -2.96 to -0.059), but inferior to corticosteroid injection (SMD: 0.526, 95%CI: 0.161 to 0.89) and extracorporeal shock wave therapy in the short-term (SMD: 0.484, 95%CI: 0.145 to 0.822). Randomized controlled trials showed a better pain improvement in the long-term for patients treated with DPT compared to corticosteroid (P = .002) and exercise control (P < .05). No significant differences were found between patients treated with DPT and patients treated with platelet-rich plasma., Conclusion: Dextrose prolotherapy was a safe and effective treatment option for plantar fasciitis that may have long-term benefits for patients. The effects were comparable to extracorporeal shock wave therapy or platelet-rich plasma injection. Further studies with standardized protocols and long-term follow-up are needed to address potential biases., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Rationale: : Reinforcement of thinned or necrotizing sclera has been conducted using various materials, including allogeneic sclera, allogenic cornea, amniotic membrane, fascia lata, pericardium, periosteum, and perichondrium. Among them, good outcomes have traditionally been obtained using preserved scleral grafts. However, scleral patch grafts have complications such as graft retraction, thinning, dehiscence, and necrosis. Furthermore, to promote epithelial healing, scleral patch grafting must be accompanied by procedures such as amniotic membrane transplantation (AMT) or grafting using conjunctival flaps or autografts. Recently, acellular preserved human corneas have been used in various ophthalmic surgeries, with emerging evidence supporting its use for treating scleral defects as an option that does not require AMT or conjunctival autografting. We investigated whether corneal patch grafting would show wound healing and tectonic success rate outcomes comparable to those of existing techniques., Patient Presentation: : Three patients presented with intractable ocular pain. Slit-lamp examination showed marked scleral thinning at the nasal side., Diagnosis: : Scleral thinning progressed with conservative treatment; microbial staining and culturing were performed. Infectious or non-infectious scleritis was diagnosed according to slit-lamp examination and microbial culture results., Interventions: : A preserved corneal lamellar patch was grafted at the scleral thinning area., Outcomes: All patients achieved tectonic success with reduction of inflammation following corneal patch grafting. Two patients achieved complete re-epithelialization within 7 days, while 25 days were required for the third patient. No patients experienced graft thinning, rejection, or infection., Lessons: : Our report suggests the feasibility of using acellular preserved human cornea patch grafts to reinforce inflammatory scleral defects and obtain successful outcomes in terms of wound healing. This technique shows a comparable tectonic success rate and superior effect on scleral defect healing without the need for adjunctive AMT or conjunctival autografting., Competing Interests: The authors have no funding and conflicts of interests to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Fucosylation is involved in a wide range of biological processes from cellular adhesion to immune regulation. Although the upregulation of fucosylated glycans was reported in diseased corneas, its implication in ocular surface disorders remains largely unknown. In this study, we analyzed the expression of a fucosylated glycan on the ocular surface in two mouse models of dry eye disease (DED), the NOD.B10.H2 b mouse model and the environmental desiccating stress model. We furthermore investigated the effects of aberrant fucosylation inhibition on the ocular surface and DED. Results demonstrated that the level of type 2 H antigen, an α(1,2)-fucosylated glycan, was highly increased in the cornea and conjunctiva both in NOD.B10.H2 b mice and in BALB/c mice subjected to desiccating stress. Inhibition of α(1,2)-fucosylation by 2-deoxy-D-galactose (2-D-gal) reduced corneal epithelial defects and increased tear production in both DED models. Moreover, 2-D-gal treatment suppressed the levels of inflammatory cytokines in the ocular surface and the percentages of IFN-γ + CD4 + cells in draining lymph nodes, whereas it did not affect the number of conjunctival goblet cells, the MUC5AC level or the meibomian gland area. Together, the findings indicate that aberrant fucosylation underlies the pathogenesis of DED and may be a novel target for DED therapy.

We investigated whether aging-dependent changes in dendritic cell (DC) distributions are distinct in autoimmune dry eye compared with an aging-related murine model. Corneal staining and tear secretion were evaluated in young and aged C57BL/6 (B6) and NOD.B10.H2b mice (NOD). In the corneolimbus, lacrimal gland (LG), and mesenteric lymph node (MLN), CD11b - and CD11b + DCs, CD103 + DCs and MHC-II hi B cells were compared between young and aged B6 and NOD mice. With increased corneal staining, tear secretion decreased in both aged B6 and NOD mice ( p < 0.001). In both aged B6 and NOD mice, the percentages of corneolimbal CD11b + DCs were higher ( p < 0.05) than those in young mice. While, the percentages of lymph nodal CD103 + DCs were higher in aged B6 and NOD mice ( p < 0.05), the percentages of corneolimbal CD103 + DCs were only higher in aged NOD mice ( p < 0.05). In aged NOD mice, the proportions of lacrimal glandial and lymph nodal MHC-II hi B cells were also higher than those in young mice ( p < 0.05). It indicates that corneolimbal or lacrimal glandial distribution of CD103 + DCs or MHC-II hi B cells may be distinct in aged autoimmune dry eye models compared to those in aged immune competent murine models.

Background: While aging is a potent risk factor of dry eye disease, age-related gut dysbiosis is associated with inflammation and chronic geriatric diseases. Emerging evidence have demonstrated that gut dysbiosis contributes to the pathophysiology or exacerbation of ocular diseases including dry eye disease. However, the relationship between aging-related changes in gut microbiota and dry eye disease has not been elucidated. In this pilot study, we investigated the association between aging-dependent microbiome changes and dry eye severity in C57BL/6 male mice., Results: Eight-week-old (8 W, n = 15), one-year-old (1Y, n = 10), and two-year-old (2Y, n = 8) C57BL/6 male mice were used. Dry eye severity was assessed by corneal staining scores and tear secretion. Bacterial genomic 16 s rRNA from feces was analyzed. Main outcomes were microbiome compositional differences among the groups and their correlation to dry eye severity. In aged mice (1Y and 2Y), corneal staining increased and tear secretion decreased with statistical significance. Gut microbiome α-diversity was not different among the groups. However, β-diversity was significantly different among the groups. In univariate analysis, phylum Firmicutes, Proteobacteria, and Cyanobacteria, Firmicutes/Bacteroidetes ratio, and genus Alistipes, Bacteroides, Prevotella, Paraprevotella, and Helicobacter were significantly related to dry eye severity. After adjustment of age, multivariate analysis revealed phylum Proteobacteria, Firmicutes/Bacteroidetes ratio, and genus Lactobacillus, Alistipes, Prevotella, Paraprevotella, and Helicobacter to be significantly associated with dry eye severity., Conclusions: Our pilot study suggests that aging-dependent changes in microbiome composition are related to severity of dry eye signs in C57BL/6 male mice.

Background: The collection and analysis of alert logs are necessary for hospital administrators to understand the types and distribution of alert categories within the organization and reduce alert fatigue. However, this is not readily available in most homegrown Computerized Physician Order Entry (CPOE) systems., Objective: To present a novel method that can collect alert information from a homegrown CPOE system (at an academic medical center in Taiwan) and conduct a comprehensive analysis of the number of alerts triggered and alert characteristics., Methods: An alert log collector was developed using the Golang programming language and was implemented to collect all triggered interruptive alerts from a homegrown CPOE system of a 726-bed academic medical center from November 2017 to June 2018. Two physicians categorized the alerts from the log collector as either clinical or non-clinical (administrative)., Results: Overall, 1,625,341 interruptive alerts were collected and classified into 1,474 different categories based on message content. The sum of the top 20, 50, and 100 categories of most frequently triggered alerts accounted for approximately 80, 90 and 97 percent of the total triggered alerts, respectively. Among alerts from the 100 most frequently triggered categories, 1,266,818 (80.2%) were administrative and 312,593 (19.8%) were clinical alerts., Conclusion: We have successfully developed an alert log collector that can serve as an extended function to retrieve alerts from a homegrown CPOE system. The insight generated from the present study could also potentially bring value to hospital system designers and hospital administrators when redesigning their CPOE system., Competing Interests: The authors have declared that no competing interests exist.

Background: Precise measurement of ocular biometry is critical for determining intraocular lens power. Newly developed swept-source optical coherence tomography (SS-OCT) - based ocular biometric devices, ANTERION and CASIA2 provide ocular biometric measurements as IOLMaster 700. This study aimed to assess agreement between three devices., Methods: This retrospective comparative study includes patients with cataract who underwent ocular biometric measurements with three devices, ANTERION, CASIA2, and IOLMaster 700, at Seoul National University Hospital, in April 2020. Anterior keratometry, total keratometry, central corneal thickness (CCT), anterior chamber depth (ACD), lens thickness (LT), and axial length (AL) were the main parameters for the comparison. To assess the agreement between the devices, intraclass coefficient (ICC) and Bland-Altman analysis with 95% limits of agreement (LoA) were used., Results: A total of 47 eyes of 29 patients were measured with three devices. Average anterior keratometry showed excellent agreement (ICC ≥ 0.989), and the mean difference was less than 0.1 D. However, the ICC of the total average keratometry ranged from 0.808 to 0.952, and the difference was more than 0.43 D. The AL measured by ANTERION and IOLMaster 700 showed excellent agreement (ICC = 0.999), and the mean difference was 0.005 mm. The ANTERION and IOLMaster 700 did not obtain AL in six (12.8%) and three (6.4%) cases, respectively (P = 0.001 by Fisher's exact test). The CCT, ACD, and LT also showed excellent agreement (ICC > 0.9)., Conclusions: The new SS-OCT-based devices, ANTERION, and CASIA2 showed a good agreement with IOLMaster 700 in measuring ocular biometry except for the total keratometry. The AL of ANTERION and IOLMaster 700 showed excellent agreement.

Background: Although most current medication error prevention systems are rule-based, these systems may result in alert fatigue because of poor accuracy. Previously, we had developed a machine learning (ML) model based on Taiwan's local databases (TLD) to address this issue. However, the international transferability of this model is unclear., Objective: This study examines the international transferability of a machine learning model for detecting medication errors and whether the federated learning approach could further improve the accuracy of the model., Methods: The study cohort included 667,572 outpatient prescriptions from 2 large US academic medical centers. Our ML model was applied to build the original model (O model), the local model (L model), and the hybrid model (H model). The O model was built using the data of 1.34 billion outpatient prescriptions from TLD. A validation set with 8.98% (60,000/667,572) of the prescriptions was first randomly sampled, and the remaining 91.02% (607,572/667,572) of the prescriptions served as the local training set for the L model. With a federated learning approach, the H model used the association values with a higher frequency of co-occurrence among the O and L models. A testing set with 600 prescriptions was classified as substantiated and unsubstantiated by 2 independent physician reviewers and was then used to assess model performance., Results: The interrater agreement was significant in terms of classifying prescriptions as substantiated and unsubstantiated (κ=0.91; 95% CI 0.88 to 0.95). With thresholds ranging from 0.5 to 1.5, the alert accuracy ranged from 75%-78% for the O model, 76%-78% for the L model, and 79%-85% for the H model., Conclusions: Our ML model has good international transferability among US hospital data. Using the federated learning approach with local hospital data could further improve the accuracy of the model., (©Yen Po Harvey Chin, Wenyu Song, Chia En Lien, Chang Ho Yoon, Wei-Chen Wang, Jennifer Liu, Phung Anh Nguyen, Yi Ting Feng, Li Zhou, Yu Chuan Jack Li, David Westfall Bates. Originally published in JMIR Medical Informatics (http://medinform.jmir.org), 27.01.2021.)

The search for alternatives to allotransplants is driven by the shortage of corneal donors and is demanding because of the limitations of the alternatives. Indeed, current progress in genetically engineered (GE) pigs, the introduction of gene-editing technology by clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9, and advanced immunosuppressants have made xenotransplantation a possible option for a human trial. Porcine corneal xenotransplantation is considered applicable because the eye is regarded as an immune-privileged site. Furthermore, recent non-human primate studies have shown long-term survival of porcine xenotransplants in keratoplasty. Herein, corneal immune privilege is briefly introduced, and xenogeneic reactions are compared with allogeneic reactions in corneal transplantation. This review describes the current knowledge on special issues of xenotransplantation, xenogeneic rejection mechanisms, current immunosuppressive regimens of corneal xenotransplantation, preclinical efficacy and safety data of corneal xenotransplantation, and updates of the regulatory framework to conduct a clinical trial on corneal xenotransplantation. We also discuss barriers that might prevent xenotransplantation from becoming common practice, such as ethical dilemmas, public concerns on xenotransplantation, and the possible risk of xenozoonosis. Given that the legal definition of decellularized porcine cornea (DPC) lies somewhere between a medical device and a xenotransplant, the preclinical efficacy and clinical trial data using DPC are included. The review finally provides perspectives on the current standpoint of corneal xenotransplantation in the fields of regenerative medicine., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: This study aimed to investigate the outcome of therapeutic penetrating keratoplasty (TPK) for medically-uncontrolled infectious keratitis, and to determine the factors associated with the recurrence of infection after TPK., Methods: A 10-year retrospective study of medically-uncontrolled infectious keratitis with positive culture results, who received TPK at a tertiary referral center in Korea was performed. Data collection included patient demographics, medical history, pre- and post-operative findings, surgical procedures, causative microorganisms, and visual acuities (VA). The primary outcome measure was the recurrence of infection after TPK, and the factors were compared between patients with and without recurrence., Results: A total of 19 patients (19 eyes) were analyzed, of which 6 eyes (31.6%) had infection recurrence at 21.6 ± 22.84 months after TPK. Recurrence occurred more frequently in the female sex (vs. male, p = 0.013) and in longer duration (>30 days) from infection onset to TPK (vs. ≤30 days, p = 0.025). Final best-corrected-VA was poorer in patients with recurrence than those without (LogMAR 1.60 ± 0.97 vs. 2.40 ± 0.46, p = 0.026). Evisceration was performed in 2 out of 6 patients with recurrence (33.3%), while none was performed in those without recurrence ( p = 0.028)., Conclusion: Infection recurrence after TPK was 31.6%. Given the poor outcome of TPK in eyes with recurrence, close monitoring and intensive treatment are required post-TPK.

Using metagenomics, continuing evidence has elicited how intestinal microbiota trigger distant autoimmunity. Sjögren's syndrome (SS) is an autoimmune disease that affects the ocular surface, with frequently unmet therapeutic needs requiring new interventions for dry eye management. Current studies also suggest the possible relation of autoimmune dry eye with gut microbiota. Herein, we review the current knowledge of how the gut microbiota interact with the immune system in homeostasis as well as its influence on rheumatic and ocular autoimmune diseases, and compare their characteristics with SS. Both rodent and human studies regarding gut microbiota in SS and environmental dry eye are explored, and the effects of prebiotics and probiotics on dry eye are discussed. Recent clinical studies have commonly observed a correlation between gut dysbiosis and clinical manifestations of SS, while environmental dry eye portrays characteristics in between normal and autoimmune. Moreover, a decrease in both the Firmicutes / Bacteroidetes ratio and genus Faecalibacterium have most commonly been observed in SS subjects. The presumable pathways forming the "gut dysbiosis-ocular surface-lacrimal gland axis" are introduced. This review may provide perspectives into the link between the gut microbiome and dry eye, enhance our understanding of the pathogenesis in autoimmune dry eye, and be useful in the development of future interventions.

Goblet cells (GCs) in the conjunctiva are specialized epithelial cells producing mucins on the ocular surface. GCs play important roles in maintaining homeostasis of the ocular surface, and GC dysfunction is associated with various complications including dry eye diseases. Current GC examination methods, which are conjunctival impression cytology and confocal reflection microscopy, have limitations for routine examination. Fluorescence microscopy using moxifloxacin was recently introduced as a non-invasive and high-contrast imaging method, but further development is needed to be used for GC examination. Here we developed a non-invasive high-speed high-contrast GC imaging method, called moxifloxacin based axially swept wide-field fluorescence microscopy (MBAS-WFFM). This method acquired multiple fluorescence images with the axial sweeping of the focal plane to capture moxifloxacin labeled GCs on the tilted conjunctival surface in focus and generated all-in-focus images by combining the acquired images. The imaging field of view and imaging speed were increased to 1.6 mm × 1.6 mm and 30 fps. An image processing method was developed for the analysis of GC density. MBAS-WFFM was applied to alkali burn mouse models and detected GC damage and recovery via longitudinal imaging. MBAS-WFFM could assess the status of GCs rapidly and non-invasively. We anticipate MBAS-WFFM to be a starting point for non-invasive GC examination and the diagnosis of GC associated diseases. For example, MBAS-WFFM could be used to classify dry eye diseases into detail categories for effective treatment., Competing Interests: SK, MJK, and KHK are authors of a patent filed for moxifloxacin-based imaging of goblet cells., (© 2020 Optical Society of America under the terms of the OSA Open Access Publishing Agreement.)

It is not known how biological changes in the lacrimal (LGs) and meibomian (MGs) glands contribute to dry eye disease (DED) in a time-dependent manner. In this study, we investigated time-sequenced changes in the inflammation, oxidative stress, and senescence of stem cells in both glands of an aging-related DED mouse model. Eight-week (8W)-, one-year (1Y)-, and two-year (2Y)-old C57BL/6 male mice were used. MG areas of the upper and lower eyelids were analyzed by transillumination meibography imaging. The number of CD45 + , 8-OHdG + , Ki-67 + , and BrdU + cells was compared in both glands. Increased corneal staining and decreased tear secretion were observed in aged mice. The MG dropout area increased with aging, and the age-adjusted MG area in lower lids was negatively correlated with the National Eye Institute (NEI) score. Increased CD4 + interferon (IFN)-γ + cells in LGs were found in both aged mice. An increase in 8-OHdG + cells in both glands was evident in 2Y-old mice. Reduced Ki-67 + cells, but no change in CD45 + cells, was observed in the MGs of 1Y-old mice. Increased BrdU + cells were observed in the LGs of aged mice. This suggests that age-dependent DED in C57BL/6 mice is related to inflammation of the LGs, the development of MG atrophy, and oxidative stress in both glands.

Background: Currently, various types of toric intraocular lenses (IOL) have been manufactured and can be divided into three types according to the location of correction component; front-toric IOL (correction on anterior IOL surface), back-toric IOL (correction on posterior IOL surface), and bi-toric IOL (correction on both anterior and posterior IOL surfaces). In this study, we aimed to investigate the effectiveness of reducing corneal astigmatism of either normal or post-penetrating keratoplasty (PKP) corneas according to the type of implanted toric IOLs., Methods: Medical records were retrospectively reviewed in 370 patients who had undergone phacoemulsification with posterior chamber toric IOL insertion (front-toric IOL, back-toric IOL or bi-toric IOL). Subjects were divided into 2 groups; subjects who had no history of corneal disease with corneal astigmatism more than 1.00 diopters (D) (G1) and subjects who received previous PKP with all corneal sutures removed and had corneal astigmatism more than 1.25 D (G2). Preoperatively intended target from SRK/T was evaluated. Refractive astigmatism and its vector analysis (J0, J45), mean numerical error (MNE) and mean absolute error (MAE) were assessed at least a month after cataract surgery., Results: Mean preoperative corneal astigmatisms were 2.2 D and 4.0 D in G1 and G2, respectively. There was significant reduction of mean postoperative refractive astigmatism to 0.89 D in G1 and to 2.33 D in G2. In G1, bi-toric IOL showed significantly more improved refractive astigmatism than back-toric IOL. In G2, no difference in refractive astigmatism according to toric IOL type was observed. While G2 showed no difference in MNE among toric IOLs, in G1, bi-toric IOL showed significant hyperopic shift compared to back-toric IOL. In both groups, there was no significant difference in MAE according to type of IOL. No postoperative complications were observed., Conclusion: Our study suggests that all types of toric IOL are beneficial in correcting astigmatism of normal and post-PKP corneas. Noticeably, bi-toric IOL showed significantly better results in refractive astigmatism than back-toric IOL in normal cornea. However, bi-toric IOL showed a more hyperopic shift compared to back-toric IOL. Among post-PKP corneas, all types of toric IOL showed similar results.

In this report we use a case study of risk of sudden unexpected death in epilepsy (SUDEP) to illustrate the contribution of systematic literature reviews of disease-specific ethical issues (DSEI). In particular, we show how ethically-relevant empirical data from such reviews can be used in the examination of the reasons for and against a particular normative approach to our DSEI. That is, we have attempted to offer a normative recommendation in response to the question of whether or not the risk of SUDEP should be disclosed to all patients. This case study functions as a form of empirical bioethics by providing a means of assessing empirical claims underlying reasons. As a result of this process, we are then able to provide clear and transparent, if not definitive, justification for a normative recommendation in response to a question of interest.

Purpose: To investigate the effects of topical autologous serum application on the ocular surface in patients with toxic corneal epitheliopathy induced by anti-glaucoma drugs., Methods: The patients who had corneal epitheliopathy because of preservative-containing anti-glaucoma eye drops were prospectively enrolled. The epitheliopathy was refractory to preservative-free artificial tear treatment. The patients topically applied 20% autologous serum to the eye eight times per day for 1 month. Baseline and one-month change in symptoms and signs were assessed by the Ocular Surface Disease Index (OSDI) questionnaire, tear film break-up time (TFBUT), Schirmer I values, corneoconjunctival staining scores, corneal sensitivity, InflammaDry ® tear immunoassay, and tear cytokine profiles using a bead-based multiplex assay., Results: A total of ten consecutive patients were enrolled between January and August 2018 and evaluated after one-month treatment with 20% autologous serum eye drops. Significant improvement was observed in symptoms (OSDI scores from 25.5 ± 20.9 to 10.5 ± 12.0; P = .039), TFBUT (from 3.1 ± 1.8 s to 5.4 ± 2.3 s; P = .025), corneoconjunctival staining scores (from 7.7 ± 1.8 to 1.8 ± 1.9 NEI scale; P = .005), corneal sensitivity (from 4.6 ± .9 cm to 5.8 ± .5 cm; P = .013), and metalloproteinase-9 levels (P = .013). There were no significant changes in Schirmer I values and tear cytokine levels on multiplex assays. Treatment-related side effects were not detected., Conclusions: Topical instillation of 20% autologous serum is an effective treatment for toxic corneal epitheliopathy associated with anti-glaucoma eye drops., Trial Registration Number: KCT0003827.