Exploring Single-cell RNA sequencing as a decision-making tool in the clinical management of Fuchs' Endothelial Corneal Dystrophy.

Single-cell RNA sequencing (scRNA-seq) has enabled the identification of novel gene signatures and cell heterogeneity in numerous tissues and diseases. Here we review the use of this technology for Fuchs' Endothelial Corneal Dystrophy (FECD). FECD is the most common indication for corneal endothelial transplantation worldwide. FECD is challenging to manage because it is genetically heterogenous, can be autosomal dominant or sporadic, and progress at different rates. Single-cell RNA sequencing has enabled the discovery of several FECD subtypes, each with associated gene signatures, and cell heterogeneity. Current FECD treatments are mainly surgical, with various Rho kinase (ROCK) inhibitors used to promote endothelial cell metabolism and proliferation following surgery. A range of emerging therapies for FECD including cell therapies, gene therapies, tissue engineered scaffolds, and pharmaceuticals are in preclinical and clinical trials. Unlike conventional disease management methods based on clinical presentations and family history, targeting FECD using scRNA-seq based precision-medicine has the potential to pinpoint the disease subtypes, mechanisms, stages, severities, and help clinicians in making the best decision for surgeries and the applications of therapeutics. In this review, we first discuss the feasibility and potential of using scRNA-seq in clinical diagnostics for FECD, highlight advances from the latest clinical treatments and emerging therapies for FECD, integrate scRNA-seq results and clinical notes from our FECD patients and discuss the potential of applying alternative therapies to manage these cases clinically.

Polygenic Prediction of Keratoconus and its Measures: Cross-Sectional and Longitudinal Analyses in Community-Based Young Adults.

AIM: This study evaluates the performance of a multitrait polygenic risk score (PRS) in an independent cohort to predict incident or progression of keratoconus. DESIGN: Prospective cross-sectional and cohort study METHODS: Setting: Single-center; Study population: 1478 community-based young adults (18-30 years; 51% female), including 609 (52% female) who returned for an 8-year follow-up; Observation procedures: Scheimpflug imaging (Pentacam, Oculus), genotyping and development of a multitrait PRS previously validated to predict keratoconus in older adults.; Main outcome measure: Belin/Ambrόsio enhanced ectasia display (BAD-D) score and keratoconus, defined as BAD-D ≥2.6, were each analyzed against the PRS using linear and logistic regression, respectively. RESULTS: Prevalence of keratoconus was 2.5% (95% confidence interval [CI] = 1.9-3.6) in the cross-sectional cohort. Each z-score increase in PRS was associated with worse BAD-D z-score by 0.13 (95%CI = 0.08-0.18) and 1.6 increased odds of keratoconus. The 8-year keratoconus incidence was 2.6% (95%CI = 1.3-4.0). Participants in the highest PRS decile were more likely to have incident keratoconus compared to the rest of the cohort (odds ratio = 3.85, 95%CI = 1.21-12.22). For each z-score increase in PRS, 8-year change in BAD-D z-score worsened by 0.11 (95%CI = 0.04-0.17). CONCLUSIONS: A PRS for keratoconus could be useful in predicting incident keratoconus and progression, demonstrating its potential utility in clinical settings to identify patients at high risk of postsurgery ectasia or those who may benefit most from keratoconus intervention.

FROSTED BRANCH ANGIITIS ASSOCIATED WITH MIXED CONNECTIVE TISSUE DISEASE.

PURPOSE: To present a case of frosted branch angiitis associated with an exacerbation of mixed connective tissue disease (MCTD). METHODS: Single case report. RESULTS: A 31-year-old woman presented with a flare of her long-standing MCTD after a change in her immunosuppressive medications. She developed blurred vision and floaters first in the left eye but eventually in both eyes. Fundoscopy showed patchy perivascular sheathing of tertiary branch venules surrounded by retinal hemorrhages characterized as frosted branch angiitis. The patient's MCTD symptoms and retinal vasculitis improved with continued immunosuppressive therapy. At 1-month follow-up, her visual acuity had improved to 20/20 bilaterally with complete resolution on fundoscopy. CONCLUSION: To the authors' knowledge, this is the first report of frosted branch angiitis seen in association with MCTD. The improvement in the patient's visual acuity and fundoscopic findings in this case supports the role of immunosuppressive therapy to treat secondary frosted branch angiitis associated with an autoimmune condition such as MCTD. However, it is recommended that a comprehensive medical workup is performed to exclude an infective cause, particularly in immunocompromised patients.

ROCK inhibitors in ophthalmology: A critical review of the existing clinical evidence.

Rho kinase (ROCK) inhibitors have emerged as a key therapeutic class of interest in ophthalmology over the last decade. Promising in vitro studies laid the foundations for the development of novel therapeutic agents that target the ROCK signalling pathway in ocular disease, with subsequent clinical trials supporting their use. Corneal endothelial disease, glaucoma, and vitreoretinal disease are the major pathologies in which ROCK inhibitors have been investigated to date. Ripasudil and netarsudil represent the current leaders in this pharmaceutical group, having been extensively validated and approved for use in glaucoma in some countries. Less substantial evidence exists for fasudil in ophthalmic use. ROCK inhibitors are also increasingly used in cultured endothelial cell grafting and as an adjunct to aid in endothelial cell migration and replication in Descemet's stripping procedures or Descemet's membrane injuries. This review has synthesised both established and emerging research to provide a practical guide to prescribing in this drug class. Drug efficacies, side effect profiles, and the demographic and clinical characteristics of appropriate drug candidates are discussed.

Diagnosis and Management of Keratoconus-A Narrative Review of Clinicians' Perspectives.

This review discusses the current practices, attitudes, and trends in diagnosing and managing keratoconus (KC) in adults and children by optometrists and ophthalmologists in order to highlight the differences on a global scale. Two independent reviewers searched the electronic databases and grey literature for all potential articles published from 1 January 2000 to 1 June 2022 on management of KC. Keywords used in searches included "keratoconus", "diagnosis", "management", "treatment", "attitude", "practices", "opinion", "optometrist", "ophthalmologist", "consensus", and "protocol". A total of 19 articles was included in this review-12 from the database search and seven from the grey literature. Although a common stepwise approach of non-surgical management was noted, there were differences in the rates of prescribing rigid gas permeable lenses. Furthermore, while clinicians agreed on the need for early diagnosis, the timeline and type of referral varied significantly. A similar discordance was found in the milestones for surgical intervention and preferred surgical techniques. Practice patterns in keratoconus diagnosis and management vary throughout the world. Multiple recommendations and suggestions to minimise the differences have been provided in the literature, with the main themes being improvement in education, interdisciplinary patient care, and further research to reach consensus.

Cross-Linking Improves the Quality of Life of People With Keratoconus: A Cross-Sectional and Longitudinal Study From the Save Sight Keratoconus Registry.

PURPOSE: The purpose of this study was to comprehensively evaluate the patient-reported quality-of-life (QoL) outcomes after corneal cross-linking for keratoconus. METHODS: This Save Sight Keratoconus Registry study used cross-sectional and longitudinal designs. For the cross-sectional study, 532 patients with keratoconus (mean age 30.9 ± 11.9 years; 31.6% female) completed the Keratoconus Outcomes Research Questionnaire (KORQ) and 343 patients with keratoconus (mean age 28.3 ± 10.7 years; 32.7% female) completed the Impact of Vision Impairment (IVI) questionnaires. Similarly, for the longitudinal study, 39 patients (mean age 24.2 ± 8.4 years; 23.1% female) completed the KORQ and 16 patients (mean age 27.9 ± 17.1 years; 50.0% female) completed the IVI questionnaire before and after 6 months of cross-linking. The QoL data were analyzed using the Andrich Rating Scale Model of Rasch analysis. RESULTS: For both cross-sectional and longitudinal studies, the KORQ and IVI scales demonstrated satisfactory psychometric properties [ordered and well-spaced categories, variance explained by the measure 52%-73%, person separation index 2.4-3.9, and fit statistics <1.3 (most cases)]. The patients who had not undergone corneal cross-linking had worse mean activity limitation than those with cross-linking (P = 0.008). However, the differences in symptoms and emotional scores between the groups were not statistically significant (both P > 0.05). The longitudinal study showed that cross-linking was associated with improved activity limitation, symptoms, and emotional scores. CONCLUSIONS: The KORQ and IVI are psychometrically robust tools to evaluate the QoL outcomes of corneal cross-linking. Cross-linking is associated with improved activity limitation, symptoms, and emotional status.

Face Mask-Associated Recurrent Corneal Erosion Syndrome and Corneal Infection.

ABSTRACT: In the current coronavirus disease 2019 (COVID-19) pandemic, important public health measures such as the utilization of face masks has been widely enforced, including community-wide mandatory face mask use. During this period, there have been observations of an increasing number of patients presenting with dry eye symptoms among regular mask users with no history of ocular surface pathology. Individuals have reported being aware of air blowing upward from the mask into their eyes that is likely to increase the evaporation of their tear film leading to ocular irritation. Although face mask use is essential in combatting the COVID-19 pandemic, it is important to recognize the potential effects it may have on ocular health. We report a case of face mask-associated ocular complication. After an initial cornea abrasion from mask use, the patient developed recurrent corneal erosion syndrome that was complicated by microbial keratitis after the enforcement of mandatory mask use in public areas.

Prevalence of Keratoconus Based on Scheimpflug Imaging: The Raine Study.

PURPOSE: To describe the prevalence and systemic associations of keratoconus in young adults in Perth, Western Australia. DESIGN: Cross-sectional study. PARTICIPANTS: One thousand two hundred fifty-nine participants 20 years of age. METHODS: The Raine Study is a multigenerational, longitudinal cohort study based in Perth, Western Australia. This study represents a cross-sectional analysis of the birth cohort on returning for a 20-year follow-up. Participants underwent a detailed ophthalmic examination, including visual acuity assessment and Scheimpflug imaging using the Pentacam (Oculus, Wetzlar, Germany), and completed a health questionnaire. Keratoconus was defined as a Belin/Ambrόsio enhanced ectasia display score of 2.6 or more in either eye based on Pentacam imaging. MAIN OUTCOME MEASURES: Prevalence of keratoconus in this cohort. RESULTS: Of the 1259 participants, 50.8% were women and 85.7% were White. Fifteen participants had keratoconus in at least 1 eye, giving a prevalence of 1.2% (95% confidence interval, 0.7%-1.9%), or 1 in 84. A significant difference was found in best-corrected visual acuity (0.01 logarithm of the minimum angle of resolution vs. -0.05 logarithm of the minimum angle of resolution; P = 0.007), cylinder (1.25 diopters [D] vs. 0.25 D cylinder; P < 0.001) and spherical equivalent (-1.42 D vs. -0.50 D sphere; P = 0.02) on objective refraction, mean keratometry of the steep meridian (45.19 D vs. 43.76 D; P < 0.001), and mean corneal thickness at the thinnest point (475 µm vs. 536 µm; P < 0.001) between those with and without keratoconus. Keratoconus was associated with regular cigarette smoking (38.5% vs. 14.6%; P = 0.04), but showed no association with gender, race, body mass index, use of spectacles or contact lenses, history of allergic eye disease, or pregnancy. CONCLUSIONS: The prevalence of keratoconus in this Australian population-based study of 20-year-old adults was 1.2% (95% confidence interval, 0.7%-1.9%), or 1 in 84, which is one of the highest reported in the world. This has important implications for screening individuals at a younger age so that treatment can be initiated before disease progression.

Evaluation of Total Donor Endothelial Viability After Endothelium-Inward Versus Endothelium-Outward Loading and Insertion in Descemet Membrane Endothelial Keratoplasty.

PURPOSE: This study compares endothelial cell density (ECD) and viability between 2 different techniques used to prepare and insert Descemet membrane endothelial keratoplasty (DMEK) donor tissues. The first technique uses the naturally forming Descemet membrane (DM) scroll where the endothelial cells face outward; in the second technique, the DM is folded into thirds (trifold) with the endothelial cells facing inward. METHODS: Eighteen cadaveric corneas from 9 donors (matched pairs) were used to compare the 2 tissue-insertion techniques. In the scroll, endothelium-outward technique, standard DMEK preparation was used, and the naturally forming DM scroll was inserted into a Geuder Cartridge. In the trifold, endothelium-inward technique, DMEK preparation was undertaken by folding the donor tissue into thirds before being pulled into the EndoGlide Ultrathin. In each case, the tissue was injected onto a glass slide. Endothelial cell counting was performed using microscopy preinjection and postinjection, and vital staining using calcein acetoxymethyl (AM) was used for quantitative cell viability analysis across the whole tissue. RESULTS: Manual ECDs using direct microscopy did not demonstrate a statistically significant difference in ECD between the 2 injection techniques. Using vital staining of the entire 8.0-mm diameter tissue, there was a significantly higher percentage of viable cells using the trifold, endothelium-inward technique (63.1%) compared with the scroll, endothelium-outward technique (41.5%) (P = 0.013). There was no difference in the pattern of cell loss between the 2 groups. CONCLUSIONS: Greater endothelial cell viability was observed using the trifold, endothelium-inward technique compared with the scroll, endothelium-outward technique.

Optical coherence tomography analysis of patients with untreated diabetic macular edema.

PURPOSE: Diabetic macular edema (DME) is a major cause of vision loss. Diabetes patients with mild macular edema and good visual acuity are often observed carefully so that treatment can be instituted when central vision is threatened. Optimal frequency of monitoring of these patients is unknown. Our study aimed to gather more information to determine a safe interval for monitoring of patients with eyes that were not undergoing active treatment for DME and to correlate outcomes with clinical risk factors. METHODS: Study population: Ninety-seven eyes with optical coherence tomography (OCT) evidence of DME of 97 patients with diabetes. Study procedures: Retrospective review of medical records and macular OCT scans at a 6-12-month interval. Primary outcomes: Change in visual acuity and change in central subfield thickness (CSFT) between the initial and follow-up OCT scans. RESULTS: There was no significant change from median baseline visual acuity 6/9 (inter-quartile range 6/6-6/12) or from median baseline CSFT (290 µm, inter-quartile range 270-312 µm) over a median duration of 8 months (inter-quartile range 7-10 months). The numbers of eyes where CSFT had increased ≥ 25 µm, reduced ≥ 25 µm, or remained unchanged were 16 (16%), 6 (6%), and 74 (76%), respectively. Patients with hemoglobin A1c ≥ 8.5% were 5.7 times more likely to develop central subfield thickening (95% CI 1.1-30.1, P = 0.038). CONCLUSIONS: Majority of eyes with DME on OCT had stable CSFT without treatment over a median duration of 8 months. Hemoglobin A1c may be useful for risk stratification.

The Treat-and-Extend Injection Regimen Versus Alternate Dosing Strategies in Age-related Macular Degeneration: A Systematic Review and Meta-analysis.

PURPOSE: To assess outcomes of the treat-and-extend (T&E) injection regimen for neovascular age-related macular degeneration (AMD) as compared to either a monthly or a pro re nata (PRN) treatment strategy. DESIGN: Systematic review and meta-analysis. METHODS: Studies that compared the T&E regimen with either monthly or PRN dosing for treatment-naïve AMD were included. Trial eligibility, data extraction, and risk of bias were assessed according to Cochrane review methods. Estimates were pooled using random-effects meta-analysis. RESULTS: Four eligible studies were identified, all using ranibizumab (total N = 940 eyes), including 2 randomized controlled trials comparing T&E to monthly and 2 retrospective reviews comparing T&E to PRN. No studies evaluating aflibercept were identified. Improvements in vision and central retinal thickness were similar between T&E and monthly at 12 months, with a mean difference of -1.79 letters (95% confidence interval [CI]: 3.70, 0.13) and 3.76 µm (95% CI: -13.78, 21.30) in favor of monthly injections. In contrast, visual gains were higher in the T&E compared to the PRN group (difference of +6.18 letters, 95% CI: 3.28, 9.08). Fewer injections were required using the T&E regimen when compared to monthly (mean of -1.6 and -6.9 injections at 12 and 24 months, respectively). A mean of 1.44 more injections was required for the T&E compared to PRN regimen at 12 months; however, this was achieved with fewer visits. CONCLUSION: Despite the growing preference for the T&E regimen, there is limited head-to-head evidence comparing dosing strategies. The evidence available, however, suggests that at 12 months, T&E is comparable to monthly and superior to PRN dosing for both efficacy and safety outcomes when using ranibizumab.

High myopia and cataract surgery.

PURPOSE OF REVIEW: Cataract surgery in high myopes is challenging. Using third-generation intraocular lens (IOL) formulas, without adjustments, hyperopic refractive outcomes are common. We discuss these issues, focusing on the various lens formulas and transformations that have improved postoperative accuracy. RECENT FINDINGS: Axial length measurement error has been largely overcome by the use of optical interferometry. Despite this, consistent hyperopic errors are still reported. We reviewed the postoperative refraction results compared with the predicted refractions using: standard formulas (Holladay 1, SRK/T, Hoffer Q, and Haigis) with manufacturers' optical lens constants, the User Group for Laser Interference Biometry (ULIB) constants, manufacturers' constants with axial length adjustment method, and fourth-generation IOL formulas (Barrett Universal II, Holladay 2, and Olsen). SUMMARY: Improved predictive results is obtained with the Barrett Universal II (software constants), Haigis (ULIB), SRK/T, Holladay 2 (software constants), and Olsen (software constants) formulas in eyes with axial lengths greater than 26.0 mm and IOL powers greater than 6.0 D. In eyes with axial lengths greater than 26.0 mm and IOL less than 6.0 D, the Barrett Universal II formula (software constants) and the Haigis (axial length adjusted) and Holladay 1 formulas (axial length-adjusted) should be used.

Age Related Macular Degeneration and Total Hip Replacement Due to Osteoarthritis or Fracture: Melbourne Collaborative Cohort Study.

Osteoarthritis is the leading cause of total hip replacement, accounting for more than 80% of all total hip replacements. Emerging evidence suggests that osteoarthritis has a chronic inflammatory component to its pathogenesis similar to age-related macular degeneration. We evaluated the association between age-related macular degeneration and total hip replacement as proxy for severe osteoarthritis or fractured neck of femur in the Melbourne Collaborative Cohort Study. 20,744 participants had complete data on both age-related macular degeneration assessed from colour fundus photographs taken during 2003-2007 and total hip replacement. Total hip replacements due to hip osteoarthritis and fractured neck of femur during 2001-2011 were identified by linking the cohort records to the Australian Orthopedic Association National Joint Replacement Registry. Logistic regression was used to examine the association between age-related macular degeneration and risk of total hip replacement due to osteoarthritis and fracture separately, adjusted for confounders. There were 791 cases of total hip replacement for osteoarthritis and 102 cases of total hip replacement due to fractured neck of femur. After adjustment for age, sex, body mass index, smoking, and grouped country of birth, intermediate age-related macular degeneration was directly associated with total hip replacement for osteoarthritis (odds ratio 1.22, 95% CI 1.00-1.49). Late age-related macular degeneration was directly associated with total hip replacement due to fractured neck of femur (odds ratio 5.21, 95% CI2.25-12.02). The association between intermediate age-related macular degeneration and an increased 10-year incidence of total hip replacement due to osteoarthritis suggests the possibility of similar inflammatory processes underlying both chronic diseases. The association of late age-related macular degeneration with an increased 10-year incidence of total hip replacement due to fractured neck of femur may be due to an increased prevalence of fractures in those with poor central vision associated with the late complications of age-related macular degeneration.