Plasma cell dyscrasias are a wide range of severe monoclonal gammopathies caused by pre-malignant or malignant plasma cells that over-secrete an abnormal monoclonal antibody. These disorders are associated with various systemic findings, including ophthalmological disorders. A search of PubMed, EMBASE, Scopus and Cochrane databases was performed in March 2021 to examine evidence pertaining to ocular complications in patients diagnosed with plasma cell dyscrasias. This review outlines the ocular complications associated with smoldering multiple myeloma and monoclonal gammopathy of undetermined significance, plasmacytomas, multiple myeloma, Waldenström's macroglobulinemia, systemic amyloidosis, Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal gammopathy and Skin changes (POEMS) syndrome, and cryoglobulinemia. Although, the pathological mechanisms are not completely elucidated yet, wide-ranging ocular presentations have been identified over the years, evolving both the anterior and posterior segments of the eye. Moreover, the presenting symptoms also help in early diagnosis in asymptomatic patients. Therefore, it is imperative for the treating ophthalmologist and oncologist to maintain a high clinical suspicion for identifying the ophthalmological signs and diagnosing the underlying disease, preventing its progression through efficacious treatment strategies.

PURPOSE: Foveal herniation occurs when neuroretinal tissue protrudes through and above the level of an epiretinal membrane. This study describes the visual symptoms and spectral domain optical coherence tomography findings associated with foveal herniation and evaluates the postoperative visual, anatomical, and surgical outcomes. METHODS: A multicenter retrospective review of patients diagnosed with epiretinal membrane identified 59 patients with preoperative foveal herniation on spectral domain optical coherence tomography. Data regarding visual symptoms, preoperative and postoperative best-corrected visual acuity (BCVA), central retinal thickness, macular volume, and size of foveal herniation were collected, and statistical analysis was performed. RESULTS: A total of 58 of the 59 patients with foveal herniation underwent surgical epiretinal membrane peeling, with foveal contour restored in 53.5% of patients after surgery. Average BCVA improved from 20/80 to 20/40 Snellen equivalent at most-recent postoperative visit (P < 0.0001). The average central retinal thickness decreased from 632 µm to 432 µm (P < 0.0001) and the average macular volume decreased from 11.3 mm3 to 9.5 mm3 (P < 0.0001) at 3 months postoperatively. Preoperatively, greater herniation height was associated with worse BCVA (P = 0.008), greater central retinal thickness (P = 0.01), retinoschisis, cystoid macular edema, foveolar detachment, ellipsoid zone abnormality, and external limiting membrane abnormalities (P < 0.05). Postoperatively, there was a decrease in retinoschisis, cystoid macular edema, foveolar detachment, ellipsoid zone, and external limiting membrane abnormality (P < 0.05) on spectral domain optical coherence tomography. CONCLUSION: Patients with larger foveal herniation height had greater preoperative central retinal thickness, worse preoperative and postoperative BCVA, and more intraretinal abnormalities on spectral domain optical coherence tomography. Surgical epiretinal membrane peeling in patients with foveal herniation resulted in a significant improvement in patients' BCVA and microstructural abnormalities.

IMPORTANCE: Electronic clinical decision support systems apply clinical guidelines in real time and offer a new approach to improve referral and utilization of low vision rehabilitation (LVR) care. OBJECTIVE: To characterize patients and factors associated with LVR service utilization with and without the use of an electronic health record (EHR) clinical decision support system (CDSS) alert. DESIGN, SETTING, AND PARTICIPANTS: Quality improvement study using EHR data to compare patients who did and did not utilize LVR service after referral between November 6, 2017, and October 5, 2019, (primary) and to assess overall service utilization rate from September 1, 2016, to April 2, 2021, regardless of referral status (secondary). Participants in the primary analysis were patients at a large ophthalmology department in an academic medical center in the US who received an LVR referral recommendation from their ophthalmologist according to the CDSS alert. The secondary analysis included patients with best documented visual acuity (BDVA) worse than 20/40 before, during, and after the CDSS implementation. Data were analyzed from August 2021 to April 2022. EXPOSURES: Number and locations of referral recommendations for LVR service according to the CDSS alert in the primary analysis; active CDSS implementation in the secondary analysis. MAIN OUTCOMES AND MEASURES: LVR service utilization rate was defined as the number of patients who accessed service among those who were referred (primary) and among those with BDVA worse than 20/40 (secondary). EHR data on patient demographics (age, sex, race, ethnicity) and ophthalmology encounter characteristics (numbers of referral recommendations, encounter location, and BDVA) were extracted. RESULTS: Of the 429 patients (median [IQR] age, 71 [53 to 83] years; 233 female [54%]) who received a CDSS-based referral recommendation, 184 (42.9%) utilized LVR service. Compared with nonusers of LVR, users were more likely to have received at least 2 referral recommendations (12.5% vs 6.1%; χ21 = 5.29; P = .02) and at an ophthalmology location with onsite LVR service (87.5% vs 78.0%; χ21 = 6.50; P = .01). Onsite LVR service (odds ratio, 2.06; 95% CI, 1.18-3.61) persisted as the only statistically significant factor after adjusting for patient demographics and other referral characteristics. Among patients whose BDVA was worse than 20/40 before, during, and after the CDSS implementation regardless of referral status, the LVR service utilization rate was 6.1%, 13.8%, and 7.5%, respectively. CONCLUSIONS AND RELEVANCE: In this quality improvement study, ophthalmologist referral recommendations and onsite LVR services at the location where patients receive other ophthalmic care were significantly associated with service utilization. Ophthalmology CDSSs are promising tools to apply clinical guidelines in real time to improve connection to care.

BACKGROUND: Bilastine is a second-generation antihistamine approved for the symptomatic treatment of allergic rhinoconjunctivitis and urticaria. This trial evaluated the efficacy and safety of a new bilastine 0.6% preservative-free eye-drops formulation for the symptomatic treatment of allergic conjunctivitis. METHODS: This phase 3, multicenter, double-masked, randomized study evaluated the efficacy, safety and tolerability of bilastine 0.6% ophthalmic solution compared to ketotifen 0.025% and vehicle. The primary efficacy endpoint was ocular itching reduction. The Ora-CAC® Allergen Challenge Model was used to assess ocular and nasal symptoms at 15 minutes (onset of action) and 16 hours post-treatment. RESULTS: Subjects (N=228) were 59.6% male, and the mean (SD) age was 44.1 (13.4) years. Bilastine demonstrated efficacy in reducing ocular itching compared to vehicle at both onset of action and 16 hours post-treatment (P <0.001). Ketotifen showed improvement compared to vehicle 15 minutes post-treatment (P <0.001). Bilastine demonstrated statistical non-inferiority to ketotifen for all 3 post-CAC timepoints at 15 minutes post-instillation, based on an inferiority margin of 0.4. Bilastine demonstrated improvement over vehicle (P <0.05) for conjunctival redness, ciliary redness, episcleral redness, chemosis, eyelid swelling, tearing, rhinorrhea, ear and palate pruritus and nasal congestion at 15 minutes post-treatment. Ophthalmic bilastine was safe and well tolerated. Mean drop comfort scores were significantly better (P <0.05) for bilastine compared with ketotifen immediately upon instillation, and similar compared with vehicle. CONCLUSIONS: Ophthalmic bilastine effectively reduced ocular itching for 16 hours post-treatment, suggesting that it could be used as a once-daily treatment for the signs and symptoms of allergic conjunctivitis. ClinicalTrials.gov identifier: NCT03479307.

PURPOSE: Genetic variants in regions that include the mitochondrial genes TXNRD2 and ME3 are associated with primary open-angle glaucoma (POAG) in genome-wide association studies (GWAS). To assess their clinical impact, we investigated whether TXNRD2 and ME3 genetic risk scores (GRSs) are associated with specific glaucoma phenotypes. DESIGN: Cross-sectional study PARTICIPANTS: 2617 POAG cases and 2634 controls from the NEIGHBORHOOD consortium. METHODS: All POAG-associated single nucleotide polymorphisms (SNPs) in the TXNRD2 and ME3 loci were identified using GWAS data (p<0.05). Of these, 20 TXNRD2 and 24 ME3 SNPs were selected after adjusting for linkage disequilibrium. The correlation between SNP effect size and gene expression levels was investigated using the Gene-Tissue Expression (GTEx) database. GRSs were constructed for each individual using the unweighted sum of TXNRD2, ME3, and TXNRD2+ME3 combined risk alleles. Age and gender-adjusted odds ratios (ORs) for POAG diagnosis were calculated per decile for each GRS. Additionally, the clinical features of POAG cases in the top 1, 5, and 10% of each GRS were compared to the bottom 1, 5, and 10%, respectively. MAIN OUTCOME MEASURES: POAG OR per GRS decile; maximal treated intraocular pressure (IOP) and prevalence of paracentral visual field loss among POAG cases with high vs. low GRSs. RESULTS: Increased SNP effect size strongly correlated with higher TXNRD2 and lower ME3 expression levels (r=0.95 and -0.97, respectively, p<0.05 for both). Individuals in decile 10 of TXNRD2+ME3 GRS had the highest odds of POAG diagnosis (OR=1.79 compared to decile 1, p<0.001). POAG cases in the top 1% of TXNRD2 GRS had higher mean maximal treated IOP compared to the bottom 1% (19.9 mmHg vs 15.6 mmHg, adjusted p=0.03). POAG cases in the top 1% of ME3 and TXNRD2+ME3 GRS had a higher prevalence of paracentral field loss compared to the bottom 1% (72.7-88.9% vs 14.3-33.3%; adjusted p=0.03 for both). CONCLUSIONS: POAG patients with higher TXNRD2 and ME3 GRSs had higher treated IOP and a greater prevalence of paracentral field loss. Functional studies exploring how these variants impact mitochondrial function in glaucoma patients are warranted.

PURPOSE: To assess the risk of vaccine-associated uveitis (VAU) after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination and evaluate uveitis onset interval and clinical presentations in the patients. DESIGN: A retrospective study from December 11, 2020, to May 9, 2022, using the Centers for Disease Control and Prevention Vaccine Adverse Event Reporting System. PARTICIPANTS: Patients diagnosed with VAU after administration of BNT162b2 (Pfizer-BioNTech, Pfizer Inc/BioNTech SE), mRNA-1273 (Moderna, Moderna Therapeutics Inc), and Ad26.COV2.S (Janssen, Janssen Pharmaceuticals) vaccine worldwide. METHODS: A descriptive analysis of the demographics, clinical history, and presentation was performed. We evaluated the correlation among the 3 vaccines and continuous and categorical variables. A post hoc analysis was performed between uveitis onset interval after vaccination and age, dose, and vaccine type. Finally, a 30-day risk analysis for VAU onset postvaccination was performed. MAIN OUTCOME MEASURES: The estimated global crude reporting rate, observed to expected ratio of VAU in the United States, associated ocular and systemic presentations, and onset duration. RESULTS: A total of 1094 cases of VAU were reported from 40 countries with an estimated crude reporting rate (per million doses) of 0.57, 0.44, and 0.35 for BNT162b2, mRNA-1273, and Ad26.COV2.S, respectively. The observed to expected ratio of VAU was comparable for BNT162b2 (0.023), mRNA-1273 (0.025), and Ad26.COV2.S (0.027). Most cases of VAU were reported in patients who received BNT162b2 (n = 853, 77.97%). The mean age of patients with VAU was 46.24 ± 16.93 years, and 68.65% (n = 751) were women. Most cases were reported after the first dose (n = 452, 41.32%) and within the first week (n = 591, 54.02%) of the vaccination. The onset interval for VAU was significantly longer in patients who received mRNA-1273 (21.22 ± 42.74 days) compared with BNT162b2 (11.42 ± 23.16 days) and rAd26.COV2.S (12.69 ± 16.02 days) vaccines (P < 0.0001). The post hoc analysis revealed a significantly shorter interval of onset for the BNT162b2 compared with the mRNA 1273 vaccine (P < 0.0001). The 30-day risk analysis showed a significant difference among the 3 vaccines (P < 0.0001). CONCLUSIONS: The low crude reporting rate and observed to expected ratio suggest a low safety concern for VAU. This study provides insights into a possible temporal association between reported VAU events and SARS-CoV-2 vaccines; however, further investigations are required to delineate the associated immunological mechanisms.

Diabetic retinal disease (DRD) remains a leading cause of vision loss and blindness globally. Although treatments can be effective when given at vision-threatening stages of DRD, there is a lack of knowledge about the earliest mechanisms leading to the development of clinically evident DRD. Recent advances in retinal imaging methods for patients with diabetes allow a more precise and granular characterization of the different stages of DRD than is provided by the classic Diabetic Retinopathy Severity Scale based on fundus photographs. In addition, recent clinical studies have yielded more information on how to adjust blood glucose levels, lipid levels and blood pressure to minimize the risk of DRD. Given the incomplete success of current therapies, there is a critical need for better understanding of the mechanisms underlying DRD and novel treatment targets that address the entire neurovascular retina. Moreover, the causes for interindividual variability in the development of DRD in patients with similar glycemic history and other metabolic factors are not yet clarified either. Finally, greater focus on patients' experience with visual disabilities and treatment effects should be addressed in research in this field.

PURPOSE: To provide an overview of the impact of retinopathy of prematurity (ROP), and the challenges in the screening, diagnosis, and treatment of ROP worldwide. METHODS: A comprehensive search was conducted using the PubMed database from January 2011 to October 2021 using the following keywords: retinopathy of prematurity, laser, and anti-vascular endothelial growth factor (VEGF). Data on patient characteristics, ROP treatment type, and recurrence rates were collected. The countries included in these studies were classified based on 2021-2022 World Bank definitions of high, upper-middle, lower-middle, and low-income groups. Moreover, a search for surgical outcomes for ROP and screening algorithms and artificial intelligence for ROP was conducted. RESULTS: Thirty-nine studies met the inclusion criteria. ROP treatment and outcomes showed a trend towards intravitreal anti-VEGF injections as the initial treatment for ROP globally and the treatment of recurrent ROP in high-income countries. However, laser remains the treatment of choice for ROP recurrence in middle-income countries. Surgical outcomes for ROP stage 4A, 4B and 5 are similar worldwide. The incidence of ROP and ROP-related visual impairment continue to increase globally. Although telemedicine and artificial intelligence offer potential solutions to ROP screening in resource-limited areas, the current models require further optimization to reflect the global diversity of ROP patients. CONCLUSION: ROP screening and treatment paradigms vary widely based on country income group due to disparities in resources, limited access to care, and lack of universal guidelines.

The phenotypic and genetic links between body fat phenotypes and primary open-angle glaucoma (POAG) are unclear. We conducted a meta-analysis of relevant longitudinal epidemiological studies to evaluate the phenotypic link. To identify genetic links, we performed genetic correlation analysis and pleiotropy analysis of genome-wide association study summary statistics datasets of POAG, intraocular pressure (IOP), vertical cup-to-disc ratio, obesity, body mass index (BMI), and waist-to-hip ratio. In the meta-analysis, we first established that obese and underweight populations have a significantly higher risk of POAG using longitudinal data. We also discovered positive genetic correlations between POAG and BMI and obesity phenotypes. Finally, we identified over 20 genomic loci jointly associated with POAG/IOP and BMI. Among them, the genes loci CADM2, RP3-335N17.2, RP11-793K1.1, RPS17P5, and CASC20 showed the lowest false discovery rate. These findings support the connection between body fat phenotypes and POAG. The newly identified genomic loci and genes render further functional investigation.

Dominant missense pathogenic variants in cardiac myosin heavy chain cause hypertrophic cardiomyopathy (HCM), a currently incurable disorder that increases risk for stroke, heart failure and sudden cardiac death. In this study, we assessed two different genetic therapies-an adenine base editor (ABE8e) and a potent Cas9 nuclease delivered by AAV9-to prevent disease in mice carrying the heterozygous HCM pathogenic variant myosin R403Q. One dose of dual-AAV9 vectors, each carrying one half of RNA-guided ABE8e, corrected the pathogenic variant in ≥70% of ventricular cardiomyocytes and maintained durable, normal cardiac structure and function. An additional dose provided more editing in the atria but also increased bystander editing. AAV9 delivery of RNA-guided Cas9 nuclease effectively inactivated the pathogenic allele, albeit with dose-dependent toxicities, necessitating a narrow therapeutic window to maintain health. These preclinical studies demonstrate considerable potential for single-dose genetic therapies to correct or silence pathogenic variants and prevent the development of HCM.