Trends in Anti-Vascular Endothelial Growth Factor Original Medicare Part B Claims in the United States, 2014-2019.

PURPOSE: To characterize trends in use of and expenditure for the intravitreal injection of anti-vascular endothelial growth factor (anti-VEGF) agents aflibercept, ranibizumab, and bevacizumab among the population enrolled in Original Medicare from 2014 to 2019. METHODS: The Centers for Medicare and Medicaid Services Physician and Other Supplier Public Use File was used to extract Medicare Part B fee-for-service outpatient injection claims data submitted by ophthalmologists. Multivariable linear regression models were used to evaluate the association between reimbursement, ophthalmologist availability, and agent administration rate. RESULTS: Between 2014 and 2019, 17,588,995 intravitreal injection claims were filed by 4218 US ophthalmologists. Medicare costs for anti-VEGF injections increased from 2.51 B USD in 2014 to 4.02 B USD in 2019. Increased state-level ophthalmologist availability and incremental increases in average reimbursement amounts were found to be significantly associated with a 6.8-fold variation in 2019 overall anti-VEGF injection rates across states. CONCLUSIONS: Medicare injection rates and costs for anti-VEGF injections have both increased between 2014 and 2019, largely driven by increased aflibercept use. There is a significant association between ophthalmologist availability and anti-VEGF injection rate on the state level, suggesting access to care may contribute to the observed state-level disparities in intravitreal injection rates. Further characterization of factors contributing to the state-level variation in injection rates of individual anti-VEGF agents may help inform interventions promoting equitable access to and use of these drugs.

Open Globe Injuries From Garage Door Springs.

We describe seven patients who were attempting to repair their garage door when a spring dislodged at high velocity, resulting in open globe injury. All patients were seen at Massachusetts Eye and Ear between the years 2008 and 2023. Their final visual acuities ranged from 20/125 to no light perception. Open globe injury appears to be a risk of attempts to repair a garage door by people who are inexperienced in doing so. [Ophthalmic Surg Lasers Imaging Retina 2023;54:666-669.].

Structure-based network analysis predicts mutations associated with inherited retinal disease.

With continued advances in gene sequencing technologies comes the need to develop better tools to understand which mutations cause disease. Here we validate structure-based network analysis (SBNA)1,2 in well-studied human proteins and report results of using SBNA to identify critical amino acids that may cause retinal disease if subject to missense mutation. We computed SBNA scores for genes with high-quality structural data, starting with validating the method using 4 well-studied human disease-associated proteins. We then analyzed 47 inherited retinal disease (IRD) genes. We compared SBNA scores to phenotype data from the ClinVar database and found a significant difference between benign and pathogenic mutations with respect to network score. Finally, we applied this approach to 65 patients at Massachusetts Eye and Ear (MEE) who were diagnosed with IRD but for whom no genetic cause was found. Multivariable logistic regression models built using SBNA scores for IRD-associated genes successfully predicted pathogenicity of novel mutations, allowing us to identify likely causative disease variants in 37 patients with IRD from our clinic. In conclusion, SBNA can be meaningfully applied to human proteins and may help predict mutations causative of IRD.

Overlap of Genetic Loci for Central Serous Chorioretinopathy With Age-Related Macular Degeneration.

Importance: Central serous chorioretinopathy (CSC) is a serous maculopathy of unknown etiology. Two of 3 previously reported CSC genetic risk loci are also associated with AMD. Improved understanding of CSC genetics may broaden our understanding of this genetic overlap and unveil mechanisms in both diseases. Objective: To identify novel genetic risk factors for CSC and compare genetic risk factors for CSC and AMD. Design, Setting, and Participants: Using International Classification of Diseases, Ninth (ICD-9) and Tenth (ICD-10) Revision code-based inclusion and exclusion criteria, patients with CSC and controls were identified in both the FinnGen study and the Estonian Biobank (EstBB). Also included in a meta-analysis were previously reported patients with chronic CSC and controls. Data were analyzed from March 1 to September 31, 2022. Main Outcomes and Measures: Genome-wide association studies (GWASs) were performed in the biobank-based cohorts followed by a meta-analysis of all cohorts. The expression of genes prioritized by the polygenic priority score and nearest-gene methods were assessed in cultured choroidal endothelial cells and public ocular single-cell RNA sequencing data sets. The predictive utility of polygenic scores (PGSs) for CSC and AMD were evaluated in the FinnGen study. Results: A total of 1176 patients with CSC and 526 787 controls (312 162 female [59.3%]) were included in this analysis: 552 patients with CSC and 343 461 controls were identified in the FinnGen study, 103 patients with CSC and 178 573 controls were identified in the EstBB, and 521 patients with chronic CSC and 3577 controls were included in a meta-analysis. Two previously reported CSC risk loci were replicated (near CFH and GATA5) and 3 novel loci were identified (near CD34/46, NOTCH4, and PREX1). The CFH and NOTCH4 loci were associated with AMD but in the opposite direction. Prioritized genes showed increased expression in cultured choroidal endothelial cells compared with other genes in the loci (median [IQR] of log 2 [counts per million], 7.3 [0.6] vs 4.7 [3.7]; P = .004) and were differentially expressed in choroidal vascular endothelial cells in single-cell RNA sequencing data (mean [SD] fold change, 2.05 [0.38] compared with other cell types; P < 7.1 × 10-20). A PGS for AMD was predictive of reduced CSC risk (odds ratio, 0.76; 95% CI, 0.70-0.83 per +1 SD in AMD-PGS; P = 7.4 × 10-10). This association may have been mediated by loci containing complement genes. Conclusions and Relevance: In this 3-cohort genetic association study, 5 genetic risk loci for CSC were identified, highlighting a likely role for genes involved in choroidal vascular function and complement regulation. Results suggest that polygenic AMD risk was associated with reduced risk of CSC and that this genetic overlap was largely due to loci containing complement genes.

Effectiveness of a telemedicine program for triage and diagnosis of emergent ophthalmic conditions.

BACKGROUND: To study the utility of a teleophthalmology program to diagnose and triage common ophthalmic complaints presenting to an ophthalmic emergency room. METHODS: Prospective, observational study of 258 eyes of 129 patients presenting to the Massachusetts Eye and Ear Infirmary Emergency Ward (MEE EW) who completed a questionnaire to gather chief complaint (CC), history of present illness, and medical history. Anterior and posterior segment photographs were collected via iPhone 5 C camera and a Canon non-mydriatic fundus camera, respectively. Ophthalmic vital signs were collected. All information was reviewed remotely by three ophthalmologists; a diagnosis and urgency designation were recorded. The remote assessment was compared to gold standard in-person assessment. RESULTS: The 129 recruited patients collectively contributed 220 visual complaints, of which 121 (55%) were from females with mean age 56.5 years (range 24-89). Sensitivities and specificities for telemedical triage were as follows: eye pain (n = 56; sensitivity: 0.58, CI [0.41, 0.74]; specificity: 0.91, CI [0.80, 1]), eye redness (n = 54; 0.68, CI [0.50, 0.86]; 0.93, CI [0.84, 1]), blurry vision (n = 68; 0.73, CI [0.60, 0.86]; 0.91, CI [0.80, 1]), and eyelid complaints (n = 42; 0.67, CI [0.43, 0.91]; 0.96, CI [0.89, 1]). The remote diagnostic accuracies, as stratified by CC, were eye pain (27/56; 48.21%), eye redness: (32/54; 59.26%), blurry vision: (30/68; 44.11%), eyelid (24/42; 57.14%). CONCLUSIONS: Telemedical examination of emergent ophthalmic complaints consisting of a patient questionnaire, anterior segment and fundus photos, and ophthalmic vital signs, may be useful to reliably triage eye disease based on presenting complaint.

Two Cases of Cutibacterium acnes (C acnes) Endophthalmitis Manifesting With Unusual Epiretinal Deposits.

This article describes two cases of delayed-onset Cutibacterium acnes (C acnes) endophthalmitis 1 month after cataract surgery manifesting with unusual epiretinal deposits. Both patients were referred for persistent inflammation after cataract surgery. After failing to respond to a vitreous tap with injection of antibiotics, the patients underwent pars plana vitrectomy and in one of the cases partial posterior capsulectomy for a posterior capsular plaque. Intraoperatively, both cases were found to have unusual multifocal epiretinal deposits. The clinical presentations described here represent a highly unique manifestation of C acnes endophthalmitis distinct from the classic anterior segment findings. [Ophthalmic Surg Lasers Imaging Retina. 2022;53:164-167.].

Hypopyon and White Cataract Due to an Intraocular Helminth.

We describe a case of a 29-year-old man with a history of intravenous drug use and vague history of eye trauma who presented with a hypopyon and white cataract in the right eye. He underwent pars plana vitrectomy and lensectomy; his anterior chamber aspirate revealed a single helminth on calcofluor stain. We suspect that his helminth infection may be secondary to unsanitary eating and drinking practices. As overall hygiene and dietary habits have improved during the years, parasitic helminth infections are relatively rare in nonendemic areas, especially in the nonpediatric population. [Ophthalmic Surg Lasers Imaging Retina. 2022;53:168-171.].

Bacillary Layer Detachment Associated With Endogenous Fungal Endophthalmitis.

Purpose: To recognize the novel finding of a bacillary layer detachment (BALAD) secondary to endogenous fungal endophthalmitis. Methods: Chart review, literature review. Results: BALAD is a recently described condition in which the photoreceptor layer splits at the level of the inner segment myoid. We describe a case of BALAD associated with endogenous fungal endophthalmitis and subsequent development of choroidal neovascularization, although it is unclear if BALAD contributed to neovessel formation. Conclusions: BALAD is generally seen in the setting of inflammatory or infectious retinal diseases. This is the first report of BALAD secondary to endogenous fungal endophthalmitis.

SARS-CoV-2 RNA Detected in Vitreous Samples Obtained at Autopsy.

Purpose: This work aims to examine the vitreous of autopsy patients with COVID-19 for the presence of SARS-CoV-2 RNA. Methods: Four deceased patients with COVID-19 had an autopsy at Massachusetts General Hospital. Two control specimens were obtained from patients undergoing retinal detachment repair with negative preoperative polymerase chain reaction (PCR) testing for SARS-CoV-2 RNA. Vitreous specimens were obtained from autopsy patients with COVID-19 after povidone was placed on the ocular surface to decrease the risk of contamination of the vitreous specimen. SARS-CoV-2 RNA for gene N (nucleocapsid) was tested using reverse transcription-PCR. Results: SARS-CoV-2 RNA was detected in the vitreous of 2 of 4 autopsy patients who died from complications of COVID-19. Conclusions: SARS-CoV-2 RNA can penetrate into the vitreous of systemically infected patients, which might present risks to operating room personnel during ophthalmic surgical procedures.

Aflibercept for Retinopathy of Prematurity: A Systematic Review and Meta-Analysis.

BACKGROUND AND OBJECTIVE: To determine the effectiveness of aflibercept in retinopathy of prematurity (ROP). PATIENTS AND METHODS: We performed a systematic review and meta-analysis of proportions from the literature in PubMed and Cochrane Library using search terms related to the use of aflibercept in ROP. Studies in non-preterm infants or that did not use aflibercept as the initial treatment were excluded. Risk of bias was assessed by the ROBINS-I (Risk Of Bias in Non-randomized Studies of Interventions) tool. RESULTS: We identified six case series. Collectively, 218 eyes were treated with aflibercept for ROP. We found an average 97% (95% confidence interval [CI], 93% to 99%) regression rate with aflibercept and an average 16% (95% CI, 5% to 41%) recurrence rate. With the exception of one outlier study, these numbers are similar to previous reports using anti-vascular endothelial growth factor (VEGF) agents in ROP. CONCLUSIONS: Aflibercept holds promise for use in ROP and has been demonstrated to be efficacious in six case series. Randomized, controlled clinical trials appear warranted to compare aflibercept with other anti-VEGF agents. [Ophthalmic Surg Lasers Imaging. 2021;52:673-681.].

Structure-guided T cell vaccine design for SARS-CoV-2 variants and sarbecoviruses.

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants that escape convalescent and vaccine-induced antibody responses has renewed focus on the development of broadly protective T-cell-based vaccines. Here, we apply structure-based network analysis and assessments of HLA class I peptide stability to define mutationally constrained CD8+ T cell epitopes across the SARS-CoV-2 proteome. Highly networked residues are conserved temporally among circulating variants and sarbecoviruses and disproportionately impair spike pseudotyped lentivirus infectivity when mutated. Evaluation of HLA class I stabilizing activity for 18 globally prevalent alleles identifies CD8+ T cell epitopes within highly networked regions with limited mutational frequencies in circulating SARS-CoV-2 variants and deep-sequenced primary isolates. Moreover, these epitopes elicit demonstrable CD8+ T cell reactivity in convalescent individuals but reduced recognition in recipients of mRNA-based vaccines. These data thereby elucidate key mutationally constrained regions and immunogenic epitopes in the SARS-CoV-2 proteome for a global T-cell-based vaccine against emerging variants and SARS-like coronaviruses.

HLA class-I-peptide stability mediates CD8+ T cell immunodominance hierarchies and facilitates HLA-associated immune control of HIV.

Defining factors that govern CD8+ T cell immunodominance is critical for the rational design of vaccines for viral pathogens. Here, we assess the contribution of human leukocyte antigen (HLA) class-I-peptide stability for 186 optimal HIV epitopes across 18 HLA alleles using transporter associated with antigen processing (TAP)-deficient mono-allelic HLA-expressing cell lines. We find that immunodominant HIV epitopes increase surface stabilization of HLA class-I molecules in comparison to subdominant epitopes. HLA class-I-peptide stability is also strongly correlated with overall immunodominance hierarchies, particularly for epitopes from high-abundance proteins (e.g., Gag). Moreover, HLA alleles associated with HIV protection are preferentially stabilized by epitopes derived from topologically important viral regions at a greater frequency than neutral and risk alleles. These findings indicate that relative stabilization of HLA class-I is a key factor for CD8+ T cell epitope immunodominance hierarchies, with implications for HIV control and the design of T-cell-based vaccines.

Single-cell RNA sequencing: An overview for the ophthalmologist.

Understanding the molecular composition of pathogenic tissues is a critical step in understanding the pathophysiology of disease and designing therapeutics. First described in 2009, single cell RNA sequencing (scRNAseq) is a methodology whereby thousands of cells are simultaneously isolated into individual micro-environments that can be altered experimentally and the genome-wide RNA expression of each cell is captured. It has undergone significant technological improvement over the last decade and gained tremendous popularity. scRNAseq is an improvement over prior pooled RNA analyses which cannot identify the cellular composition and heterogeneity of a tissue of interest. This new approach offers new opportunity for new discovery, as tissue samples can now be sub-categorized into groups of cell types based on genome-wide gene expression in an unbiased fashion. As ophthalmologists, we are uniquely positioned to obtain pathologic samples from the eye for further study. ScRNAseq has already been applied in ophthalmology to characterize retinal tissue, and it may offer the key to understanding various pathological processes in the future.

Site of Origin of the Ophthalmic Artery Influences the Risk for Retinal Versus Cerebral Embolic Events.

BACKGROUND: Embolic events leading to retinal ischemia or cerebral ischemia share common risk factors; however, it has been well documented that the rate of concurrent cerebral infarction is higher in patients with a history of transient ischemic attack (TIA) than in those with monocular vision loss (MVL) due to retinal ischemia. Despite the fact that emboli to the ophthalmic artery (OA) and middle cerebral artery share the internal carotid artery (ICA) as a common origin or transit for emboli, the asymmetry in their final destination has not been fully explained. We hypothesize that the anatomic location of the OA takeoff from the ICA may contribute to the differential flow of small emboli to the retinal circulation vs the cerebral circulation. METHODS: We report a retrospective, comparative, case-control study on 28 patients with retinal ischemia and 26 patients with TIA or cerebral infarction caused by embolic events. All subjects underwent either computed tomography angiography or MRA. The location of the ipsilateral OA origin off the ICA was then graded in a blinded fashion and compared between cohorts. Vascular risk factors were collected for all patients, including age, sex, hypertension, hyperlipidemia, arrhythmia, diabetes, coronary artery disease, and smoking. RESULTS: We find that in patients with retinal ischemia of embolic etiology, the ipsilateral OA takeoff from the ICA is more proximal than in patients with cerebral infarcts or TIA (P = 0.0002). We found no statistically significant differences in demographic, vascular, or systemic risk factors. CONCLUSIONS: We find that the mean anatomical location of the OA takeoff from the ICA is significantly more proximal in patients with MVL due to retinal ischemia compared with patients with TIA or cerebral ischemia. This finding contributes significantly to our understanding of a long observed but poorly understood phenomenon that patients with MVL are less likely to have concurrent cerebral ischemia than are patients with TIA.

Factors Associated With Increased Risk of Serious Ocular Injury in the Setting of Orbital Fracture.

Importance: Orbital fractures are common in ocular trauma, and there is a need to develop predictive tools to estimate risk of concurrent ocular injury. Objective: To identify clinical and radiographic features that are associated with increased risk of substantial ocular injury in the setting of orbital fracture. Design, Setting, and Participants: Retrospective consecutive case series of patients who sustained orbital fractures between 2012 and 2018. Examinations were done at 1 of 2 level 1 trauma centers in the emergency or inpatient setting. A total of 430 consecutive patients (500 eyes) between 2012 and 2017 met inclusion criteria for the training sample. After building a predictive model, 88 additional consecutive patients (97 eyes) between 2017 and 2018 who met inclusion criteria were collected as a test sample. Main Outcomes and Measures: The primary outcome measure was substantial ocular injury distinct from orbital fracture. Results: The mean age of our patient population was 53.5 years (range, 16-100 years). The overall rate of substantial ocular injury was 20.4%, and the rate of injury requiring immediate ophthalmic attention was 14.4%. Five variables were found to be associated with increased risk of substantial ocular injury: blunt trauma with a foreign object (odds ratio [OR], 19.4; 95% CI, 6.3-64.1; P < .001), inability to count fingers (OR, 10.1; 95% CI, 2.8-41.1; P = .002), roof fracture (OR, 9.1; 95% CI, 2.8-30.0; P = .002), diplopia on primary gaze (OR, 6.7; 95% CI, 1.7-25.1; P = .003), and conjunctival hemorrhage or chemosis (OR, 4.2; 95% CI, 2.2-8.5; P < .001). The results were translated into a bedside tool that was tested in an independent group of eyes (n = 97) and found to be associated with substantial ocular injury with a 95% sensitivity (95% CI, 77.2-99.9), 40% specificity (95% CI, 28.9-52.0), 31.8% positive predictive value (95% CI, 27.5-36.5), and 96.8% negative predictive value (95% CI, 81.3-99.5). Conclusions and Relevance: A minority of patients with an orbital fracture had a substantial ocular injury. Certain radiographic and clinical findings were associated with substantial ocular injury. Testing of the algorithm in prospective longitudinal settings appears warranted.

Traumatic Retinal Detachment in Patients with Self-Injurious Behavior: An International Multicenter Study.

PURPOSE: To describe the clinical characteristics, surgical outcomes, and management recommendations in patients with traumatic rhegmatogenous retinal detachment (RRD) resulting from self-injurious behavior (SIB). DESIGN: International, multicenter, retrospective, interventional case series. PARTICIPANTS: Patients with SIB from 23 centers with RRD in at least 1 eye. METHODS: Clinical histories, preoperative assessment, surgical details, postoperative management, behavioral intervention, and follow-up examination findings were reviewed. MAIN OUTCOME MEASURES: The rate of single-surgery anatomic success (SSAS) was the primary outcome. Other outcomes included new RRD in formerly attached eyes, final retinal reattachment, and final visual acuity. RESULTS: One hundred seven eyes with RRDs were included from 78 patients. Fifty-four percent of patients had bilateral RRD or phthisis bulbi in the fellow eye at final follow-up. The most common systemic diagnoses were autism spectrum disorder (35.9%) and trisomy 21 (21.8%) and the most common behavior was face hitting (74.4%). The average follow-up time was 3.3 ± 2.8 years, and surgical outcomes for operable eyes were restricted to patients with at least 3 months of follow-up (81 eyes). Primary initial surgeries were vitrectomy alone (33.3%), primary scleral buckle (SB; 26.9%), and vitrectomy with SB (39.7%), and 5 prophylactic SBs were placed. Twenty-three eyes (21.5%) with RRDs were inoperable. The SSAS was 23.1% without tamponade (37.2% if including silicone oil), and final reattachment was attained in 80% (36.3% without silicone oil tamponade). Funnel-configured RRD (P = 0.006) and the presence of grade C proliferative vitreoretinopathy (P = 0.002) correlated with re-detachment. The use of an SB predicted the final attachment rate during the initial surgery (P = 0.005) or at any surgery (P = 0.008. These associations held if restricting to 64 patients with ≥12 months followup. Anatomic reattachment correlated with better visual acuity (P < 0.001). CONCLUSIONS: RRD resulting from SIB poses therapeutic challenges because of limited patient cooperation, bilateral involvement, chronicity, and ongoing trauma in vulnerable and neglected patients. The surgical success rates were some of the lowest in the modern retinal detachment literature. The use of an SB may result in better outcomes, and visual function can be restored in some patients.