Gene therapy for age-related macular degeneration: potential, feasibility, and pitfalls.

PURPOSE OF REVIEW: The landscape for age-related macular degeneration (AMD) is rapidly changing with addition of biosimilars and now United States Food and Drug Administration (FDA) approved nonneovascular AMD (nnAMD) treatment options. These developments have inspired a burgeoning pipeline of gene therapy approaches focused on similar antivascular endothelial growth factors (VEGF) and complement related pathways. Historic and more recent setbacks in the gene therapy pipeline, including intraocular inflammatory reactions, have raised important concerns for adverse events related to AMD therapeutics both for gene and nongene approaches. The specific clinical profile of these therapeutics approaching later stage clinical trials are complex and under active investigation; however, these options hold promise to disrupt the current landscape and change management paradigms for one of the leading causes of vision loss worldwide. RECENT FINDINGS: This review covers current gene therapy approaches for neovascular AMD (nAMD) and nnAMD. Intravitreal, suprachoroidal, and subretinal delivery routes are discussed with attention to technical procedure, capabilities for transgene delivery to target tissue, immunogenicity, and collateral effects. Suprachoroidal delivery is an emerging approach which may bridge some of the practical drawbacks for intravitreal and subretinal methods, though with less elaborated immunologic profile. In parallel to delivery modification, viral vectors have been cultivated to target specific cells, with promising enhancements in adeno-associated viral (AAV) vectors and persistent interest in alternate viral and nonviral delivery vectors. Ongoing questions such as steroid or immunosuppressive regimen and economic considerations from a payer and societal perspective are discussed. SUMMARY: The present review discusses emerging gene therapy options which could foster new, more durable nAMD and nnAMD therapeutics. These options will need refinement with regards to route, vector, and dosage, and specialists must decipher the specific clinical risk benefit profile for individual patients. Ongoing concerns for immunogenicity or dosage related adverse events could stifle progress, while further vector development and refined delivery techniques have the potential to change the safety and efficacy of currently options in the pipeline.

Q Fever-Associated Chorioretinitis.

Coxiella burnetii is the causative agent in Q fever, a zoonotic disease. Ocular manifestations of this disease are extremely rare and have been infrequently reported. In this report, we describe a rare case of chorioretinitis in a patient incompletely treated for Q fever. We highlight the unique ocular manifestation with multimodal imaging, and the importance of a thorough history and prompt and correct treatment of the disease with systemic therapy. [Ophthalmic Surg Lasers Imaging Retina 2024;55:412-414.].

Ophthalmology Workforce Projections in the United States, 2020 to 2035.

PURPOSE: To analyze ophthalmology workforce supply and demand projections from 2020 to 2035. DESIGN: Observational cohort study using data from the National Center for Health Workforce Analysis (NCHWA). METHODS: Data accessed from the Department of Health and Human Services, Health Resources and Services Administration (HRSA) website were compiled to analyze the workforce supply and demand projections for ophthalmologists from 2020 to 2035. MAIN OUTCOME MEASURES: Projected workforce adequacy over time. RESULTS: From 2020 to 2035, the total ophthalmology supply is projected to decrease by 2650 full-time equivalent (FTE) ophthalmologists (12% decline) and total demand is projected to increase by 5150 FTE ophthalmologists (24% increase), representing a supply and demand mismatch of 30% workforce inadequacy. The level of projected adequacy was markedly different based on rurality by year 2035 with 77% workforce adequacy versus 29% workforce adequacy in metro and nonmetro geographies, respectively. By year 2035, ophthalmology is projected to have the second worst rate of workforce adequacy (70%) of 38 medical and surgical specialties studied. CONCLUSIONS: The HRSA's Health Workforce Simulation Model forecasts a sizeable shortage of ophthalmology supply relative to demand by the year 2035, with substantial geographic disparities. Ophthalmology is one of the medical specialties with the lowest rate of projected workforce adequacy by 2035. Further dedicated workforce supply and demand research for ophthalmology and allied professionals is needed to validate these projections, which may have significant future implications for patients and providers. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Comparison of Incremental Costs and Medicare Reimbursement for Simple vs Complex Cataract Surgery Using Time-Driven Activity-Based Costing.

Importance: Cataract surgery is one of the most commonly performed surgeries across medicine and an integral part of ophthalmologic care. Complex cataract surgery requires more time and resources than simple cataract surgery, yet it remains unclear whether the incremental reimbursement for complex cataract surgery, compared with simple cataract surgery, offsets the increased costs. Objective: To measure the difference in day-of-surgery costs and net earnings between simple and complex cataract surgery. Design, Setting, and Participants: This study is an economic analysis at a single academic institution using time-driven activity-based costing methodology to determine the operative-day costs of simple and complex cataract surgery. Process flow mapping was used to define the operative episode limited to the day of surgery. Simple and complex cataract surgery cases (Current Procedural Terminology codes 66984 and 66982, respectively) at the University of Michigan Kellogg Eye Center from 2017 to 2021 were included in the analysis. Time estimates were obtained using an internal anesthesia record system. Financial estimates were obtained using a mix of internal sources and prior literature. Supply costs were obtained from the electronic health record. Main Outcomes and Measures: Difference in day-of-surgery costs and net earnings. Results: A total of 16 092 cataract surgeries were included, 13 904 simple and 2188 complex. Time-based day-of-surgery costs for simple and complex cataract surgery were $1486.24 and $2205.83, respectively, with a mean difference of $719.59 (95% CI, $684.09-$755.09; P < .001). Complex cataract surgery required $158.26 more for costs of supplies and materials (95% CI, $117.00-$199.60; P < .001). The total difference in day-of-surgery costs between complex and simple cataract surgery was $877.85. Incremental reimbursement for complex cataract surgery was $231.01; therefore, complex cataract surgery had a negative earnings difference of $646.84 compared with simple cataract surgery. Conclusions and Relevance: This economic analysis suggests that the incremental reimbursement for complex cataract surgery undervalues the resource costs required for the procedure, failing to cover increased costs and accounting for less than 2 minutes of increased operating time. These findings may affect ophthalmologist practice patterns and access to care for certain patients, which may ultimately justify increasing cataract surgery reimbursement.

Implications of the presence of private equity in ophthalmology: an academic perspective.

PURPOSE OF REVIEW: Private equity acquisitions of ophthalmology private practices have been steadily increasing over the past decade with far-reaching implications. Ophthalmology departments at academic medical centers are not insulated from the impact of this trend. RECENT FINDINGS: The limited data on this subject in the ophthalmology literature identify the growing number of practice acquisitions. However, the lack of transparency obfuscates a clear understanding of the effect on patients and practice patterns. SUMMARY: Leaders at academic medical centers need to be aware of surrounding practice consolidation because of private equity as this could affect revenue streams and patient referral patterns, accelerating expansion. Trainees are entering an uncertain job marketplace that may create a compelling argument to practice in an academic medical center ophthalmology department.

Potential Cost Savings Associated with a Multiuse Preoperative and Preinjection Eyedrop Protocol.

PURPOSE: To calculate the cost savings associated with a multiuse preoperative and preinjection eyedrop protocol. DESIGN: Economic analysis. PARTICIPANTS: Adults undergoing ophthalmic surgical procedures requiring preoperative dilation and intravitreal injections. METHODS: Economic modeling with scenario analysis was used to derive the value for cost savings secondary to a protocol in which perioperative mydriatic eyedrop bottles are used across multiple patients versus the current protocol in which drop bottles are wasted after single-patient use. Similar analyses were performed for a multiuse povidone-iodine protocol for intravitreal injections. Sensitivity analyses were used to test baseline model assumptions with varying degrees of waste and patient volume. RESULTS: The multiuse mydriatic protocol allowed for a 97.1% reduction in the number of eyedrop bottles required for the single-use protocol (1037 bottles vs. 35 850 bottles). This led to an estimated 5-year cost savings of approximately $240 000 (nominal) per institution (performing an average of 1434 cases/year) in the base case. This savings varied minimally in sensitivity analyses accounting for practical limitations (loss, expiration, or contamination) of multiuse containers, with savings of 97.54% to 95.00% for excess supply ranges from 0% to 100% in the multiuse protocol. Likewise, the cost savings varied minimally in sensitivity analyses for eyedrop sizes, with savings of 99.23% to 96.69% for mydriatic eyedrop sizes of 15 µl per drop to 65 µl per drop, respectively, in the multiuse protocol. Over a 5-year period, for povidone-iodine drops before performing intravitreal injection, the multiuse protocol required 153 bottles compared with 41 954 bottles (99.6% reduction) for the current single-use protocol, resulting in a nominal cost savings of $41 801, which varied minimally in sensitivity analyses. CONCLUSIONS: Multiuse perioperative mydriatic eyedrops are a viable option for cost and environmental waste reduction for ophthalmologic procedures and surgeries requiring dilation. Likewise, multiuse povidone-iodine may allow for large relative cost reduction for in-office procedures. The total potential savings over 5 years was estimated at more than $280 000 before adjusting for inflation.

Annulus-shaped I-125 plaque brachytherapy for conjunctival melanoma.

Purpose: To report successful ring-shaped iodine-125 plaque brachytherapy for conjunctival melanoma. Observations: Eye Physics (EP) plaque brachytherapy, designed with Plaque Simulator software, proved to be an effective treatment modality with some corneal irritation and no recurrence at 12-months post radiation. Conclusion and importance: Management of conjunctival melanoma is complicated by the lack of gold standard adjuvant treatments. I-125 EP plaque brachytherapy represents a viable option for these malignancies. Specifically, ring-shaped plaque geometries allow for targeted radiotherapy.

Health Care Price Transparency in Ophthalmology.

IMPORTANCE: Health care price transparency legislation is intended to reduce the ambiguity of hospital charges and the resultant financial stress faced by patients. OBJECTIVE: To evaluate the availability, usability, and variability of standard reported prices for ophthalmologic procedures at academic hospitals. DESIGN, SETTING, AND PARTICIPANTS: In this multicenter economic evaluation study, publicly available price transparency web pages from Association of American Medical Colleges affiliate hospitals were parsed for standard charges and usability metrics. Price transparency data were collected from hospital web pages that met the inclusion criteria. Geographic practice cost indices for work, practice expense, and malpractice were sourced from the Centers for Medicare & Medicaid Services. Data were sourced from February 1 to April 30, 2021. Multiple regression was used to study the geographic influence on standard charges and assess the correlation between standard charges. MAIN OUTCOMES AND MEASURES: Availability and variability of standard prices for Current Procedural Terminology (CPT) codes 66984 (removal of cataract with insertion of lens) and 66821 (removal of recurring cataract in lens capsule using laser). RESULTS: Of 247 hospitals included, 191 (77.3%) provided consumer-friendly shoppable services, most commonly in the form of a price estimator or online tool. For CPT code 66984, 102 hospital (53.4%) provided discount cash pay estimates with a mean (SD) price of $7818.86 ($5407.91). For CPT code 66821, 71 hospital (37.2%) provided discount cash pay estimates with a mean (SD) price of $2041.72 ($2106.44). The top quartile of hospitals, prices wise, listed included prices higher than $10 400 for CPT code 66984 and $2324 for CPT code 66821. Usability issues were noted for 36 hospitals (18.8%), including requirements for personal information or web page navigability barriers. Multiple regression analysis found minimal explanatory value for geographic practice cost indices for cash discount prices for CPT codes 66984 (adjusted R2 = 0.54; 95% CI, 0.41-0.67; P < .001) and 66821 (adjusted R2 = 0.64; 95% CI, 0.51-0.77; P < .001). CONCLUSIONS AND RELEVANCE: Despite recent legislature that codified price transparency requirements, some current standard charges remain ambiguous, with substantial interhospital variability not explained by geographic variability in costs. Given the potential for ambiguous pricing to burden vulnerable, uninsured patients, additional legislation might consider allowing hospitals to defer price estimates or rigorously define standards for actionable cash discount percentages with provisions for displaying relevant benchmark prices.

Chorioretinal Biopsy-Proven Ocular Sarcoidosis in a Patient with a History of B-Cell Lymphoma.

The purpose of this report is to describe biopsy-proven ocular sarcoidosis (OS) in a 67-year-old patient with a history of sarcoidosis and diffuse large B-cell lymphoma (DLBCL). Nonspecific posterior chorioretinal lesions in a patient with prior malignancy necessitated chorioretinal biopsy to rule out metastatic lymphoma. The association between sarcoidosis and malignancy remains unclear and can complicate management of similar patients with nonspecific posterior segment findings. Chorioretinal biopsy may, therefore, be required to rule out malignancy in patients with a leading history.

Correlation Between Ophthalmology Market Saturation and Medicare Utilization Rates.

PURPOSE: To characterize usage of ophthalmologic services by Medicare Fee-For-Service (FFS) beneficiaries relative to geography-specific market saturation, demographics, and contextual factors DESIGN: Cross-sectional study METHODS: Data sets from Centers for Medicare & Medicaid Services, US Census Bureau, US Department of Agriculture, and Housing and Urban Development, were used to calculate county- and state-level ophthalmologic service usage, market saturation, and demographic characteristics. Negative binomial regression models were used to evaluate the association between results and demographic or population-specific variables. RESULTS: Ophthalmologic service usage ranged from 58.2% to 15.2%, whereas saturation ranged from 21,763 to 91.4 FFS beneficiaries per registered ophthalmologist. Usage was significantly associated with demographic characteristics in each geography: lower proportion of African American (P = .009), Hispanic (P < .001), and other race beneficiaries (P < .001), relative to white beneficiaries; a higher proportion of female (P < .001) relative to male; a higher proportion of adults having completed an associate degree or some college (P = .001), or holding a bachelor's degree or higher (P < .001), relative to a high school diploma; a lower proportion of adults in each geography experiencing poverty (P = .009), geographies with lower Multidimensional Deprivation Index (P < .001); a higher urban-influence code (P < .001). There was no significant correlation between the usage of ophthalmologic services and the geographic market saturation of ophthalmologists (Spearman rho, -0.030, P = .227). CONCLUSIONS AND RELEVANCE: Ophthalmologic service usage is significantly influenced by population demographics; however, increased provider density alone appears insufficient to promote the usage of eye care services.

Racial/Ethnic Disparities in Ophthalmology Clinical Trials Resulting in US Food and Drug Administration Drug Approvals From 2000 to 2020.

IMPORTANCE: Diverse, representative enrollment in pivotal clinical trials is vital to sufficiently power subgroup analyses and ensure equity and validity of trial results. OBJECTIVE: To evaluate the racial/ethnic representation, trends, and disparities in clinical trials leading to US Food and Drug Administration (FDA) ophthalmology drug approvals from 2000 to 2020. DESIGN, SETTING, AND PARTICIPANTS: This cohort study used data from participants in clinical trials of drugs for neovascular age-related macular degeneration (AMD), open-angle glaucoma (OAG), and expanded indications for diabetic retinopathy (DR) from January 1, 2000, to December 31, 2020. Trial data were sourced from FDA reviews, ClinicalTrials.gov, and relevant linked studies. National expected racial/ethnic proportions were sourced from public National Eye Institute prevalence data as well as published rates scaled using US Census Bureau data. MAIN OUTCOMES AND MEASURES: The primary outcome measures were the distribution of and change over time in the racial/ethnic proportion of participants in clinical trials leading to FDA approval of drugs for AMD, OAG, and DR. RESULTS: During the 20-year period, 31 clinical trials were identified for 13 medications with 18 410 participants. The distribution of trial participants was different from the expected trial distribution for most approvals with regard to race/ethnicity (12 drugs) and sex (10 drugs). Compared with the first decade (2000-2010), trials conducted in the second decade (2011-2020) showed increases in enrollment of Asian (odds ratio [OR], 2.30; 95% CI, 1.97-2.68; P < .001) and Hispanic or Latinx participants (OR, 1.74; 95% CI, 1.49-2.03; P < .001) for AMD, Asian participants (OR, 2.21; 95% CI, 1.46-3.42; P < .001) for DR, and Black (OR, 1.60; 95% CI, 1.43-1.78; P < .001) and Hispanic or Latinx participants (OR, 10.31; 95% CI, 8.05-13.35; P < .001) for OAG. There was a decrease in Black participants in DR trials (OR, 0.58; 95% CI, 0.42-0.79; P < .001). Based on these trends, the enrollment incidence ratio is expected to worsen by 2050, with overrepresentation of white participants vs underrepresentation of Black and Hispanic or Latinx participants in trials of drugs for AMD (1.08 vs 0.04 vs 0.77), DR (1.83 vs 0.87 vs 0.59), and OAG (1.62 vs 0.90 vs 0.37). CONCLUSIONS AND RELEVANCE: In this cohort study, Black, Hispanic or Latinx, and other non-White participants were underrepresented in clinical trials leading to FDA ophthalmology drug approvals compared with the expected disease burden and racial/ethnic distribution in the US. Although there was meaningful improvement from 2000 to 2020, further efforts to increase minority enrollment in clinical trials seem to be warranted.

Cost Analysis of Routine Vitrectomy Surgery.

PURPOSE: To use electronic health record (EHR) time logs to calculate the complete cost profiles of routine pars plana vitrectomy surgery. DESIGN: Economic analysis. PARTICIPANTS: Patients undergoing elective vitrectomy procedures (Current Procedural Terminology codes 67040, 67041, and 67042) at Vanderbilt University Medical Center in fiscal year 2019. METHODS: Process flow mapping for routine vitrectomy surgery was used to define the operative episode. De-identified time logs were sourced from an internal perioperative data warehouse to calculate procedure-level durations. The costs of materials and overhead were calculated from internal financial management software. Costs per minute for space, equipment, and personnel were based on internal figures. These inputs were used for a time-driven activity-based costing (TDABC) analysis. MAIN OUTCOME MEASURES: Complete cost profile of routine pars plana vitrectomy surgery. RESULTS: Cost analysis of routine vitrectomy surgery resulted in a total cost of $7169.79 per patient, which was $2053.85 more than the maximum Medicare reimbursement for the equivalent episode, $5115.93. Vitrectomy cases do not break even unless the case duration is fewer than 26.81 minutes, overhead is reduced by 53.78%, or reimbursement is increased by 40.15%. Reimbursement does not compensate for variable costs alone for cases lasting longer than 55.09 minutes. In the cohort used here, 68% of cases are completely unprofitable, with increasing losses directly proportional to the length of the case. CONCLUSIONS: This analysis showed that true costs for routine vitrectomy procedures are significantly more than the maximum allowable Medicare reimbursement. Academic ophthalmology departments may benefit from more accurate costing approaches using existing EHR data. These approaches may be informative for policy discussion regarding appropriate reimbursement.

Value of Anti-Vascular Endothelial Growth Factor Gene Therapy for Neovascular Age-Related Macular Degeneration.

PURPOSE: To use discounted cash flow (DCF) analysis to estimate the value creation associated with anti-vascular endothelial growth factor (VEGF) genetic therapy for neovascular age-related macular degeneration (nAMD). DESIGN: Economic analysis. PARTICIPANTS: Adults undergoing serial intravitreal anti-VEGF injections in 1 eye for nAMD. METHODS: Discounted cash flow modeling with scenario analysis was used to derive a present value for a 1-time alternative treatment to lifelong anti-VEGF treatment for nAMD. Multiple sensitivity analyses were performed on the basis of patient age at time of first injection and frequency interval of intravitreal injection. MAIN OUTCOME MEASURES: Present values of DCF and scenario analyses. RESULTS: Discounted cash flow analysis of intravitreal anti-VEGF treatment for nAMD resulted in a base-case valuation of $208 420.61, $219 093.31, and $17 379.41 for a 1-time alternative treatment to aflibercept, ranibizumab, and bevacizumab, respectively. This figure covaried significantly with anti-VEGF agent according to the patient age at first injection ($78 323.19-$292 449.87) and frequency of injections ($148 422.91-$388 096.81). In addition, for bevacizumab, variability was driven by the hypothetical degree of clinical superiority of 1-time therapy to repeated intravitreal injections due to reduction in adverse events ($17 379.41-$18 250.79) or reduction in direct or indirect costs associated with age-related macular degeneration ($17 379.41-$657 406.55). CONCLUSIONS: Anti-VEGF gene therapy approaches can create significantly different value propositions based on the agent modeled, patient age at first injection, frequency of injections, and clinical profile of the medication. Although the use of aflibercept or ranibizumab as a comparative cost metric is logical from a bioequivalence perspective, the disparity in medication costs should not be the primary value driver in applied models. Instead, bevacizumab should be the base case ($17 379.41), with additional value driven from an improvement in quality of life through clinical superiority. A reduction in direct and indirect costs can be used to approximate the value from maintained visual acuity, which is elaborated in the DCF analysis approach described in this article. This model can serve as a basis for assessing the price ceiling of myriad gene therapy approaches. Given the high present values for these therapeutics, innovative costing and reimbursement mechanisms should be further explored, with contingencies for sustained efficacy.

An amelanotic choroidal melanoma arising in a young man with tattoo-associated sarcoidosis.

PURPOSE: To describe a patient with an amelanotic choroidal melanoma, originally misdiagnosed as a choroidal granuloma, following his systemic diagnosis of tattoo-associated sarcoidosis. OBSERVATIONS: The amelanotic choroidal tumor, suspected to be a granuloma, failed initial steroid treatment. Full-thickness chorioretinal biopsy demonstrated histologic presence of uveal melanoma and tumor genetics via GEP analysis demonstrated a PRAME negative, Class 1A lesion. The amelanotic choroidal melanoma was treated successfully with I-125 plaque brachytherapy. CONCLUSION AND IMPORTANCE: Despite a systemic diagnosis which predisposes a patient to uveal granuloma, amelanotic choroidal melanomas can still occur and should be considered. The association of uveal melanoma and sarcoidosis remains rare and of unclear significance.

In a randomized trial in prostate cancer patients, dietary protein restriction modifies markers of leptin and insulin signaling in plasma extracellular vesicles.

Obesity, metabolic syndrome, and hyperleptinemia are associated with aging and age-associated diseases including prostate cancer. One experimental approach to inhibit tumor growth is to reduce dietary protein intake and hence levels of circulating amino acids. Dietary protein restriction (PR) increases insulin sensitivity and suppresses prostate cancer cell tumor growth in animal models, providing a rationale for clinical trials. We sought to demonstrate that biomarkers derived from plasma extracellular vesicles (EVs) reflect systemic leptin and insulin signaling and respond to dietary interventions. We studied plasma samples from men with prostate cancer awaiting prostatectomy who participated in a randomized trial of one month of PR or control diet. We found increased levels of leptin receptor in the PR group in total plasma EVs and in a subpopulation of plasma EVs expressing the neuronal marker L1CAM. Protein restriction also shifted the phosphorylation status of the insulin receptor signal transducer protein IRS1 in L1CAM+ EVs in a manner suggestive of improved insulin sensitivity. Dietary PR modifies indicators of leptin and insulin signaling in circulating EVs. These findings are consistent with improved insulin and leptin sensitivity in response to PR and open a new window for following physiologic responses to dietary interventions in humans.

Plasma Extracellular Vesicles Enriched for Neuronal Origin: A Potential Window into Brain Pathologic Processes.

Our team has been a pioneer in harvesting extracellular vesicles (EVs) enriched for neuronal origin from peripheral blood and using them as a biomarker discovery platform for neurological disorders. This methodology has demonstrated excellent diagnostic and predictive performance for Alzheimer's and other neurodegenerative diseases in multiple studies, providing a strong proof of concept for this approach. Here, we describe our methodology in detail and offer further evidence that isolated EVs are enriched for neuronal origin. In addition, we present evidence that EVs enriched for neuronal origin represent a more sensitive and accurate base for biomarkers than plasma, serum, or non-enriched total plasma EVs. Finally, we proceed to investigate the protein content of EVs enriched for neuronal origin and compare it with other relevant enriched and non-enriched populations of plasma EVs. Neuronal-origin enriched plasma EVs contain higher levels of signaling molecules of great interest for cellular metabolism, survival, and repair, which may be useful as biomarkers and to follow response to therapeutic interventions in a mechanism-specific manner.