Elevated tumor necrosis factor alpha and vascular endothelial growth factor in intermediate age-related macular degeneration and geographic atrophy.

Introduction: Tumor necrosis factor alpha (TNF-α) is an inflammatory cytokine implicated in pathological changes to the retinal pigment epithelium that are similar to changes in geographic atrophy (GA), an advanced form of age related macular degeneration (AMD). TNF-α also modulates expression of other cytokines including vascular endothelial growth factor (VEGF), leading to choroidal atrophy in models of AMD. The purpose of this study was to investigate systemic TNF-α and VEGF in patients with GA and intermediate AMD (iAMD) compared to controls without AMD. Methods: We examined plasma levels of TNF-α and VEGF in patients with GA, iAMD, and controls without AMD from the University of Colorado AMD registry (2014 to 2021). Cases and controls were characterized by multimodal imaging. TNF-α and VEGF were measured via multiplex immunoassay and data were analyzed using a non-parametric rank based linear regression model fit to plasma biomarkers. Results: There were 97 GA, 199 iAMD patients and 139 controls. TNF-α was significantly increased in GA (Median:9.9pg/ml, IQR:7.3-11.8) compared to iAMD (Median:7.4, IQR:5.3-9.1) and in both GA and iAMD compared to controls (Median:6.4, IQR:5.3-7.8), p<0.01 for all comparisons. VEGF was significantly increased in iAMD (Median:8.9, IQR:4.8-14.3) compared to controls (Median:7.7, IQR:4.6-11.1), p<0.01. There was a significant positive correlation between TNF-α and VEGF in GA (0.46, p<0.01), and iAMD (0.20, p=0.01) with no significant interaction between TNF-α and VEGF in any group. Discussion: These findings suggest TNF-α and VEGF may contribute to systemic inflammatory processes associated with iAMD and GA. TNF-α and VEGF may function as systemic biomarkers for disease development.

Differences in imaging biomarkers between patients with intermediate and advanced non-neovascular age-related macular degeneration (AMD) in the University of Colorado AMD registry.

PURPOSE: To quantify and compare the different prevalence rates of specific retinal imaging biomarkers in patients with intermediate AMD (iAMD) and advanced non-neovascular AMD (nnAMD). METHODS: Cross-sectional study of patients with iAMD and advanced nnAMD. Imaging studies were reviewed for qualitative imaging biomarkers. Choroidal thickness measurements were obtained subfoveally and in 1000 um and 2000 um intervals away from the fovea. The Chi-squared test and Fisher's exact test were used to compare rates of imaging biomarkers among the two cohorts. P-value of <0.05 was considered significant. RESULTS: 376 eyes of 197 patients with iAMD and 187 eyes of 97 patients with advanced nnAMD were recruited. There were significantly lower rates of the following imaging biomarkers in the iAMD compared with the advanced nnAMD cohorts: soft drusen (66.0% vs. 84.2%, p = 0.001), calcified drusen (4.3% vs. 40.0%, p < 0.0001), RPD (26.2% vs. 53.3%, p < 0.0001), ORT (0.5% vs. 46.9%, p < 0.0001), RP (1.1% vs. 46.3%, p < 0.0001), pigment migration (53.2% vs. 100%, p < 0.0001), and iRORA (17.9% vs. 80.2%, p < 0.0001). In the iAMD cohort, choroidal thickness was significantly greater at 188 µm (SD: 60) and 194 µm (SD: 69), compared to the advanced nnAMD with measurements of 153 µm (SD: 68), and 161 µm (SD: 76). This difference was statistically significant (p < 0.0001 and p = 0.0002). CONCLUSIONS: Our results highlight significant differences in imaging biomarkers between both cohorts. Key biomarkers, such as iRORA, RPD, pigment migration, and thinner choroidal thickness, were associated with advanced nnAMD. Identifying these biomarkers early may help target patients who could benefit from new treatments, potentially delaying vision loss.

Healthcare Resource Utilization and Costs in an At-Risk Population With Diabetic Retinopathy.

Purpose: Several investigators have suggested the cost-effectiveness of earlier screening, management of risk factors, and early treatment for diabetic retinopathy (DR). We aimed to evaluate the extent of health care utilization and cost of delayed care by insurance type in a vulnerable patient population. Methods: A retrospective analysis of patients with DR was conducted using electronic medical record (EMR) data from January 2014 to December 2020 at Denver Health Medical Center, a safety net institution. Patients were classified by disease severity and insurance status. DR-specific costs were assessed via Current Procedural Terminology (CPT) codes over a 24-month follow-up period. Results: Among the 313 patients, a higher proportion of non-English speaking patients were uninsured. Rates of proliferative DR at presentation differed across insurance groups (62% of uninsured, 42% of discount plan, and 33% of Medicare/Medicaid, P = 0.016). There was a significant difference in the total median cost between discount plan patients ($1258, interquartile range [IQR] = $0 - $5901) and both Medicare patients ($751, IQR = $0, $7148, P = 0.037) and Medicaid patients ($593, IQR = $0 - $6299, P = 0.025). Conclusions: There were higher rates of proliferative DR at presentation among the uninsured and discount plan patients and greater total median cost in discount plan patients compared to Medicare or Medicaid. These findings prioritize mitigating gaps in insurance coverage and barriers to preventative care among vulnerable populations. Translational Relevance: Advanced diabetic disease and increased downstream health care utilization and cost vary across insurance type, suggesting improved access to preventative care is needed in these specific at-risk populations.

Interleukin-4 Plasma Levels Stratified by Sex in Intermediate Age-Related Macular Degeneration and Geographic Atrophy.

Purpose: Chronic local inflammation underlies the pathogenesis of age-related macular degeneration (AMD) causing damage to the neurosensory retina. However, there is minimal research on systemic cell-mediated inflammation in AMD. Interleukin-4 (IL-4) is an immunoregulatory cytokine with an important role in modulating inflammation in chronic immune mediated disease. The purpose of this study was to: (1) investigate the role of systemic IL-4 in patients with intermediate AMD (iAMD) and in geographic atrophy (GA), an advanced form of AMD, compared to controls without AMD, and (2) determine if IL-4 levels are moderated by sex. Methods: We examined plasma levels of IL-4 in patients with iAMD, GA, and controls without AMD included in the University of Colorado AMD registry (August 2014 to June 2021). Cases and controls were defined by multimodal imaging. IL-4 was measured by multiplex immunoassay. Data were analyzed using a nonparametric rank based linear regression model fit to IL-4. Results: There were 199 patients with iAMD, 97 patients with GA, and 139 controls, with a percentage of female patients 61%, 55%, and 66%, respectively. We demonstrated significantly higher median IL-4 levels in GA (35.3; interquartile range [IQR] = 22.8-50.5) compared to iAMD (6.1; IQR = 2.2-11.3, P < 0.01) and controls (10.7; IQR = 5.0-16.8, P < 0.01). There were no significant differences in levels of IL-4 for cases and controls when stratified by sex. Conclusions: These findings demonstrate a systemic immunological difference between iAMD and GA, indicating IL-4 may be a systemic biomarker for GA development. Translational Relevance: The plasma biomarker IL-4 is significantly elevated in patients with GA.

Small Heat Shock Proteins in Retinal Diseases.

This review summarizes the latest findings on small heat shock proteins (sHsps) in three major retinal diseases: glaucoma, diabetic retinopathy, and age-related macular degeneration. A general description of the structure and major cellular functions of sHsps is provided in the introductory remarks. Their role in specific retinal diseases, highlighting their regulation, role in pathogenesis, and possible use as therapeutics, is discussed.

Using Blockchain Technology to Mitigate Challenges in Service Access for the Homeless and Data Exchange Between Providers: Qualitative Study.

BACKGROUND: In the homeless population, barriers to housing and supportive services include a lack of control or access to data. Disparate data formats and storage across multiple organizations hinder up-to-date intersystem access to records and a unified view of an individual's health and documentation history. The utility of blockchain to solve interoperability in health care is supported in recent literature, but the technology has yet to be tested in real-life conditions encompassing the complex regulatory standards in the health sector. OBJECTIVE: This study aimed to test the feasibility and performance of a blockchain system in a homeless community to securely store and share data across a system of providers in the health care ecosystem. METHODS: We performed a series of platform demonstrations and open-ended qualitative feedback interviews to determine the key needs and barriers to user and stakeholder adoption. Account creation and data transactions promoting organizational efficiency and improved health outcomes in this population were tested with homeless users and service providers. RESULTS: Persons experiencing homelessness and care organizations could successfully create accounts, grant and revoke data sharing permissions, and transmit documents across a distributed network of providers. However, there were issues regarding the security of shared data, user experience and adoption, and organizational preparedness for service providers as end users. We tested a set of assumptions related to these problems within the project time frame and contractual obligations with an existing blockchain-based platform. CONCLUSIONS: Blockchain technology provides decentralized data sharing, validation, immutability, traceability, and integration. These core features enable a secure system for the management and distribution of sensitive information. This study presents a concrete evaluation of the effectiveness of blockchain through an existing platform while revealing limitations from the perspectives of user adoption, cost-effectiveness, scalability, and regulatory frameworks.

Stimulation of the frontal eye field reveals persistent effective connectivity after controlled behavior.

Our ability to choose nonhabitual controlled behavior instead of habitual automatic behavior is based on a flexible control mechanism subserved by neural activity representing the behavior-guiding rule. However, it has been shown that the behavior slows down more when switching from controlled to automatic behavior than vice versa. Here we show that persistent effective connectivity of the neural network after execution of controlled behavior is responsible for the behavioral slowing on a subsequent trial. We asked normal human subjects to perform a prosaccade or antisaccade task based on a cue and examined the effective connectivity of the neural network based on the pattern of neural impulse transmission induced by stimulation of the frontal eye field (FEF). Effective connectivity during the task preparation period was dependent on the task that subjects had performed on the previous trial, regardless of the upcoming task. The strength of this persistent effective connectivity was associated with saccade slowing especially on trials after controlled antisaccade. In contrast, the pattern of regional activation changed depending on the upcoming task regardless of the previous task and the decrease in activation was associated with errors in upcoming antisaccade task. These results suggest that the effective connectivity examined by FEF stimulation reflects a residual functional state of the network involved in performance of controlled antisaccade and its persistence may account for the behavioral slowing on the subsequent trial.