Cytokines in PD-1 immune checkpoint inhibitor adverse events and implications for the treatment of uveitis.

Immune checkpoint inhibitors (ICI) such as Programmed cell Death 1 (PD-1) inhibitors have improved cancer treatment by enhancing the immune system's ability to target malignant cells. Their use is associated with immune-related adverse events (irAEs), including uveitis. The profile of pro-inflammatory cytokines underlying Anti-PD-1-induced uveitis shares significant overlap with that of non-infectious uveitis. Current corticosteroid treatments for uveitis while effective are fraught with vision threatening side effects. The cytokine profile in ICI-related uveitis has a large overlap with that of noninfectious uveitis, this overlap strongly supports the potential for therapy that activates the PD-1 axis in the eye to treat uveitis. Indeed, ICI related uveitis often resolves with cessation of the ICI, restoring the endogenous PD-1 axis. The potential benefit of targeting many pro-inflammatory cytokines via local PD-1 axis activation is mitigating ocular inflammation while minimizing adverse effects.

Gonioscopy-Assisted Transluminal Trabeculotomy for the Treatment of Glaucoma in Uveitic Eyes.

PURPOSE: To evaluate the outcomes of gonioscopy-assisted transluminal trabeculotomy (GATT) in adult eyes with uncontrolled uveitic glaucoma. METHODS: We reviewed 16 eyes from 13 patients. Surgical success was defined as intraocular pressure (IOP) reduction >20% from baseline or IOP between 5 and 21 mmHg by the 3-month visit while on a stable number or fewer IOP-lowering agents and no need for additional glaucoma surgery. RESULTS: At 12 months, the cumulative success rate was 81%. Mean IOP was 37.8 ± 13.0 mmHg at baseline and 12.2 ± 3.0 mmHg at 12 months (68% reduction; p < .0001). The average number of glaucoma medications was 4.6 ± 1.3 at baseline and 2.2 ± 0.7 at 12 months (52% reduction; p < .0001). Transient hyphema was seen in 44% of eyes at 1 week. CONCLUSIONS: This small retrospective study suggests that GATT is effective and safe as an initial surgical treatment for medically refractory glaucoma in uveitic adult eyes.

Geographic and socioeconomic access disparities to Phase 3 clinical trials in ophthalmology in the United States.

BACKGROUND/OBJECTIVE: To identify geographic and socioeconomic variables associated with residential proximity to Phase 3 ophthalmology clinical trial sites. METHODS: The geographic location of clinical trial sites for Phase 3 clinical trials in ophthalmology was identified using ClinicalTrials.gov. Driving time from each United States (US) census tract centroid to nearest clinical trial site was calculated using real traffic patterns. Travel data were crosslinked to census-tract level public datasets from United States Census Bureau American Community Survey (ACS). Cross-sectional multivariable regression was used to identify associations between census-tract sociodemographic factors and driving time (>60 min) from each census tract centroid to the nearest clinical trial site. RESULTS: There were 2330 unique clinical trial sites and 71,897 census tracts. Shortest median time was to retina sites [33.7 min (18.7, 70.1 min)]. Longest median time was to neuro-ophthalmology sites [119.8 min (48.7, 240.4 min)]. Driving >60 min was associated with rural tracts [adjusted odds ratio (aOR) 7.60; 95% CI (5.66-10.20), p < 0.0001]; Midwest [aOR 1.84(1.15-2.96), p = 0.01], South [aOR 2.57 (1.38-4.79), p < 0.01], and West [aOR 2.52 (1.52-4.17), p < 0.001] v. Northeast; and tracts with higher visual impairment [aOR 1.07 (1.03-1.10), p < 0.001)]; higher poverty levels [4th v.1st Quartile of population below poverty, aOR 2.26 (1.72-2.98), p < 0.0001]; and lower education levels [high school v. Bachelor's degree or higher aOR 1.02 (1.00-1.03), p = 0.0072]. CONCLUSIONS: There are significant geographic and socioeconomic disparities in access to ophthalmology clinical trial sites for rural, non-Northeastern, poorer, and lower education level census tracts, and for census tracts with higher levels of self-reported visual impairment.

GEOGRAPHIC ACCESS DISPARITIES TO CLINICAL TRIALS IN RETINOPATHY OF PREMATURITY IN THE UNITED STATES.

BACKGROUND/PURPOSE: To identify geographic and socioeconomic variables predictive of residential proximity to retinopathy of prematurity (ROP) clinical trial locations. METHODS: This cross-sectional epidemiological study used census tract-level data from three national public data sets and trial-level data from ClinicalTrials.gov. Socioeconomic predictors of driving distance and time to the nearest ROP clinical trial location were identified. Primary outcomes were time >60 minutes and distance >60 miles traveled to the nearest ROP clinical trial site. RESULTS: Multivariate analysis showed that residents were more likely to travel >60 minutes to the nearest ROP clinical trial site if they lived in census tracts that were rural (adjusted odds ratio 1.20, P = 0.0002), had higher percentages of the population living ≤ federal poverty level (fourth quartile vs. first quartile, adjusted odds ratio 1.19, P < 0.0001), or had less education (associate vs. bachelor's degree, adjusted odds ratio 1.01, P <0.007). By contrast, counties with higher percentages of births with birth weight <1500 g (adjusted odds ratio 0.88, P = 0.0062) were less likely to travel >60 minutes. Similar variables predicted travel distance. CONCLUSION: Although counties with higher incidences of very low-birth-weight infants were closer to ROP clinical trial sites, residents living in rural and low-income census tracts had significantly greater travel burdens.

Geographic Access Disparities of Clinical Trials in Neovascular Age-Related Macular Degeneration in the United States.

To identify geographic and socioeconomic variables predictive of residential proximity to neovascular age-related macular degeneration (nAMD) clinical trial locations. DESIGN: Retrospective, cross-sectional study. METHODS: Census tract-level data from public datasets and trial-level data from ClinicalTrials.gov were analyzed. We calculated the driving distance (>60 miles) and time (>60 minutes) from the population-weighted US census tract centroid to the nearest clinical trial site. RESULTS: We identified 42 trials studying nAMD across 829 unique clinical trial sites in the United States. In a multivariable model, driving distance >60 miles had a significant association with rural location (adjusted odds ratio [aOR] 5.54; 95% confidence interval [CI] 3.86-7.96, P < .0001) and with Midwest (aOR 2.30; 95% CI 1.21-4.38, P = .01) and South (aOR 2.43; 95% CI 1.21-4.91, P = .01) as compared to the Northeast region, and with some college or an associate's degree, as compared to a bachelor's degree (aOR 1.02; 95% CI 1.01-1.04, P = .0007, and aOR 1.05; 95% CI 1.00-1.10, P = .04, respectively). Lower odds of traveling >60 miles to the nearest nAMD trial site were associated with census tracts with a higher percentage of blacks (aOR 0.98; 95% CI 0.97-0.99, P < .0001), Hispanics (aOR 0.97; 95% CI 0.95-0.99, P = .002), and Asians (aOR 0.90; 95% CI 0.88-0.93, P < .0001), as compared to whites, and with a lower percentage of the population <200% of the federal poverty level. Similar predictors were found in time traveled >60 minutes. CONCLUSIONS: There are geographic access disparities of clinical trial sites for nAMD in the United States.

Geographic Access Disparities to Clinical Trials in Diabetic Eye Disease in the United States.

PURPOSE: To identify geographic and socioeconomic variables predictive of residential proximity to diabetic eye disease clinical trial locations. DESIGN: Cross-sectional, retrospective study. PARTICIPANTS: De-identified census tract-level data from public datasets and trial-level data from ClinicalTrials.gov. METHODS: Using public data from ClinicalTrials.gov, we identified all active interventional clinical trials in diabetic eye disease since 2017. After geolocating every trial site, we used an origin-destination cost-matrix to calculate the driving distance and travel time from the population-weighted United States census tract centroid to the nearest site. We then used public databases to identify census tract-level socioeconomic factors predictive of driving distance and time. MAIN OUTCOME MEASURES: Driving distance > 60 miles and time traveled > 60 minutes to the nearest clinical trial site. RESULTS: In a multivariate model, driving distance of more than 60 miles had a significant association with rural versus urban location (adjusted odds ratio, 5.22; 95% confidence interval [CI], 3.75-7.26; P < 0.001), percentage of population at less than 200% of federal poverty level compared with the fourth quartile (first quartile: adjusted odds ratio, 0.40 [95% CI, 0.29-0.55]; second quartile: adjusted odds ratio, 0.60 [95% CI, 0.47-0.77]; third quartile: adjusted odds ratio, 0.76 [95% CI, 0.63-0.91]; P < 0.001) and the Midwest (adjusted odds ratio, 2.15; 95% CI, 1.13-4.07; P = 0.02), South (adjusted odds ratio, 2.71; 95% CI, 1.23-5.99; P = 0.01), and West (adjusted odds ratio, 3.01; 95% CI, 1.21-7.54; P = 0.02) regions as compared with the Northeast. Driving distance was associated with county-level prevalence of diabetes in the univariate model (odds ratio, 1.12; 95% CI, 1.06-1.19; P < 0.001), although it was nonsignificant in the multivariate model. Similar predictors were found for time traveled in minutes. CONCLUSIONS: Geographic maldistributions of clinical trial sites exist for diabetic eye disease in the United States. Those with higher travel burden are more likely to reside in a census tract that is rural, low income, and from areas outside the Northeast.

Sustained centrosome-cortical contact ensures robust polarization of the one-cell C. elegans embryo.

In C. elegans, the anterior-posterior axis is established at the one-cell stage when the embryo polarizes along its long axis. One model suggests that a cue from the centrosome triggers symmetry breaking and is then dispensable for further steps in the process. In the absence of the initial centrosome cue, a redundant mechanism, reliant on the centrosome's microtubules, can polarize the cell. Despite this model, data from multiple sources suggest that direct centrosome-contact with the cortex may play a role in ensuring robust polarization. Some of this past work includes analysis of pam-1 mutants, which lack a functional puromycin-sensitive aminopeptidase and have aberrant centrosome positioning and variable polarization defects. To better understand the role of centrosome dynamics in polarization, we looked in detail at centrosome behavior in relation to key polarity landmarks in pam-1 mutants as well as those lacking cortical flows. We provide evidence for a model in which sustained direct contact between the centrosome and the cortex acts to reinforce both the actomyosin and the microtubule-dependent pathways. This contact is necessary for polarization when flows are inhibited.