Race/Ethnicity Analysis of Vascular Alterations in Optical Coherence Tomography Angiography in Diabetic Patients.

PURPOSE: Racial and ethnic minorities have a higher prevalence of diabetic retinopathy (DR) and present at advanced stages of disease. In an urban hospital population, we investigated microvascular differences in optical coherence tomography angiography (OCTA) between racial/ethnic groups while adjusting for socioeconomic status (SES). METHODS: 3 × 3 mm2 macular OCTA scans were obtained for analysis of foveal avascular zone (FAZ) area, FAZ perimeter as well as superficial (SCP) and deep capillary plexus (DCP) vessel density (VD), vessel length density (VLD), and adjusted flow index (AFI). SES was measured using the Area Deprivation Index. Multivariable regression models were used to adjust estimates for relevant confounders. RESULTS: 217 non-diabetic and 1,809 diabetic patients were included in the study, consisting of 42.2% Hispanic, 24.9% non-Hispanic (NH) Asian, 6.8% NH Black, 9.7% NH White and 16.3% Other patients. NH White was used as the reference group. Hispanic, NH Asian, and NH Black patients had significantly greater FAZ areas and FAZ perimeters, and lower DCP VD and VLD, among both non-diabetic and diabetic patients (Benjamini-Hochberg adjusted P-values <0.05). The addition of SES scores in the models did not modify any regressions significantly. CONCLUSIONS: In patients with and without diabetes, racial and ethnic minorities have significant retinal microvasculature differences when compared to NH White patients, regardless of SES. These differences are pronounced in DCP and may predispose racial/ethnic minorities to worse outcomes in DR, thus widening disparities in ophthalmic care.

Individual and Systems-Based Risk Factors for Diabetic Vitrectomy in an Urban Safety-Net Hospital.

OBJECTIVE: To identify individual and systems-focused risk factors for pars plana vitrectomy among patients with proliferative diabetic retinopathy (PDR) in a diverse, urban, safety-net hospital setting. DESIGN: Single-center, retrospective, observational, case-control study at Zuckerberg San Francisco General Hospital and Trauma Center between 2017 and 2022. SUBJECTS: Two hundred twenty-two patients with PDR over a 5-year span (2017-2022), consisting of 111 cases who underwent vitrectomy for vision-threatening complications (tractional retinal detachment, nonclearing vitreous hemorrhage, and neovascular glaucoma) and 111 controls with PDR with no history of vitrectomy or vision-threatening complications. Controls were matched 1:1 through incidence density sampling. METHODS: Medical records were reviewed from time of entry into hospital system to vitrectomy date (or date-matched clinic visit for controls). Individual-focused exposures included age, gender, ethnicity, language, homelessness, incarceration, smoking status, area deprivation index, insurance status, baseline retinopathy stage, baseline visual acuity, baseline hemoglobin A1c, panretinal photocoagulation status, and cumulative anti-VEGF treatments. System-focused exposures included external department involvement, referral route, time within hospital and ophthalmology systems, interval between screening and ophthalmology appointment, interval between conversion to proliferative disease and panretinal photocoagulation or first treatment, and loss-to-follow-up in intervals of active proliferative disease. MAIN OUTCOME MEASURES: Odds ratios (ORs) for each exposure on vision-threatening diabetic complications requiring vitrectomy. RESULTS: The absence of panretinal photocoagulation was the primary significant individual-focused risk factor for vitrectomy in the multivariable analysis (OR, 4.78; P = 0.011). Systems-focused risk factors included longer interval between PDR diagnosis and initial treatment (weeks; OR, 1.06; P = 0.024) and greater cumulative duration of loss-to-follow-up during intervals of active PDR (months; OR, 1.10; P = 0.002). Greater duration in the ophthalmology system was the primary systems-focused protective factor against vitrectomy (years; OR, 0.75; P = 0.035). CONCLUSIONS: Largely modifiable variables modulate risk of complications requiring diabetic vitrectomy. Each additional month of loss-to-follow-up for patients with active proliferative disease increased odds of vitrectomy by 10%. Optimizing modifiable factors to promote earlier treatment and maintain critical follow-up in proliferative disease may reduce vision-threatening complications requiring vitrectomy in a safety-net hospital setting. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Dual genome-wide coding and lncRNA screens in neural induction of induced pluripotent stem cells.

Human chromosomes are pervasively transcribed, but systematic understanding of coding and lncRNA genome function in cell differentiation is lacking. Using CRISPR interference (CRISPRi) in human induced pluripotent stem cells, we performed dual genome-wide screens - assessing 18,905 protein-coding and 10,678 lncRNA loci - and identified 419 coding and 201 lncRNA genes that regulate neural induction. Integrative analyses revealed distinct properties of coding and lncRNA genome function, including a 10-fold enrichment of lncRNA genes for roles in differentiation compared to proliferation. Further, we applied Perturb-seq to obtain granular insights into neural induction phenotypes. While most coding hits stalled or aborted differentiation, lncRNA hits were enriched for the genesis of diverse cellular states, including those outside the neural lineage. In addition to providing a rich resource (danlimlab.shinyapps.io/dualgenomewide) for understanding coding and lncRNA gene function in development, these results indicate that the lncRNA genome regulates lineage commitment in a manner fundamentally distinct from coding genes.

A Genome-wide Haploid Genetic Screen Identifies Regulators of Glutathione Abundance and Ferroptosis Sensitivity.

The tripeptide glutathione suppresses the iron-dependent, non-apoptotic cell death process of ferroptosis. How glutathione abundance is regulated in the cell and how this regulation alters ferroptosis sensitivity is poorly understood. Using genome-wide human haploid genetic screening technology coupled to fluorescence-activated cell sorting (FACS), we directly identify genes that regulate intracellular glutathione abundance and characterize their role in ferroptosis regulation. Disruption of the ATP binding cassette (ABC)-family transporter multidrug resistance protein 1 (MRP1) prevents glutathione efflux from the cell and strongly inhibits ferroptosis. High levels of MRP1 expression decrease sensitivity to certain pro-apoptotic chemotherapeutic drugs, while collaterally sensitizing to all tested pro-ferroptotic agents. By contrast, disruption of KEAP1 and NAA38, leading to the stabilization of the transcription factor NRF2, increases glutathione levels but only weakly protects from ferroptosis. This is due in part to concomitant NRF2-mediated upregulation of MRP1. These results pinpoint glutathione efflux as an unanticipated regulator of ferroptosis sensitivity.