Deep Learning of the Retina Enables Phenome- and Genome-Wide Analyses of the Microvasculature.

BACKGROUND: The microvasculature, the smallest blood vessels in the body, has key roles in maintenance of organ health and tumorigenesis. The retinal fundus is a window for human in vivo noninvasive assessment of the microvasculature. Large-scale complementary machine learning-based assessment of the retinal vasculature with phenome-wide and genome-wide analyses may yield new insights into human health and disease. METHODS: We used 97 895 retinal fundus images from 54 813 UK Biobank participants. Using convolutional neural networks to segment the retinal microvasculature, we calculated vascular density and fractal dimension as a measure of vascular branching complexity. We associated these indices with 1866 incident International Classification of Diseases-based conditions (median 10-year follow-up) and 88 quantitative traits, adjusting for age, sex, smoking status, and ethnicity. RESULTS: Low retinal vascular fractal dimension and density were significantly associated with higher risks for incident mortality, hypertension, congestive heart failure, renal failure, type 2 diabetes, sleep apnea, anemia, and multiple ocular conditions, as well as corresponding quantitative traits. Genome-wide association of vascular fractal dimension and density identified 7 and 13 novel loci, respectively, that were enriched for pathways linked to angiogenesis (eg, vascular endothelial growth factor, platelet-derived growth factor receptor, angiopoietin, and WNT signaling pathways) and inflammation (eg, interleukin, cytokine signaling). CONCLUSIONS: Our results indicate that the retinal vasculature may serve as a biomarker for future cardiometabolic and ocular disease and provide insights into genes and biological pathways influencing microvascular indices. Moreover, such a framework highlights how deep learning of images can quantify an interpretable phenotype for integration with electronic health record, biomarker, and genetic data to inform risk prediction and risk modification.

Association of the Affordable Care Act with Eye-Related Emergency Department Utilization in the United States.

PURPOSE: To investigate the association of the Affordable Care Act (ACA) with nationwide eye-related emergency department (ED) use. DESIGN: Retrospective, cross-sectional study. PARTICIPANTS: All patients who presented to the ED with an eye-related primary diagnosis were eligible for inclusion. METHODS: Nationally representative data from the US Nationwide Emergency Department Sample were used to analyze eye-related ED visits before (2010-2013) and after (2014-2017) the ACA was mandated. All ED visits were categorized as emergent or nonemergent or could not be determined. MAIN OUTCOME MEASURES: The primary outcome was to compare the nationwide and regional incidence of eye-related ED visits per 100 000 US population before (2010-2013) and after (2014-2017) the ACA was mandated. Secondary outcome measures included change in payor status, proportion of urgent versus nonurgent visits, proportion of visits at teaching versus nonteaching hospitals, associated charges, and discharge disposition. RESULTS: A total of 16 808 343 eye-related ED visits occurred in the United States during the study period from 2010 to 2017. Of these, 8 088 203 ED visits occurred before the ACA was mandated (2010-2013), and 8 720 766 ED visits occurred after the ACA was mandated (2014-2017). After the ACA was mandated in 2014, there was an initial decline in incidence of eye-related ED visits from 652.4 per 100 000 population in 2013 to 593.0 per 100 000 population in 2014, followed by a rapid increase in incidence to 658.5 per 100 000 population in 2015, with a further increase to 746.6 per 100 000 population in 2016. The percentage of uninsured patients decreased from 19.0% to 14.3%. The increase in ED use was greatest for individuals in the lowest income quartile (895.1 per 100 000 population in 2013 to 964.0 per 100 000 in 2017). Overall, 44.8% of ED visits were due to nonemergent eye conditions. CONCLUSIONS: Although the ACA increased insurance coverage for Americans, theoretically increasing access to outpatient ophthalmic care, this did not decrease ED reliance for management of ophthalmic conditions. Additional measures beyond expanding insurance coverage may be necessary to provide high-quality, efficient, and equitable outpatient ophthalmic care to all Americans.

Posterior ocular structural and vascular alterations in severe COVID-19 patients.

PURPOSE: This study aimed to evaluate posterior ocular structural and vascular changes in severe coronavirus disease 2019 (COVID-19) patients. METHODS: This was an observational, prospective, and controlled study including 106 eyes of 53 severe COVID-19 patients, compared to after recovery and 106 eyes of 53 age- and gender-matched healthy controls. All subjects were previously healthy adults and were assessed using spectral domain optical coherence tomography (SD-OCT) and ImageJ software. Subfoveal over a 1500-µm span and macular over a 6000-µm span cross-sectional areas of the vascular, stromal, and total choroid were measured. RESULTS: Of the 53 included patients, 28 (52.8%) were male, and 25 (47.2%) were female, with a mean age of 50.2 ± 7.4 years. In the active period of the disease, compared to after recovery and healthy controls, the outer plexiform layer thickness showed a significant increase (p = 0.004), and mean choroidal thickness was significantly higher (p < 0.0001); however, choroidal vascularity was significantly lower (p < 0.0001). The stromal area to vascular area (S/V) ratio of the choroid was significantly increased (p < 0.0001). All quadrants of the peripapillary retinal nerve fiber layer (RNFL) thicknesses were significantly increased (for all, p < 0.05). The reflectivity of OCT echo of the choroid and peripapillary RNFL was significantly higher (p = 0.023, p < 0.0001, respectively). CONCLUSION: This study detected significant posterior ocular structural and vascular alterations in patients with severe COVID-19 infections. These findings may be associated with direct host-virus interaction or linked to an autoimmune process, vasculopathy, or viral-mediated inflammation.

VISUAL OUTCOME OF EARLY VITRECTOMY AND INTRAVITREAL ANTIBIOTICS IN ACUTE POSTSURGICAL AND POSTINTRAVITREAL INJECTION ENDOPHTHALMITIS: European Vitreo-Retinal Society Endophthalmitis Study Report Two.

PURPOSE: To evaluate the visual outcome associated with intravitreal antibiotics (IVA) and pars plana vitrectomy (PPV) for acute postprocedure endophthalmitis. METHODS: Data from 237 eyes presenting with acute postprocedure endophthalmitis were collected from 57 retina specialists in 28 countries. All eyes were treated with IVA on the day of presentation. We classified eyes according to the method of treatment used as IVA and early PPV (IVA + PPV within 1 week of presentation) groups. RESULTS: After exclusion of ineligible eyes, data from 204 eyes were analyzed. The mean (SD) age of patients was 62.7 (21.8) years and 69.3 (12.7) years in the IVA and PPV groups, respectively (P = 0.18). Endophthalmitis secondary to cataract, intravitreal injections, PPV, and other intraocular procedures represented 64.2%, 16.2%, 13.7%, and 5.9% of cases, respectively. Intravitreal antibiotics alone were administered in 55 eyes (27.0%), and early PPV was performed in 149 eyes (73.0%). No difference was found between groups in the final visual acuity of ≥20/60 (43.6%, 65 eyes vs. 34.5%, 19 eyes) and ≤counting fingers (30.9%, 46 eyes vs. 36.4%, 20 eyes) for IVA versus early PPV groups, respectively. Vision of light perception (odds ratio = 12.2; 95% confidence interval: 2.0-72.6) and retinal detachment (odds ratio = 7.7; 95% confidence interval: 1.5-409) at baseline were predictive of vision of ≤counting fingers. Retinal detachment at baseline (odds ratio = 20.4; 95% confidence interval: 1.1-372.1) was predictive of final retinal detachment status. CONCLUSION: The current retrospective multicenter cohort of eyes with acute postprocedure endophthalmitis reports similar outcomes after treatment with IVA alone when compared with IVA and early PPV within 1 week of presentation.

Claudins regulate gene and protein expression of the retinal pigment epithelium independent of their association with tight junctions.

Claudin-19 is the major claudin in the tight junctions of the retinal pigment epithelium (RPE). Claudin-3 is also uniformly expressed albeit in lesser amounts. Besides modulating transepithelial diffusion, claudins modulate gene expression. The absence of claudin-19 and claudin-3 in the RPE cell lines, ARPE-19 and hTERT-RPE-1, provide an opportunity to examine whether exogenous claudins regulate gene expression in the absence of tight junctions. Quantitative RT-PCR was used to compare gene expression in ARPE-19 and hTERT-RPE-1 with that of highly differentiated, human fetal RPE. Claudin-19 and claudin-3 were exogenously expressed using an adenoviral vector. The transepithelial electrical resistance (TER) was measured using Endohm electrodes, and the effects of claudin on the actin cytoskeleton were determined by immunocytochemistry. The effect of claudin on gene expression was examined by quantitative RT-PCR and western blotting. Aside from claudin-19 and claudin-3, ARPE-19 and hTERT-RPE-1 expressed most junction-associated mRNAs in amounts comparable to human fetal RPE, but some RPE signature and maturation genes were under-expressed. Unlike ARPE-19, hTERT-RPE-1 failed to form tight junctions or develop a TER. Claudins exogenously expressed in hTERT-RPE-1 failed to crystalize an apical junctional complex. Actin filaments were not redistributed from stress fibers to cortical bands, and a TER was not established. In hTERT-RPE-1, claudins were found only in internal vesicular-like structures. Nonetheless, claudins increased the expression of the mRNAs for a collection of RPE-enriched proteins. Claudin-19 and claudin-3 had different effects on gene and protein expression indicating activation of overlapping, but distinct, signaling pathways. A major difference was the ability of claudin-19 to affect steady-state levels of ADAM9 and tyrosinase in ARPE-19. In conclusion, claudins can increase the barrier function of a pre-existing apical junctional complex, but on its own it cannot recruit tight junction proteins to form a complex de novo. Many effects of claudin on gene expression did not require an association with the apical junctional complex. Although claudin-19 shared many effects with claudin-3, claudin-19 exerted unique effects on the maturation of RPE.

Trends of Anti-Vascular Endothelial Growth Factor Use in Ophthalmology Among Privately Insured and Medicare Advantage Patients.

PURPOSE: To characterize the first 10 years of intravitreal anti-vascular endothelial growth factor (VEGF) medication use for ophthalmic disease, including bevacizumab, ranibizumab, and aflibercept. DESIGN: A retrospective cohort study using administrative claims data from January 1, 2006 to December 31, 2015. SUBJECTS: Total of 124 835 patients 18 years of age or over in the United States. METHODS: OptumLabs Data Warehouse, which includes administrative claims data for over 100 million commercially insured and Medicare Advantage individuals, was used to identify patients receiving intravitreal anti-VEGF injections based on Current Procedural Terminology codes. MAIN OUTCOME MEASURES: Total and annual numbers of intravitreal anti-VEGF injections, as well as injections per 1000 enrolled patients per general category of ophthalmic disease, overall and for each available medication. RESULTS: There were 959 945 anti-VEGF injections among 124 835 patients from 2006 to 2015. Among all injections, 64.6% were of bevacizumab, 22.0% ranibizumab, and 13.4% aflibercept; 62.7% were performed to treat age-related macular degeneration (AMD), 16.1% to treat diabetic retinal diseases (including 0.9% of all injections that were for proliferative diabetic retinopathy), 8.3% to treat retinal vein occlusions, and 12.9% for all other uses. Use of bevacizumab and ranibizumab for AMD plateaued as of 2011/2012 and decreased thereafter (in 2006, 58.8 and 35.3 injections/1000 AMD patients, respectively; in 2015, 294.4 and 100.7 injections/1000), whereas use of aflibercept increased (1.1 injections/1000 AMD patients in 2011 to 183.0 injections/1000 in 2015). Bevacizumab use increased each year for diabetic retinal disease (2.4 injections/1000 patients with diabetic retinal disease in 2009 to 13.6 per 1000 in 2015) while that of ranibizumab initially increased significantly and then declined after 2014 (0.1 in 2009 to 4.0 in 2015). Aflibercept use increased each year in patients with diabetic retinal diseases and retinal vein occlusions (both <0.1 per 1000 retinal vein occlusion patients in 2011, 5.6 and 140.2 in 2015). CONCLUSIONS: Intravitreal injections of anti-VEGF medications increased annually from 2006 to 2015. Bevacizumab was the most common medication used, despite its lacking U.S. Food and Drug Administration approval to treat ophthalmic disease, and AMD was the most common condition treated. Ranibizumab use declined after 2014 while both the absolute and relative use of bevacizumab and aflibercept increased.

Novel therapeutics for Stargardt disease.

DESCRIPTION OF SITUATION: Stargardt disease, an inherited macular dystrophy caused by mutations in the ABCA4 gene encoding a retinal transporter protein, is the most prevalent form of macular degeneration in children. Patients with Stargardt disease develop severe vision loss within their first or second decades of life, which progresses to irreversible decreased visual acuity in almost all cases. Presently, there are no standard treatments for Stargardt disease. However, encouraging progress has been made in the development of innovative approaches to preventing vision loss in Stargardt patients. OBJECTIVE OF STUDY: Among the promising treatment candidates include ALK-001, fenretinide, and A1120 as pharmacological agents to modulate the visual cycle, StarGenTM as a vector for supplementation of a functional ABCA4 gene, and stem-cell transplantation of hESC-RPE cells for regeneration of the retinal pigment epithelium. This study aims to systematically review and summarize evidence concerning the most up-to-date developments in pharmacologic, gene, and stem-cell therapies as novel therapeutic strategies to improve vision for patients with Stargardt disease.

ASSOCIATION BETWEEN THE VITREOMACULAR INTERFACE AND OPTICAL COHERENCE TOMOGRAPHY CHARACTERISTICS IN WET AGE-RELATED MACULAR DEGENERATION.

PURPOSE: To study the effect of the vitreomacular interface on various wet age-related macular degeneration (AMD) characteristics including the size and type of choroidal neovascularization (CNV), choroidal thickness, and activity of the CNV. METHODS: This was a retrospective observational cross-sectional study. The study included 43 patients (51 eyes) with treatment-naive age-related macular degeneration. Twenty-six patients with wet AMD in one eye and dry AMD in the other eye were included in a paired-eye analysis. Patients underwent optical coherence tomography examination using Heidelberg Spectralis (spectral domain optical coherence tomography) at presentation to determine the type of CNV and the vitreomacular status. In addition, various parameters were measured including the choroidal thickness and horizontal width and vertical height measurements of the CNV. RESULTS: There was no correlation between the height, width, activity or type of the CNV, and the presence or absence of vitreomacular adhesion. The mean choroidal thickness (using enhanced depth imaging) in cases with vitreomacular adhesion was 272.57 µm compared with 197.32 µm in cases with no vitreomacular adhesion, a statistically significant difference (P = 0.003). In the paired-eye study (21 patients), there was no significant difference between the eyes with wet AMD and dry AMD with regard to vitreomacular status or the choroidal thickness. In a subgroup analysis, patients with Type 1 CNV had a significantly higher percentage of vitreomacular adhesion compared with the other eye with dry AMD (P = 0.034). CONCLUSION: In conclusion, the vitreomacular interface does seem to be associated with an increased choroidal thickness in cases of wet AMD. Furthermore, the association between the vitreomacular interface and wet AMD is more significant for Type 1 CNV.

Idiopathic Epiretinal Membrane and Vitreomacular Traction Preferred Practice Pattern(®) Guidelines.

UNLABELLED: IDIOPATHIC EPIRETINAL MEMBRANE AND VITREOMACULAR TRACTION PREFERRED PRACTICE PATTERN® GUIDELINES: New evidence-based Idiopathic Epiretinal Membrane and Vitreomacular Traction Preferred Practice Pattern® (PPP) guidelines, describing recommendations for the diagnosis, treatment, and management of patients.

Retinal Vein Occlusions Preferred Practice Pattern(®) Guidelines.

UNLABELLED: RETINAL VEIN OCCLUSIONS PREFERRED PRACTICE PATTERN® GUIDELINES: New evidence-based Retinal Vein Occlusions Preferred Practice Pattern® (PPP) guidelines, discussing the prognosis and risk factors of retinal vein occlusions and the treatment options.

Claudin-3 and claudin-19 partially restore native phenotype to ARPE-19 cells via effects on tight junctions and gene expression.

Mutations of claudin-19 cause severe ocular deficits that are not easily reconciled with its role in regulating the outer blood retinal barrier. ARPE-19 is a widely used culture model of the retinal pigment epithelium (RPE). ARPE-19 is unique among epithelial cell lines, because it expresses all tight junction proteins except claudin family members. ARPE-19 also loses aspects of the RPE phenotype with cell passage. This study asks whether exogenous expression of the main RPE claudins, claudin-3 and claudin-19, would restore RPE phenotype, and whether these claudins have distinct roles in RPE. An Ussing chamber was used to measure the transepithelial electrical resistance and transepithelial electrical potential. These measurements were used to estimate the permeability co-efficients of ions. The transepithelial diffusion of polyethylene glycols were used to examine the leak pathway of tight junctions. Wound-healing, quantitative RT-PCR and immunoblotting examined diverse aspects of the RPE phenotype. Over-expression of either claudin decreased the permeability of small ions and polyethylene glycol. Both claudins were slightly cation-specific, but claudin-3 was less permeable to large solutes. Claudin expression widely affected gene expression to partially restore RPE phenotype. Claudins redistributed filamentous actin from stress fibers to circumferential bands associated with tight junctions, and made wound-healing more epithelial-like. Both claudins increased the expression of genes related to RPE core functions and increased steady-state levels of phosphorylated-AKT. In conclusion, claudin-3 and claudin-19 formed general permeability barriers and affected cell morphology, proliferation, migration, AKT signaling, and gene expression. When claudins are exogenously expressed, ARPE-19 more closely model native RPE.

Choroidal thickness measured with swept source optical coherence tomography before and after vitrectomy with internal limiting membrane peeling for idiopathic epiretinal membranes.

PURPOSE: In eyes with epiretinal membranes (ERMs), retinal arteries become dilated and tortuous. This may correlate with the hemodynamics of the affected areas and possibly with choroidal thickness. The aim of this study was to estimate choroidal thickness before and after vitrectomy for idiopathic ERM in the operated eye and in the unaffected fellow eye. METHODS: A prospective study of 21 patients with idiopathic ERMs. We obtained swept source optical coherence tomography images that simultaneously evaluated the vitreous, retina, and choroid. We performed choroidal thickness measurements before pars plana vitrectomy with ERM removal and internal limiting membrane peeling. We took subsequent images 10 days and then 3 months after surgery. We compared the images with patients' fellow eyes. In each eye, we performed 256 horizontal scans, 12 mm in length and centered on the fovea. We manually calculated choroidal thickness from the posterior edge of the retinal pigment epithelium to the choroidoscleral boundary with the built-in caliper and additionally measured it automatically using DRI-OCT mapping software. We evaluated the outer choroidoscleral boundary and performed statistical analysis. RESULTS: We observed an ERM in 50% of fellow eyes. Mean choroidal thickness did not differ between study and fellow eyes (P = 0.67). Choroidal thickness decreased from 200 µm to 173 µm (P = 0.034) 3 months after vitrectomy and internal limiting membrane peeling. In all but two cases, the outer choroidoscleral boundary was irregular. Additionally, we observed that the suprachoroidal layer consists of two bands in four cases, an inner hyperreflective band and an outer hyporeflective one. We speculate the latter correlates with the suprachoroidal space. CONCLUSION: Normalization of choroidal thickness after surgery suggests that there is some relationship between choroidal thickness and structure and the presence of idiopathic ERMs.