Retina Publications

Jacoba CMP, Celi LA, Lorch AC, Fickweiler W, Sobrin L, Gichoya JW, Aiello LP, Silva PS. Bias and Non-Diversity of Big Data in Artificial Intelligence: Focus on Retinal Diseases. Semin Ophthalmol 2023;:1-9.Abstract
Artificial intelligence (AI) applications in healthcare will have a potentially far-reaching impact on patient care, however issues regarding algorithmic bias and fairness have recently surfaced. There is a recognized lack of diversity in the available ophthalmic datasets, with 45% of the global population having no readily accessible representative images, leading to potential misrepresentations of their unique anatomic features and ocular pathology. AI applications in retinal disease may show less accuracy with underrepresented populations that may further widen the gap of health inequality if left unaddressed. Beyond disease symptomatology, social determinants of health must be integrated into our current paradigms of disease understanding, with the goal of more personalized care. AI has the potential to decrease global healthcare inequality, but it will need to be based on a more diverse, transparent and responsible use of healthcare data.
Ruran HB, Petty CR, Eliott D, Rao RC, Phipatanakul W, Young BK. Patient Perceptions of Retinal Detachment Management and Recovery through Social Media. Semin Ophthalmol 2023;:1-5.Abstract
PURPOSE: Social media support groups can provide accessibility to advice and emotional regarding medical topics, such as retinal detachment repair, but this is almost universally provided by laypersons. We sought to determine how topics related to retinal detachment repair are associated with various emotional responses and the spread of misinformation, as identified through an online social media support group. METHODS: Retrospective observational study of the largest Facebook support group for retinal detachment from 03/19/2021 to 07/19/2021. Members of the support group that posted during the study period. Comments were coded by content (Pre-procedural, Peri-procedural Post procedural, Repeat procedures) and participant response (Emotional responses, Asking for medical advice, and Misinformation). Associations between content and responses were examined using Pearson's chi-squared test, two-sample t-test, and linear regression. RESULTS: Posts that included written comments from the study period were analyzed. Negative emotional responses appeared in 30% of posts and positive emotional responses were in 16% of posts. Misinformation was more likely to appear in pre-procedure posts (5.3% versus 1.4%, p = .03). Negative emotional responses trended towards being more common in topics related to repeat procedures (40% vs 28%), although this did not reach statistical significance (p = .06). CONCLUSIONS: Surgeons should be aware that patients frequently express negative experiences on this forum, asked for medical advice, even in the post-operative period, and that these posts generated high engagement. Misinformation may be propagated in support groups, though less commonly with regard to post-procedural questions.
Han H, Yang Y, Han Z, Wang L, Dong L, Qi H, Liu B, Tian J, Vanhaesebroeck B, Kazlauskas A, Zhang G, Zhang S, Lei H. NFκB-Mediated Expression of Phosphoinositide 3-Kinase δ Is Critical for Mesenchymal Transition in Retinal Pigment Epithelial Cells. Cells 2023;12(2)Abstract
Epithelial mesenchymal transition (EMT) plays a vital role in a variety of human diseases including proliferative vitreoretinopathy (PVR), in which retinal pigment epithelial (RPE) cells play a key part. Transcriptomic analysis showed that the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway was up-regulated in human RPE cells upon treatment with transforming growth factor (TGF)-β2, a multifunctional cytokine associated with clinical PVR. Stimulation of human RPE cells with TGF-β2 induced expression of p110δ (the catalytic subunit of PI3Kδ) and activation of NFκB/p65. CRISPR-Cas9-mediated depletion of p110δ or NFκB/p65 suppressed TGF-β2-induced fibronectin expression and activation of Akt as well as migration of these cells. Intriguingly, abrogating expression of NFκB/p65 also blocked TGF-β2-induced expression of p110δ, and luciferase reporter assay indicated that TGF-β2 induced NFκB/p65 binding to the promoter of the PIK3CD that encodes p110δ. These data reveal that NFκB/p65-mediated expression of PI3Kδ is essential in human RPE cells for TGF-β2-induced EMT, uncovering hindrance of TGF-β2-induced expression of p110δ as a novel approach to inhibit PVR.
Gise R, Heidary G. The visual morbidity of optic nerve head drusen: a longitudinal review. J AAPOS 2023;Abstract
BACKGROUND: The ophthalmologic complications of optic nerve head drusen (ONHD) in adults have been documented, whereas data on the degree of visual morbidity from OHND in children are limited. METHODS: The medical records of all patients diagnosed with ONHD at a single, tertiary care ophthalmology department from January 1, 2010, until July 1, 2018, were reviewed retrospectively. Patients were identified using ICD-9 and ICD-10 codes. Inclusion criteria were age ≤18 years of age and formal documentation of ONHD by ancillary testing. RESULTS: A total of 213 patients (386 eyes with ONHD) met inclusion criteria. Mean age at diagnosis was 10.13 ± 4.09 years, and mean follow-up was 2.76 ± 2.91 years. Formal visual fields were available for 208 eyes. Repeatable visual field defects were noted in 24 eyes (11.5%). The most common defect was a nasal step, which occurred in 11 eyes (45.8%). Fifteen eyes had visual field defects at presentation, and 9 eyes developed field loss within 1.39 ± 0.55 years of diagnosis. There was no correlation found between intraocular pressure and degree of visual field loss. Choroidal neovascular membranes were clinically apparent in 5 eyes and treatment was required in 3 eyes. Nonarteritic ischemic optic neuropathy developed in 2 eyes. CONCLUSIONS: Visual morbidity associated with ONHD in children is common and may develop in a short period of time after initial diagnosis. There was no correlation found with intraocular pressure.
Hu B, Huang Y, Jakobs TC, Kang Q, Lv Z, Liu W, Wang R. Viability of mitochondria-labeled retinal ganglion cells in organotypic retinal explant cultures by two methods. Exp Eye Res 2023;226:109311.Abstract
Retinal explant cultures provide a valuable system to study retinal function in vitro. This study established a new retinal explant culture method to prolong the survival of retinal ganglion cells (RGCs). Explants were prepared in two different ways: with or without optic nerve. Retinas from newborn mice that had received an injection of MitoTracker Red into the contralateral superior colliculus to label axonal mitochondria were cultured as organotypic culture for 7 days in vitro. At several time points during the culture, viability of RGCs was assessed by multi-electrode array recording, and morphology by immunohistochemical methods. During the culture, the thickness of the retinal tissue in both groups gradually decreased, however, the structure of the layers of the retina could be identified. Massive apoptosis in the retinal ganglion cell layer (GCL) appeared on the first day of culture, thereafter the number of apoptotic cells decreased. Glial activation was observed throughout the culture, and there was no difference in morphology between the two groups. RGCs loss was exacerbated on 3rdday of culture, and RGCs loss in retinal explants with preserved optic nerve was significantly lower than in retinas that did not preserve the optic nerve. More and longer-lasting mitochondrial signals were observed in the injured area of the optic nerve-preserving explants. Retinal explants provide an invaluable tool for studying retinal function and developing treatments for ocular diseases. The optic nerve-preserving culture helps preserve the integrity of RGCs. The higher number of mitochondria in the nerve-preserving cultures may help maintain viability of RGCs.
Oke I, Hwang B, Heo H, Nguyen A, Lambert SR. Risk Factors for Retinal Detachment Repair After Pediatric Cataract Surgery in the United States. Ophthalmol Sci 2022;2(4):100203.Abstract
PURPOSE: To determine the cumulative incidence of retinal detachment (RD) repair following pediatric cataract surgery and identify the associated risk factors. DESIGN: US population-based insurance claims retrospective cohort study. PARTICIPANTS: Patients ≤ 18 years old who underwent cataract surgery in 2 large databases: Optum Clinformatics (2003-2021) and IBM MarketScan (2007-2016). METHODS: Individuals with ≥ 6 months of prior enrollment were included, and those with a history of RD, RD repair, traumatic cataract, spherophakia, or ectopia lentis were excluded. The primary outcome was time between initial cataract surgery and RD repair. The risk factors investigated included age, sex, persistent fetal vasculature (PFV), prematurity, intraocular lens (IOL) placement, and pars plana lensectomy approach. MAIN OUTCOME MEASURES: Kaplan-Meier estimated cumulative incidence of RD repair 5 years after cataract surgery and hazard ratios (HRs) with 95% confidence intervals (CIs) from multivariable Cox proportional hazards regression models. RESULTS: Retinal detachment repair was performed on 47 of 3289 children included in this study. The cumulative incidence of RD repair within 5 years of cataract surgery was 2.0% (95% CI, 1.3%-2.6%). Children requiring RD repair were more likely to have a history of prematurity or PFV and less likely to have an IOL placed (all P < 0.001). Factors associated with RD repair in the multivariable analysis included a history of prematurity (HR, 6.89; 95% CI, 3.26-14.56; P < 0.001), PFV diagnosis (HR, 8.20; 95% CI, 4.11-16.37; P < 0.001), and IOL placement (HR, 0.44; 95% CI, 0.21-0.91; P = 0.03). Age at surgery, sex, and pars plana lensectomy approach were not significantly associated with RD repair after adjusting for all other covariates. CONCLUSIONS: Approximately 2% of patients will undergo RD repair within 5 years of pediatric cataract surgery. Children with a history of PFV and prematurity undergoing cataract surgery without IOL placement are at the greatest risk.
Yu Z, Correa VSMC, Efstathiou NE, Albertos-Arranz H, Chen XH, Ishihara K, Iesato Y, Narimatsu T, Ntentakis D, Vavvas DG. UVA induces retinal photoreceptor cell death via receptor interacting protein 3 kinase mediated necroptosis. Cell Death Discov 2022;8(1):489.Abstract
Ultraviolet light A (UVA) is the only UV light that reaches the retina and can cause indirect damage to DNA via absorption of photons by non-DNA chromophores. Previous studies demonstrate that UVA generates reactive oxygen species (ROS) and leads to programmed cell death. Programmed cell death (PCD) has been implicated in numerous ophthalmologic diseases. Here, we investigated receptor interacting protein 1 and 3 (RIPK1 and RIPK3) kinases, key signaling molecules of PCD, in UVA-induced photoreceptor injury using in vitro and ex vivo models. UVA irradiation activated RIPK3 but not RIPK1 and mediated necroptosis through MLKL that lie downstream of RIPK3 and induced apoptosis through increased oxidative stress. Moreover, RIPK3 but not RIPK1 inhibition suppresses UVA-induced cell death along with the downregulation of MLKL and attenuates the levels of oxidative stress and DNA fragmentation. In conclusion, these results identify RIPK3, not RIPK1, as a critical regulator of UVA-induced necroptosis cell death in photoreceptors and highlight RIPK3 potential as a neuroprotective target.
Li A, Apivatthakakul A, Papaliodis GN, Sobrin L. High Positive Predictive Value of Fluorescein Angiography Contiguous, Perineural Retinal Vascular Leakage Pattern for Birdshot Chorioretinopathy. Ocul Immunol Inflamm 2022;:1-6.Abstract
PURPOSE: To determine the sensitivity and positive predictive value (PPV) of a contiguous, perineural retinal vascular leakage fluorescein angiography (FA) pattern in birdshot chorioretinopathy (BSCR) patients. METHODS: Patients with BSCR and other posterior uveitis/retinal vasculitis and a FA were identified. Two graders reviewed the first FA for leakage primarily around the optic nerve and along the larger arcade vessels. We compared the rates of this pattern in BSCR and non-BSCR patients and calculated sensitivity and PPV. We compared clinical characteristics of BSCR patients with and without this pattern. RESULTS: 64 BSCR and 98 non-BSCR patients were identified. The FA pattern's sensitivity, specificity, and PPV were 57.8%, 91.8%, and 82.2%. This pattern was significantly more common in BSCR patients earlier in their disease (p = .004). CONCLUSIONS: A contiguous, perineural retinal vascular leakage FA pattern can help identify potential BSCR patients for further testing. This pattern is more common closer to symptom onset.
Wang Z, Yemanyi F, Blomfield AK, Bora K, Huang S, Liu C-H, Britton WR, Cho SS, Tomita Y, Fu Z, Ma J-X, Li W-H, Chen J. Amino acid transporter SLC38A5 regulates developmental and pathological retinal angiogenesis. Elife 2022;11Abstract
Amino acid (AA) metabolism in vascular endothelium is important for sprouting angiogenesis. SLC38A5 (solute carrier family 38 member 5), an AA transporter, shuttles neutral AAs across cell membrane, including glutamine, which may serve as metabolic fuel for proliferating endothelial cells (ECs) to promote angiogenesis. Here, we found that Slc38a5 is highly enriched in normal retinal vascular endothelium, and more specifically, in pathological sprouting neovessels. Slc38a5 is suppressed in retinal blood vessels from Lrp5-/- and Ndpy/- mice, both genetic models of defective retinal vascular development with Wnt signaling mutations. Additionally, Slc38a5 transcription is regulated by Wnt/β-catenin signaling. Genetic deficiency of Slc38a5 in mice substantially delays retinal vascular development and suppresses pathological neovascularization in oxygen-induced retinopathy modeling ischemic proliferative retinopathies. Inhibition of SLC38A5 in human retinal vascular ECs impairs EC proliferation and angiogenic function, suppresses glutamine uptake, and dampens vascular endothelial growth factor receptor 2. Together these findings suggest that SLC38A5 is a new metabolic regulator of retinal angiogenesis by controlling AA nutrient uptake and homeostasis in ECs.
Raevis JJ, Lemire CA, Ramsey DJ, Riccobono J, Gonzalez E. Deformation of Aflibercept and Ranibizumab Syringes Causes Variation in Intravitreal Injection Volume and Risks Retinal Tear Formation. Ophthalmol Sci 2022;2(4):100202.Abstract
PURPOSE: The intravitreal injection volume is known to vary with plunger alignment and the speed of injection. We investigated the role that syringe stopper deformation plays in allowing excess volumes to be injected into the eye and the potential for the vitreous humor to become incarcerated when excess force is released within the eye. DESIGN: Experimental study. METHODS: Aflibercept prefilled syringes (PFSs), ranibizumab PFSs, and 1-ml tuberculin (TB) syringes were subjected to increasing injection force to assess the extent to which each design allowed for excess volumes to be expelled after the stopper reached the bottom of the syringe barrel (i.e., after the 50-μl dose was expelled). MAIN OUTCOME MEASURES: Additional volume expelled with stopper deformation. RESULTS: Syringe stoppers are capable of deformation into the dead space when additional force is applied. This allows for progressively greater medication doses to be administered. At an additional force of 3.92 N after the syringe stopper came in contact with the bottom of the syringe barrel, the aflibercept PFSs, ranibizumab PFSs, and 1-ml TB syringes dispensed an additional 17.2%, 11.4%, and 0.8% higher volume than the intended volume of 50 μl, respectively. Upon release of this force, a proportional volume was observed to be drawn back into the needle. CONCLUSIONS: The intravitreal injection volume varies with the force applied to fully depressed syringes because of syringe stopper deformation. We advise that performing forceful intravitreal injections be avoided to prevent excessive dosing of medication. We also caution that pressure applied to the plunger during intravitreal injections not be released while the needle is in the vitreous cavity to guard against vitreous incarceration, which could lead to retinal tear formation or detachment.
Baker CW, Josic K, Maguire MG, Jampol LM, Martin DF, Rofagha S, Sun JK, Sun JK. Comparison of Snellen Visual Acuity Measurements in Retinal Clinical Practice to eETDRS Protocol Visual Acuity Assessment. Ophthalmology 2022;Abstract
PURPOSE: Evaluate the differences between clinical visual acuity (VA) as recorded in medical records and electronic ETDRS (eETDRS) protocol VA measurements and factors affecting the size of the differences. DESIGN: Retrospective chart review. PARTICIPANTS: Study and fellow eyes of participants enrolled in DRCR Retina Network Protocols AC and AE (diabetic macular edema), and W (non-proliferative diabetic retinopathy) with clinical VA recorded within 3 months before the protocol visit. METHODS: Linear mixed models evaluated the differences and their association with patient and ocular factors in univariable and multivariable models, with random effects for correlations within sites and participants. MAIN OUTCOME MEASURE: Difference between VA letter scores measured by eETDRS during a study protocol visit versus measured by Snellen during a regular clinical visit (Snellen fraction converted to eETDRS). RESULTS: Data from 1016 eyes (511 participants) across 74 sites were analyzed. The mean VA measurements were 68.6 letters (Snellen equivalent 20/50) at the clinical visit and 76.3 letters (Snellen equivalent 20/32) at the protocol visit, with a mean (standard deviation, SD) of 26 (21) days between visits. Mean (SD) protocol VA was better than clinical VA by 7.6 (9.6) letters overall, 10.7 (12.6) letters in eyes with clinical VA ≤20/50 (n = 376) and 5.8 (6.6) letters in eyes with clinical VA ≥20/40 (n = 640). On average, the difference between clinical and protocol VA was 1.3 letters smaller for every 1-line (5 letters) increase in clinical VA (p < 0.001). Mean (SD) differences by clinical correction of refractive error were 3.9 (9.0) letters with refraction, 6.9 (9.2) letters with glasses/contact lenses, 7.9 (11.5) letters with pinhole and 9.8 (9.3) letters without correction (p=0.06). CONCLUSION: On average, clinical Snellen VA is likely to be 1-2 lines worse than eETDRS protocol refraction and VA testing, which may partly explain why clinical practice does not always replicate clinical trial results. Eyes with lower clinical measurements and eyes tested without clinical refraction tended to have larger differences. Considering the potential discrepancies between clinical and protocol VA measurements, refracting eyes in the clinic may benefit patients when determining treatment plans and study referrals based on vision.
Huang H, Saddala MS, Mukwaya A, Mohan RR, Lennikov A. Association of Placental Growth Factor and Angiopoietin in Human Retinal Endothelial Cell-Pericyte co-Cultures and iPSC-Derived Vascular Organoids. Curr Eye Res 2022;:1-15.Abstract
PURPOSE: Placental growth factor (PlGF) and Angiopoietin (Ang)-1 are two proteins that are involved in the regulation of endothelial cell (EC) growth and vasculature formation. In the retina and endothelial cells, pericytes are the major source of both molecules. The purpose of this study is to examine the association of PlGF and Ang-1 with human EC/pericyte co-cultures and iPSC-derived vascular organoids. METHODS: In this study, we used co-cultures of human primary retinal endothelial cells (HREC) and primary human retinal pericytes (HRP), western blotting, immunofluorescent analysis, TUNEL staining, LDH-assays, and RNA seq analysis, as well as human-induced pluripotent stem cells (iPSC), derived organoids (VO) to study the association between PlGF and Ang-1. RESULTS: Inhibition of PlGF by PlGF neutralizing antibody in HREC-HRP co-cultures resulted in the increased expression of Ang-1 and Tie-2 in a dose-dependent manner. This upregulation was not observed in HREC and HRP monocultures but only in co-cultures suggesting the association of pericytes and endothelial cells. Furthermore, Vascular endothelial growth factor receptor 1 (VEGFR1) inhibition abolished the Ang-1 and Tie-2 upregulation by PlGF inhibition. The pericyte viability in high-glucose conditions was also reduced by VEGFR1 neutralization. Immunofluorescent analysis showed that Ang-1 and Ang-2 were expressed mainly by perivascular cells in the VO. RNA seq analysis of the RNA isolated from VO in high glucose conditions indicated increased PlGF and Ang-2 expressions in the VO. PlGF inhibition increased the expression of Ang-1 and Tie-2 in VO, increasing the pericyte coverage of the VO microvascular network. CONCLUSION: Combined, these results suggest PlGF's role in the regulation of Ang-1 and Tie-2 expression through VEGFR1. These findings provide new insights into the neovascularization process in diabetic retinopathy and new targets for potential therapeutic intervention.
Fu Z, Nilsson AK, Hellstrom A, Smith LEH. Retinopathy of prematurity: Metabolic risk factors. Elife 2022;11Abstract
At preterm birth, the retina is incompletely vascularized. Retinopathy of prematurity (ROP) is initiated by the postnatal suppression of physiological retinal vascular development that would normally occur in utero. As the neural retina slowly matures, increasing metabolic demand including in the peripheral avascular retina, leads to signals for compensatory but pathological neovascularization. Currently, only late neovascular ROP is treated. ROP could be prevented by promoting normal vascular growth. Early perinatal metabolic dysregulation is a strong but understudied risk factor for ROP and other long-term sequelae of preterm birth. We will discuss the metabolic and oxygen needs of retina, current treatments, and potential interventions to promote normal vessel growth including control of postnatal hyperglycemia, dyslipidemia and hyperoxia-induced retinal metabolic alterations. Early supplementation of missing nutrients and growth factors and control of supplemental oxygen promotes physiological retinal development. We will discuss the current knowledge gap in retinal metabolism after preterm birth.