2021

Artificial intelligence (AI), with its subdivisions (machine and deep learning), is a new branch of computer science that has shown impressive results across a variety of domains. The applications of AI to medicine and biology are being widely investigated. Medical specialties that rely heavily on images, including radiology, dermatology, oncology and ophthalmology, were the first to explore AI approaches in analysis and diagnosis. Applications of AI in ophthalmology have concentrated on diseases with high prevalence, such as diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration (AMD), and glaucoma. Here we provide an overview of AI applications for diagnosis, classification, and clinical management of AMD and other macular dystrophies.

Axon regenerative failure in the mature CNS contributes to functional deficits following many traumatic injuries, ischemic injuries, and neurodegenerative diseases. The complement cascade of the innate immune system responds to pathogen threat through inflammatory cell activation, pathogen opsonization, and pathogen lysis, and complement is also involved in CNS development, neuroplasticity, injury, and disease. Here, we investigated the involvement of the classical complement cascade and microglia/monocytes in CNS repair using the mouse optic nerve injury (ONI) model, in which axons arising from retinal ganglion cells (RGCs) are disrupted. We report that central complement C3 protein and mRNA, classical complement C1q protein and mRNA, and microglia/monocyte phagocytic complement receptor CR3 all increase in response to ONI, especially within the optic nerve itself. Importantly, genetic deletion of C1q, C3, or CR3 attenuates RGC axon regeneration induced by several distinct methods, with minimal effects on RGC survival. Local injections of C1q function-blocking antibody revealed that complement acts primarily within the optic nerve, not retina, to support regeneration. Moreover, C1q opsonizes and CR3+ microglia/monocytes phagocytose growth-inhibitory myelin debris after ONI, a likely mechanism through which complement and myeloid cells support axon regeneration. Collectively, these results indicate that local optic nerve complement-myeloid phagocytic signaling is required for CNS axon regrowth, emphasizing the axonal compartment and highlighting a beneficial neuroimmune role for complement and microglia/monocytes in CNS repair.SIGNIFICANCE STATEMENT Despite the importance of achieving axon regeneration after CNS injury and the inevitability of inflammation after such injury, the contributions of complement and microglia to CNS axon regeneration are largely unknown. Whereas inflammation is commonly thought to exacerbate the effects of CNS injury, we find that complement proteins C1q and C3 and microglia/monocyte phagocytic complement receptor CR3 are each required for retinal ganglion cell axon regeneration through the injured mouse optic nerve. Also, whereas studies of optic nerve regeneration generally focus on the retina, we show that the regeneration-relevant role of complement and microglia/monocytes likely involves myelin phagocytosis within the optic nerve. Thus, our results point to the importance of the innate immune response for CNS repair.

INTRODUCTION: We evaluated the associations of clinical and demographic characteristics with visual acuity (VA) with over 5 years in a subspecialty noninfectious uveitis population. METHODS: Retrospective data from 5,530 noninfectious uveitis patients were abstracted by expert reviewers, and contemporaneous associations of VA with demographic and clinical factors were modeled. RESULTS: Patients were a median of 41 years old, 65% female, and 73% white. Eyes diagnosed ≥5 years prior to cohort entry had worse VA (-1.2 lines) than those diagnosed <6 months prior, and eyes with cataract surgery performed prior to entry had worse VA (-5.9 lines) than those performed during follow-up. Vitreous haze (-4.2 lines for 3+ vs quiet), hypotony (-2.5 lines for ≤5 mm Hg vs 6-23 mm Hg), and CNV (-1.8 lines) all were strongly associated with reduced VA. CONCLUSION: Factors associated with reduced VA included well-known structural complications, and lack of subspecialty care during cataract surgery.

PURPOSE: The International Neonatal Consortium recently published a proposed retinopathy of prematurity (ROP) activity scale intended for use in clinical trials after validation. The aim of this study was to validate the ROP activity scale (ROP-ActS) in a ROP screened cohort with protocol based collected data by evaluating the ability of the ROP-Act scores to predict ROP treatment. In addition, we aimed to evaluate the scale's sensitivity characteristic of disease severity by studying association with gestational age (GA) in comparison with conventionally used ROP stage and zone. METHODS: A cohort of 535 preterm infants with 3324 ROP examinations with an end-point of ROP treatment or end of screening in Gothenburg, Sweden, was included. Median GA was 28.1 weeks, 47.5% were girls, and 74 (13.8%) infants were treated for ROP. The validation was performed by estimating probabilities for ROP treatment, and by applying logistic and linear regression. RESULTS: The original ROP-ActS was overall well-ordered with respect to ability to predict ROP treatment but could be improved by re-ordering score 3 (zone II stage 1) and 5 (zone III stage 3) based on our clinical cohort data. The modified ROP-ActS was superior to ROP stage and zone in the prediction analysis of ROP treatment. Modified ROP-ActS was more strongly related to GA than currently used ROP stage, but not zone. CONCLUSION: In the studied cohort, the modified ROP-ActS could better predict ROP treatment compared to ROP stage and zone. Retinopathy of Prematurity Activity Scale (ROP-ActS) had a superior sensitivity characteristic studied through association to GA than conventionally used ROP stage.

BACKGROUND/AIMS: As swept-source optical coherence tomography (SS-OCT) simultaneously obtains 128 meridional scans, it is important to identify which scans are playing the main role in classifying gonioscopic angle closure to simplify the analysis. We aimed to evaluate the diagnostic performance of every meridional scan in its ability to detect gonioscopic angle closure. METHODS: Observational study with 2027 phakic subjects consecutively recruited from a community polyclinic. Gonioscopy and SS-OCT were performed. Gonioscopic angle closure was defined as non-visibility of the posterior trabecular meshwork in ≥180° of the angle, while SS-OCT was defined as iridotrabecular contact anterior to the scleral spur. The area under the receiver operating characteristic curve (AUC) was calculated to assess the diagnostic performance of each single scan, the sequential anticlockwise cumulative effect of those single scans and different combinations of them. RESULTS: The AUCs of each scan ranged from 0.73 to 0.82. The single scan at 80°-260° had the highest AUC (0.82, 95% CI 0.79 to 0.84) and performed significantly better than most of the temporonasal scans (from 0° to 52° and from 153° to 179°). The superoinferior scans achieved higher AUCs compared with the temporonasal ones. When assessing the cumulative effect of adding individual scans consecutively, the peak AUC (0.80) was obtained when considering the superoinferior scans closer to 80°-85°, but no further positive cumulative effect was seen when adding the rest of the temporonasal scans of the circumference. CONCLUSIONS: In conclusion, the single SS-OCT scan at 80°-260° had the highest diagnostic performance. Our study suggests that the 360° evaluation may not translate to better clinical utility for detection of gonioscopic angle closure.

PURPOSE: This proof-of-concept study evaluates the ability to assess eyelid measurements and the reproducibility of eyelid measurements using a simple measurement tool paired with digital cell phone photography in children. METHODS: Seventy consecutive patients and their siblings, 2-19 years of age, were prospectively enrolled. Participants underwent clinical examination and cell phone photography with a simple measurement tool. An ophthalmologist and nonophthalmologist assessed photographs for interpalpebral fissure distance (IPFD), margin reflex distance-1 (MRD1), and levator function (LF). Clinical examinations and photographs were repeated on the same day in a random sample (n = 20). The agreement of grading photographs compared to clinical examination was assessed using Bland-Altman plots. Intra-grader repeatability of the clinical examination, repeatability of photographic technique, and interobserver reproducibility of photographic assessment was evaluated with intraclass correlation coefficients (ICC). RESULTS: Of photographs acquired, both graders considered quality good/fair in 100% to assess IPFD and MRD1, and 70% to assess LF. The mean difference (limits of agreement) in mm between clinical examination and photographic assessment was 1.1 (-1.5 to 3.8) for IPFD, 0.7 (-1.8 to 3.1) for MRD1, and 1.1 (-3.5 to 5.7) for LF. Intraobserver repeatability on clinical examination was excellent for IPFD (ICC = 0.81), MRD1 (ICC = 0.88), and LF (ICC = 0.94). Repeatability of photographic technique was fair for IPFD (ICC = 0.44) and good for MRD1 (ICC = 0.74) and LF (ICC = 0.77). Interobserver photographic assessment repeatability was excellent for IPFD (ICC = 0.94), MRD1 (ICC = 0.96), and LF (ICC = 0.92). CONCLUSIONS: Photographic assessment of eyelid measurements in children is possible, highly reproducible between graders, and enables documentation for future comparison.

Importance: There is scant rigorous evidence about the real-world mobility benefit of electronic mobility aids. Objective: To evaluate the effect of a collision warning device on the number of contacts experienced by blind and visually impaired people in their daily mobility. Design, Setting, and Participants: In this double-masked randomized clinical trial, participants used a collision warning device during their daily mobility over a period of 4 weeks. A volunteer sample of 31 independently mobile individuals with severe visual impairments, including total blindness and peripheral visual field restrictions, who used a long cane or guide dog as their habitual mobility aid completed the study. The study was conducted from January 2018 to December 2019. Interventions: The device automatically detected collision hazards using a chest-mounted video camera. It randomly switched between 2 modes: active mode (intervention condition), where it provided alerts for detected collision threats via 2 vibrotactile wristbands, and silent mode (control condition), where the device still detected collisions but did not provide any warnings to the user. Scene videos along with the collision warning information were recorded by the device. Potential collisions detected by the device were reviewed and scored, including contacts with the hazards, by 2 independent reviewers. Participants and reviewers were masked to the device operation mode. Main Outcomes and Measures: Rate of contacts per 100 hazards per hour, compared between the 2 device modes within each participant. Modified intention-to-treat analysis was used. Results: Of the 31 included participants, 18 (58%) were male, and the median (range) age was 61 (25-73) years. A total of 19 participants (61%) had a visual acuity (VA) of light perception or worse, and 28 (90%) reported a long cane as their habitual mobility aid. The median (interquartile range) number of contacts was lower in the active mode compared with silent mode (9.3 [6.6-14.9] vs 13.8 [6.9-24.3]; difference, 4.5; 95% CI, 1.5-10.7; P < .001). Controlling for demographic characteristics, presence of VA better than light perception, and fall history, the rate of contacts significantly reduced in the active mode compared with the silent mode (β = 0.63; 95% CI, 0.54-0.73; P < .001). Conclusions and Relevance: In this study involving 31 visually impaired participants, the collision warnings were associated with a reduced rate of contacts with obstacles in daily mobility, indicating the potential of the device to augment habitual mobility aids. Trial Registration: ClinicalTrials.gov Identifier: NCT03057496.

Purpose: Mesenchymal stromal cells (MSCs) have been shown to enhance tissue repair as a cell-based therapy. In preparation for a phase I clinical study, we evaluated the safety, dosing, and efficacy of bone marrow-derived MSCs after subconjunctival injection in preclinical animal models of mice, rats, and rabbits. Methods: Human bone marrow-derived MSCs were expanded to passage 4 and cryopreserved. Viability of MSCs after thawing and injection through small-gauge needles was evaluated by vital dye staining. The in vivo safety of human and rabbit MSCs was studied by subconjunctivally injecting MSCs in rabbits with follow-up to 90 days. The potency of MSCs on accelerating wound healing was evaluated in vitro using a scratch assay and in vivo using 2-mm corneal epithelial debridement wounds in mice. Human MSCs were tracked after subconjunctival injection in rat and rabbit eyes. Results: The viability of MSCs after thawing and immediate injection through 27- and 30-gauge needles was 93.1% ± 2.1% and 94.9% ± 1.3%, respectively. Rabbit eyes demonstrated mild self-limiting conjunctival inflammation at the site of injection with human but not rabbit MSCs. In scratch assay, the mean wound healing area was 93.5% ± 12.1% in epithelial cells co-cultured with MSCs compared with 40.8% ± 23.1% in controls. At 24 hours after wounding, all MSC-injected murine eyes had 100% corneal wound closure compared with 79.9% ± 5.5% in controls. Human MSCs were detectable in the subconjunctival area and peripheral cornea at 14 days after injection. Conclusions: Subconjunctival administration of MSCs is safe and effective in promoting corneal epithelial wound healing in animal models. Translational Relevance: These results provide preclinical data to support a phase I clinical study.

PRECIS: A cross-sectional sample of the US ophthalmology residency graduating class of 2018 revealed that 18.4% of residents logged <5 traditional glaucoma surgeries, and 63.4% logged at least 1 microinvasive glaucoma surgery (MIGS). PURPOSE: Describe the state of MIGS in US ophthalmology residency training and propose a glaucoma procedure classification system for residents' surgical case logs. METHODS: Deidentified case logs from residents graduating in 2018 were requested from US residency program directors. RESULTS: Case logs were received for 152/488 (31%) residents from 36/115 (31%) programs. The mean number of traditional glaucoma surgeries per resident was 9.0±5.9 (range: 0 to 31). The mean number of MIGS per resident was 5.2±8.9 cases (range: 0 to 58). There were 28/152 (18.4%) residents from 16/36 (44.4%) programs who logged <5 traditional glaucoma surgeries as primary surgeon, and 3/152 (2.0%) residents from 3/36 (8.3%) programs who logged zero traditional glaucoma surgeries as primary surgeon. There were 98/152 (64.5%) residents from 32/36 (88.8%) programs who logged <5 MIGS as primary surgeon, and 48/152 (31.6%) residents from 25 of 36 (69.4%) programs who logged zero MIGS as primary surgeon. There were 104/152 (63.4%) residents from 33/36 (91.6%) programs who logged at least 1 MIGS as primary surgeon; there were 3/36 (8.3%) residency programs where no resident logged any MIGS as primary surgeon. CONCLUSIONS: US ophthalmology residents' MIGS experience varies widely. Residents can satisfy glaucoma surgery requirements with some MIGS, even in the absence of adequate traditional glaucoma surgeries. We propose a residency case log classification system that better reflects the growing role of MIGS in clinical practice and helps ophthalmic educators more accurately track procedures requiring related skills.

BACKGROUND: The severity and extent of microaneurysms (MAs) have been used to determine diabetic retinopathy (DR) severity and estimate the risk of DR progression over time. The recent introduction of ultrawide field (UWF) imaging has allowed ophthalmologists to readily image nearly the entire retina. Manual counting of MAs, especially on UWF images, is laborious and time-consuming, limiting its potential use in clinical settings. Automated MA counting techniques are potentially more accurate and reproducible compared to manual methods. METHOD: Review of available literature on current techniques of automated MA counting techniques on both ultrawide field (UWF) color images (CI) and fluorescein angiography (FA) images. RESULTS: Automated MA counting techniques on UWF images are still in the early phases of development with UWF-FA counts being further along. Early studies have demonstrated that these techniques are accurate and reproducible. CONCLUSION: Automated techniques may be an appropriate option for detecting and quantifying MAs on UWF images, especially in eyes with earlier DR severity. Larger studies are needed to appropriately validate these techniques and determine if they add substantially to clinical practice compared to standard DR grading.

Since the new coronavirus known as 2019-nCoV (severe acute respiratory syndrome coronavirus 2, SARS-CoV-2) has widely spread in Wuhan, China, with severe pneumonia, scientists and physicians have made remarkable efforts to use various options such as monoclonal antibodies, peptides, vaccines, small-molecule drugs and interferon therapies to control, prevent or treatment infections of 2019-nCoV. However, no vaccine or drug has yet been confirmed to completely treat 2019-nCoV. In this review, we focus on the use of potential available small-molecule drug candidates for treating infections caused by 2019-nCoV.

PURPOSE: The purpose of this study is to compare the severity of chronic ocular complications of Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) induced by lamotrigine (LT) vs. trimethoprim-sulfamethoxazole (TS). METHODS: This retrospective cross-sectional study evaluated all SJS/TEN patients treated within our hospital network from 2008 to 2018. Inclusion criteria included patients with reactions identified as caused by either LT or TS, and patients with at least one ophthalmology follow up in the chronic phase (≥3 months from disease onset). Primary outcome measures included LogMAR best-corrected VA at most recent visit and the presence or absence of severe ocular complications (SOC). Secondary outcome measures included chronic ocular complication severity scores using a modified Sotozono scoring system. RESULTS: Forty-eight eyes of 24 patients were included in the study. The mean duration of follow-up was 39.50 ± 35.62 vs. 48.17 ± 33.09 months, respectively (p = 0.482). The LT group had worse average VA at the most recent visit (LogMAR VA; 0.508 vs. 0.041, p < 0.0001) and had a higher prevalence of SOCs (66.7% vs. 8.3%, p = 0.0038). The LT group scored worse on Sotozono chronic complications scores for the cornea (1.875 vs. 0.5, p = 0.0018), eyelid margin (5.583 vs.3.083, p = 0.0010), and overall condition (8.500 vs. 4.833, p = 0.0015). Sub-analyses showed that a moderate or severe acute ocular severity score was a significant predictor of chronic outcomes. CONCLUSIONS: Compared to patients with TS-induced SJS/TEN, patients with LT-induced SJS/TEN developed worse chronic ocular complications on several parameters. Future prospective studies are warranted to provide additional insight into the drug type as a predictor of chronic ocular complications.

PURPOSE: To compare onset times of glaucoma progression among different glaucoma tests: disc photography (DP), visual field (VF) testing, 2-dimensional (2D) retinal nerve fiber layer (RNFL) thickness, and 3-dimensional (3D) spectral-domain (SD) OCT neuroretinal rim measurements. DESIGN: Prospective, longitudinal cohort study. PARTICIPANTS: One hundred twenty-four eyes of 124 patients with open-angle glaucoma. METHODS: Over a 5-year period, 124 patients with open-angle glaucoma underwent yearly DP, VF testing, SD OCT RNFL thickness scans, and optic nerve volume scans (Spectralis; Heidelberg Engineering), all performed on the same day. From high-density optic nerve volume scans, custom-built software calculated the minimum distance band (MDB) thickness, a 3D neuroretinal rim parameter. Patients were classified as glaucoma progressors or nonglaucoma progressors using event-based analysis. Progression by DP and VF testing occurred when 3 masked glaucoma specialists unanimously concurred. Progression by RNFL and MDB thickness occurred if change of more than test-retest variability was observed. Kaplan-Meier curves were constructed to analyze time-to-progression data. Kappa Coefficients were used to measure agreement of progressing eyes among methods. MAIN OUTCOME MEASURES: Time to glaucoma progression among all 4 methods. RESULTS: Global MDB thickness detected glaucoma progression in the highest percentage of eyes (52.4%) compared with DP (16.1%; P < 0.001) and global RNFL thickness (15.3%; P < 0.001). Global MDB thickness detected glaucoma progression earlier than either DP (23 months vs. 44 months; P < 0.001) or global RNFL thickness (23 months vs. 33 months; P < 0.001). Among MDB progressing eyes, 46.2% were confirmed simultaneously or later by other conventional methods. Agreement of glaucoma-progressing eyes for all 4 methods in paired fashion were slight to fair (κ = 0.095-0.300). CONCLUSIONS: High-density 3D SD OCT neuroretinal rim measurements detected glaucoma progression approximately 1 to 2 years earlier compared with current clinically available structural tests (i.e., DP and 2D RNFL thickness measurements).

Primary central nervous system lymphoma-ophthalmic variant (PCNSL-O) is an ocular subset of PCNSL predominantly involving subretinal pigment epithelium space, retina, and vitreous. The ophthalmic manifestations can precede, occur simultaneously, or follow other compartments of the CNS. Clinical trials have resulted in a significantly improved outcome in PCNSL patients over the past 2 decades, with a higher proportion of patients receiving frontline high dose methotrexate-based polychemotherapy regimens with curative intent; however, the current management of PCNSL-O remains controversial owing to lack of prospective data. The goals of PCNSL-O treatment are both to achieve local (ocular) control and to prevent tumor-specific mortality from further CNS involvement. Despite achieving high rates of ocular control with intravitreal agents like methotrexate and rituximab, the overall survival is poor, as 65-85% of patients eventually succumb to CNS disease. Few studies define the role of systemic chemotherapy with/without local treatment as a first line induction treatment for PCNSL-O considering limiting factors such as ocular penetration of systemically administered drugs and treatment related neurotoxicity. Also, the role of adjuvant treatment for PCNSL-O to prevent CNS progression and to improve overall survival is unknown. In this systematic review of the literature, we analyze treatment outcomes of various regimens (local, systemic, and combination) in terms of local control, CNS progression, and overall survival.

Historically, surgical access to orbital tumors has required a transcutaneous, transconjunctival or transcranial approach. Resection of orbital tumors is notoriously challenging due to the surrounding dense network of critical structures in a confined bony cavity. Advances in endoscopic endonasal surgery, initially used for sinonasal and skull base conditions, have allowed for expansion of its applications beyond the sinorbital interface. In the past decade, the evolution of techniques has enabled a purely endoscopic, minimally invasive approach to medially located orbital pathology with good outcomes. With experience and multidisciplinary collaboration between orbit and rhinologic surgeons, this has expanded to allow for a safe and effective transnasal approach to nearly all regions of the orbit with or without assistance from the orbital side. This review summarizes the relevant anatomy, variations of surgical approaches, and literature regarding outcomes of the endoscopic endonasal approach to orbital tumors.

To analyze functional and anatomical response patterns to dexamethasone (DEX) implant in diabetic macular edema (DME), to describe proportion of responders and non-responders, and to propose a new DME grading system. Retrospective, multicenter, observational cohort study. Naïve and non-naïve DME patients were treated with DEX, with visual acuity (VA) ≥ 0.2 logMAR and central subfield thickness (CST) of ≥ 300 µm. Functional and anatomical responses were graded after 2 and 4 months, and categorized as early and stable improvement, early and progressive improvement, pendular response, delayed improvement, and persistent non-response. 417 eyes were included (175 treatment naïve eyes). Compared to non-naïve eyes, naïve eyes showed a very good functional response (VA gain ≥ 10 letters) more frequently after 2 and 4 months (56% and 57% [naïve] vs. 33% and 28% [non-naïve], p < 0.001). A VA gain < 5 letters (non-response) after 2 and 4 months was seen in 18% and 16% of naïve eyes, and in 49% and 53% of non-naïve eyes (p < 0.001). A lack of anatomical response was rare in both groups, but more frequently in non-naïve eyes (12% vs. 4%, p = 0.003). Functionally and anatomically, naïve eyes showed most frequently an early and stable improvement (functionally: 77/175 44%; anatomically: 123/175 eyes, 70%). Most non-naïve eyes experienced no significant improvement functionally (97/242 eyes, 40%), despite a mostly early and stable improvement anatomical response pattern (102/242 eyes, 42%). Functional but not anatomical response patterns were influenced by baseline VA. Naïve and non-naïve eyes show different functional and anatomical response patterns to DEX implant. Functional non-responders are rare in naïve eyes, whereas anatomical non-response is unusual in both groups.

PURPOSE: To estimate the incidence of corneal endothelial transplantation and identify risk factors among patients with non-infectious ocular inflammation. DESIGN: Retrospective cohort study. METHODS: Adult patients attending United States tertiary uveitis care facilities diagnosed with non-infectious ocular inflammation were identified from the Systemic Immunosuppressive Therapy for Eye Diseases Cohort Study. Time-to-event analysis was used to estimate the incidence of corneal endothelial transplantation (CET), including penetrating keratoplasty, Descemet stripping endothelial keratoplasty, or Descemet Membrane Endothelial Keratoplasty procedures. The incidence of CET was calculated; potential risk factors for CET were also evaluated using Cox regression, accounting for correlation between eyes of the same patient. RESULTS: Overall, 14,264 eyes met eligibility criteria for this analysis with a median follow-up 1.8 eye-years. The Kaplan-Meier estimated incidence of CET within 10 years was 1.10% (95% CI, 0.68%-1.53%). Risk factors for CET included age >60 years vs. <40 years (aHR 16.5; 95% CI,4.70-57.9), anterior uveitis and scleritis vs. other types (aHR 2.97; 95% CI, 1.46-6.05 and aHR 4.14; 95% CI,1.28-13.4, respectively), topical corticosteroid treatment (aHR 2.84; 95% CI, 1.32-6.13), cataract surgery (aHR 4.44; 95% CI, 1.73-11.4), tube shunt surgery (aHR 11.9; 95% CI, 5.30-26.8), band keratopathy (aHR 5.12; 95% CI, 2.34-11.2), and hypotony (aHR 7.38; 95% CI, 3.14-17.4). Duration of uveitis, trabeculectomy, PAS, and ocular hypertension had no significant association after multivariate adjustment. CONCLUSIONS: In patients with ocular inflammation, CET occurred infrequently. Tube shunt surgery, hypotony, band keratopathy, cataract surgery, and anterior segment inflammation were associated with increased risk of undergoing corneal endothelial transplantation; these factors likely are associated with endothelial cell damage.

To describe a database of longitudinally graded telemedicine retinal images to be used as a comparator for future studies assessing grader recall bias and ability to detect typical progression (e.g. International Classification of Retinopathy of Prematurity (ICROP) stages) as well as incremental changes in retinopathy of prematurity (ROP). Cohort comprised of retinal images from 84 eyes of 42 patients who were sequentially screened for ROP over 6 consecutive weeks in a telemedicine program and then followed to vascular maturation or treatment, and then disease stabilization. De-identified retinal images across the 6 weekly exams (2520 total images) were graded by an ROP expert based on whether ROP had improved, worsened, or stayed the same compared to the prior week's images, corresponding to an overall clinical "gestalt" score. Subsequently, we examined which parameters might have influenced the examiner's ability to detect longitudinal change; images were graded by the same ROP expert by image view (central, inferior, nasal, superior, temporal) and by retinal components (vascular tortuosity, vascular dilation, stage, hemorrhage, vessel growth), again determining if each particular retinal component or ROP in each image view had improved, worsened, or stayed the same compared to the prior week's images. Agreement between gestalt scores and view, component, and component by view scores was assessed using percent agreement, absolute agreement, and Cohen's weighted kappa statistic to determine if any of the hypothesized image features correlated with the ability to predict ROP disease trajectory in patients. The central view showed substantial agreement with gestalt scores (κ = 0.63), with moderate agreement in the remaining views. Of retinal components, vascular tortuosity showed the most overall agreement with gestalt (κ = 0.42-0.61), with only slight to fair agreement for all other components. This is a well-defined ROP database graded by one expert in a real-world setting in a masked fashion that correlated with the actual (remote in time) exams and known outcomes. This provides a foundation for subsequent study of telemedicine's ability to longitudinally assess ROP disease trajectory, as well as for potential artificial intelligence approaches to retinal image grading, in order to expand patient access to timely, accurate ROP screening.

Understanding the molecular composition of pathogenic tissues is a critical step in understanding the pathophysiology of disease and designing therapeutics. First described in 2009, single cell RNA sequencing (scRNAseq) is a methodology whereby thousands of cells are simultaneously isolated into individual micro-environments that can be altered experimentally and the genome-wide RNA expression of each cell is captured. It has undergone significant technological improvement over the last decade and gained tremendous popularity. scRNAseq is an improvement over prior pooled RNA analyses which cannot identify the cellular composition and heterogeneity of a tissue of interest. This new approach offers new opportunity for new discovery, as tissue samples can now be sub-categorized into groups of cell types based on genome-wide gene expression in an unbiased fashion. As ophthalmologists, we are uniquely positioned to obtain pathologic samples from the eye for further study. ScRNAseq has already been applied in ophthalmology to characterize retinal tissue, and it may offer the key to understanding various pathological processes in the future.

BACKGROUND: Embolic events leading to retinal ischemia or cerebral ischemia share common risk factors; however, it has been well documented that the rate of concurrent cerebral infarction is higher in patients with a history of transient ischemic attack (TIA) than in those with monocular vision loss (MVL) due to retinal ischemia. Despite the fact that emboli to the ophthalmic artery (OA) and middle cerebral artery share the internal carotid artery (ICA) as a common origin or transit for emboli, the asymmetry in their final destination has not been fully explained. We hypothesize that the anatomic location of the OA takeoff from the ICA may contribute to the differential flow of small emboli to the retinal circulation vs the cerebral circulation. METHODS: We report a retrospective, comparative, case-control study on 28 patients with retinal ischemia and 26 patients with TIA or cerebral infarction caused by embolic events. All subjects underwent either computed tomography angiography or MRA. The location of the ipsilateral OA origin off the ICA was then graded in a blinded fashion and compared between cohorts. Vascular risk factors were collected for all patients, including age, sex, hypertension, hyperlipidemia, arrhythmia, diabetes, coronary artery disease, and smoking. RESULTS: We find that in patients with retinal ischemia of embolic etiology, the ipsilateral OA takeoff from the ICA is more proximal than in patients with cerebral infarcts or TIA (P = 0.0002). We found no statistically significant differences in demographic, vascular, or systemic risk factors. CONCLUSIONS: We find that the mean anatomical location of the OA takeoff from the ICA is significantly more proximal in patients with MVL due to retinal ischemia compared with patients with TIA or cerebral ischemia. This finding contributes significantly to our understanding of a long observed but poorly understood phenomenon that patients with MVL are less likely to have concurrent cerebral ischemia than are patients with TIA.