All

Hutton DW, Glassman AR, Stein JD, Bressler NM, Sun JK, Sun JK. Costs of Managing Diabetic Macular Edema with Good Visual Acuity with Aflibercept, Laser or Observation: DRCR Retina Network Protocol V. Am J Ophthalmol 2021;Abstract
PURPOSE: Since eyes with center-involved diabetic macular edema (CI-DME) and good baseline visual acuity (VA) showed no difference in VA loss when managed initially with observation, laser, or aflibercept, understanding the estimated costs of these strategies to the US population is relevant for health care planning. DESIGN: Pre-planned subgroup analysis from a randomized controlled trial METHODS, SETTING, AND PARTICIPANTS: Total costs for managing participants with CI-DME and good baseline VA assigned to aflibercept (n= 236), laser (n=240), or observation (n = 236) during the 2-year trial were calculated. Using epidemiological data and extrapolating costs, 10-year costs for caring for persons with CI-DME and good baseline VA throughout the US was estimated. INTERVENTIONS: Observation or laser groups initiated aflibercept if VA decreased. Aflibercept group received injections up to every 4 weeks. MAIN OUTCOMES AND MEASURES: Estimated 10-year U.S. population costs to manage CI-DME with good VA. RESULTS: Assuming all patients in the US with CI-DME and good baseline VA received aflibercept initially, 10-year costs were projected to be $28.80 billion compared with $14.42 billion if initially receiving laser treatment or $15.70 billion if initially observed, with aflibercept added if VA worsened in the laser or observation arms. CONCLUSIONS AND RELEVANCE: Similar VA outcomes on average are obtained by initially managing CI-DME and good baseline VA with laser or observation strategies instead of immediately using aflibercept. While any one of these three strategies might be warranted depending on an individual's specific circumstances, on a societal level, cost savings might be achieved with these first two approaches. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01909791.
Georgiou M, Fujinami K, Vincent A, Nasser F, Khateb S, Vargas ME, Thiadens AAHJ, de Carvalho ER, Nguyen X-T-A, Cabral De Guimarães TA, Robson AG, Mahroo OA, Pontikos N, Arno G, Fujinami-Yokokawa Y, Leo SM, Liu X, Tsunoda K, Hayashi T, Jimenez-Rolando B, Martin-Merida MI, Avila-Fernandez A, Carreño E, Garcia-Sandoval B, Carmen A, Sharon D, Kohl S, Huckfeldt RM, Boon CJF, Banin E, Pennesi ME, Wissinger B, Webster AR, Héon E, Khan AO, Zrenner E, Michaelides M. KCNV2-associated Retinopathy: Detailed Retinal Phenotype and Structural Endpoints - KCNV2 Study Group Report 2. Am J Ophthalmol 2021;Abstract
PURPOSE: To describe the detailed retinal phenotype of KCNV2-associated retinopathy. STUDY DESIGN: Multicenter international retrospective case series. METHODS: Review of retinal imaging including fundus autofluorescence (FAF) and optical coherence tomography (OCT), including qualitative and quantitative analyses. RESULTS: Three distinct macular FAF features were identified: i) centrally increased signal (n=35, 41.7%), ii) DAF (n=27, 31.1%), and iii) ring of increased signal (n=37, 44.0%). Five distinct FAF groups were identified based on combinations of those characteristics, with 23.5% of patients changing FAF group over a mean (range) follow-up of 5.9 years (1.9-13.1 years). Qualitative assessment was performed by grading OCT into five grades: (i) continuous EZ (20.5%), (ii) EZ disruption (26.1%), (iii) EZ absence, without optical gap and with preserved retinal pigment epithelium (RPE) complex (21.6%); iv) loss of EZ and an hyporeflective zone at the foveola (6.8%); and (v) outer retina and RPE complex loss (25.0%). Eighty-six patients had scans available from both eyes, with 83 (96.5%) having the same grade in both eyes, and 36.1% changed OCT grade over a mean follow-up of 5.5 years. The annual rate of ONL thickness change was similar for right and left eyes. CONCLUSION: KCNV2-associated retinopathy is a slowly progressive disease with early retinal changes, which are predominantly symmetric between eyes. The identification of a single OCT or FAF measurement as an endpoint to determine progression that applies to all patients may be challenging; although ONL thickness is a potential biomarker. Findings suggest a potential window for intervention until 40 years of age.
Islam R, Islam MM, Nilsson PH, Mohlin C, Hagen KT, Paschalis EI, Woods RL, Bhowmick SC, Dohlman CH, Espevik T, Chodosh J, Gonzalez-Andrades M, Mollnes TE. Combined blockade of complement C5 and TLR co-receptor CD14 synergistically inhibits pig-to-human corneal xenograft induced innate inflammatory responses. Acta Biomater 2021;127:169-179.Abstract
Inadequate supplies of donor corneas have evoked an escalating interest in corneal xenotransplantation. However, innate immune responses contribute significantly to the mechanism of xenograft rejection. We hypothesized that complement component C5 and TLR co-receptor CD14 inhibition would inhibit porcine cornea induced innate immune responses. Therefore, we measured cytokine release in human blood, induced by three forms of corneal xenografts with or without inhibitors. Native porcine cornea (NPC) induced interleukins (IL-1β, IL-2, IL-6, IL-8, IL-1ra), chemokines (MCP-1, MIP-1α, MIP-1β) and other cytokines (TNF, G-CSF, INF-γ, FGF-basic). Decellularized (DPC) and gamma-irradiated cornea (g-DPC) elevated the release of those cytokines. C5-blockade by eculizumab inhibited all the cytokines except G-CSF when induced by NPC. However, C5-blockade failed to reduce DPC and g-DPC induced cytokines. Blockade of CD14 inhibited DPC-induced cytokines except for IL-8, MCP-1, MIP-1α, and G-CSF, while it inhibited all of them when induced by g-DPC. Combined blockade of C5 and CD14 inhibited the maximum number of cytokines regardless of the xenograft type. Finally, by using the TLR4 specific inhibitor Eritoran, we showed that TLR4 activation was the basis for the CD14 effect. Thus, blockade of C5, when combined with TLR4 inhibition, may have therapeutic potential in pig-to-human corneal xenotransplantation. STATEMENT OF SIGNIFICANCE: Bio-engineered corneal xenografts are on the verge of becoming a viable alternative to allogenic human-donor-cornea, but the host's innate immune response is still a critical barrier for graft acceptance. By overruling this barrier, limited graft availability would no longer be an issue for treating corneal diseases. We showed that the xenograft induced inflammation is initiated by the complement system and toll-like receptor activation. Intriguingly, the inflammatory response was efficiently blocked by simultaneously targeting bottleneck molecules in the complement system (C5) and the TLR co-receptor CD14 with pharmaceutical inhibitors. We postulate that a combination of C5 and CD14 inhibition could have a great therapeutic potential to overcome the immunologic barrier in pig-to-human corneal xenotransplantation.
Sharifi S, Sharifi H, Guild C, Islam MM, Tran KD, Patzer C, Dohlman CH, Paschalis EI, Gonzalez-Andrades M, Chodosh J. Toward electron-beam sterilization of a pre-assembled Boston keratoprosthesis. Ocul Surf 2021;20:176-184.Abstract
PURPOSE: To evaluate the effects of electron-beam (E-beam) irradiation on the human cornea and the potential for E-beam sterilization of Boston keratoprosthesis (BK) devices when pre-assembled with a donor cornea prior to sterilization. METHODS: Human donor corneas and corneas pre-assembled in BK devices were immersed in recombinant human serum albumin (rHSA) media and E-beam irradiated at 25 kGy. Mechanical (tensile strength and modulus, and compression modulus), chemical, optical, structural, and degradation properties of the corneal tissue after irradiation and after 6 months of preservation were evaluated. RESULTS: The mechanical evaluation showed that E-beam irradiation enhanced the tensile and compression moduli of human donor corneas, with no impact on their tensile strength. By chemical and mechanical analysis, E-beam irradiation caused a minor degree of crosslinking between collagen fibrils. No ultrastructural changes due to E-beam irradiation were observed. E-beam irradiation slightly increased the stability of the cornea against collagenase-induced degradation and had no impact on glucose diffusion. The optical evaluation showed transparency of the cornea was maintained. E-beam irradiated corneal tissues and BK-cornea pre-assembled devices were stable for 6 months after room-temperature preservation. CONCLUSIONS: E-beam irradiation generated no detrimental effects on the corneal tissues or BK-cornea pre-assembled devices and improved native properties of the corneal tissue, enabling prolonged preservation at room temperature. The pre-assembly of BK in a donor cornea, followed by E-beam irradiation, offers the potential for an off-the-shelf, ready to implant keratoprosthesis device.
Wang M, Garg I, Miller JB. Wide Field Swept Source Optical Coherence Tomography Angiography for the Evaluation of Proliferative Diabetic Retinopathy and Associated Lesions: A Review. Semin Ophthalmol 2021;36(4):162-167.Abstract
Retinal imaging remains the mainstay for monitoring and grading diabetic retinopathy. The gold standard for detecting proliferative diabetic retinopathy (PDR) requiring treatment has long been the seven-field stereoscopic fundus photography and fluorescein angiography. In the past decade, ultra-wide field fluorescein angiography (UWF-FA) has become more commonly used in clinical practice for the evaluation of more advanced diabetic retinopathy. Since its invention, optical coherence tomography (OCT) has been an important tool for the assessment of diabetic macular edema; however, OCT offered little in the assessment of neovascular changes associated with PDR until OCT-A became available. More recently, swept source OCT allowed larger field of view scans to assess a variety of DR lesions with wide field swept source optical coherence tomography (WF-SS-OCTA). This paper reviews the role of WF-SS-OCTA in detecting neovascularization of the disc (NVD), and elsewhere (NVE), microaneurysms, changes of the foveal avascular zone (FAZ), intraretinal microvascular abnormalities (IRMA), and capillary non-perfusion, as well as limitations of this evolving technology.
Raval V, Binkley E, Aronow ME, Valenzuela J, Peereboom DM, Singh AD. Primary central nervous system lymphoma - ocular variant: an interdisciplinary review on management. Surv Ophthalmol 2021;66(6):1009-1020.Abstract
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.
Elhusseiny AM, MacKinnon S, Zurakowski D, Huynh E, Dagi LR. Long-term ophthalmic outcomes in 120 children with unilateral coronal synostosis: a 20-year retrospective analysis. J AAPOS 2021;Abstract
BACKGROUND: Prior studies comparing ophthalmic outcomes after treating unicoronal synostosis (UCS) by early endoscopic strip craniectomy (ESC) versus later fronto-orbital advancement (FOA) are modest in sample size, or lack consistent age adjustment. We report long-term, age-adjusted ophthalmic outcomes for a large cohort after nonrandomized treatment by one of these two options. METHODS: The following data was retrieved from a retrospective review of the medical records of patients with treated UCS born since 2000: cycloplegic refractions, sensorimotor examinations, and strabismus procedures before craniofacial repair and postoperatively at approximately 18 and 60 months of age. V-pattern strabismus was graded as mild (absent or + 1/-1 oblique dysfunction) versus moderate-to-severe (≥+2/-2 oblique dysfunction or left to right vertical alignment change of ≥20Δ or ocular torticollis >15°). RESULTS: A total of 120 infants were included: 60 treated by FOA and 60 by ESC. By the late examination, aniso-astigmatism was present in 71.8% of FOA-treated patients and 46% of ESC-treated patients (P < 0.0001). By late examination, the age-adjusted odds ratio of moderate-to-severe V-pattern strabismus after treatment by FOA versus ESC was 2.65 (95% CI, 1.37-6.28; P = 0.02); strabismus surgery was performed in 26 infants treated by FOA compared with 13 treated by ESC (OR = 2.8; P = 0.02). Amblyopia developed in 60% of FOA-treated patients compared with 35% of those treated by ESC (OR 3.0; 95% CI, 1.3-6.7; P = 0.02). CONCLUSIONS: Our age-adjusted ophthalmic results confirm better long-term outcomes after treatment of USC by endoscopic strip craniectomy. Recognition and referral of affected infants by the earliest months of life facilitates the opportunity for endoscopic repair.
Breazzano MP, Nair AA, Arevalo FJ, Barakat MR, Berrocal AM, Chang JS, Chen A, Eliott D, Garg SJ, Ghadiali Q, Gong D, Grewal DS, Handa JT, Henderson M, Leiderman YI, Leng T, Mannina A, Mendel TA, Mustafi D, de Koo LOC, Patel SN, Patel TP, Prenner J, Richards P, Singh RP, Wykoff CC, Yannuzzi NA, Yu H, Modi YS, Chang S. Frequency of Urgent or Emergent Vitreoretinal Surgical Procedures in the United States During the COVID-19 Pandemic. JAMA Ophthalmol 2021;139(4):456-463.Abstract
Importance: The American Academy of Ophthalmology (AAO) indicated that urgent or emergent vitreoretinal surgical procedures should continue during the coronavirus disease 2019 (COVID-19) pandemic. Although decreases in the frequency of critical procedures have been reported outside the field of ophthalmology, analyses are limited by volume, geography, and time. Objective: To evaluate whether the frequency of ophthalmic surgical procedures deemed urgent or emergent by the AAO changed across the United States during the COVID-19 pandemic. Design, Setting, and Participants: Vitreoretinal practices from 17 institutions throughout the US participated in this multicenter cross-sectional study. The frequency of 11 billed vitreoretinal Current Procedural Terminology (CPT) codes across respective weeks was obtained from each practice between January 1, 2019, and May 31, 2020. Data were clustered into intravitreal injections (code 67028), lasers and cryotherapy (codes 67141, 67145, and 67228), retinal detachment (RD) repairs (codes 67107, 67108, 67110, and 67113), and other vitrectomies (codes 67036, 67039, and 67040). Institutions were categorized by region (Northeast, Midwest, South, and West Coast), practice setting (academic [tax-exempt] or private [non-tax-exempt]), and date of respective statewide stay-at-home orders. Main Outcomes and Measures: Nationwide changes in the frequency of billing for urgent or emergent vitreoretinal surgical procedures during the COVID-19 pandemic. Results: A total of 526 536 CPT codes were ascertained: 483 313 injections, 19 257 lasers or cryotherapy, 14 949 RD repairs, and 9017 other vitrectomies. Relative to 2019, a weekly institutional decrease in injections was observed from March 30 to May 2, 2020, with a maximal 38.6% decrease (from a mean [SD] of 437.8 [436.3] to 273.8 [269.0] injections) from April 6 to 12, 2020 (95% CI, -259 to -69 injections; P = .002). A weekly decrease was also identified that spanned a longer interval, at least until study conclusion (March 16 to May 31, 2020), for lasers and cryotherapy, with a maximal 79.6% decrease (from a mean [SD] of 6.6 [7.7] to 1.5 [2.0] procedures) from April 6 to 12, 2020 (95% CI, -6.8 to -3.3 procedures; P < .001), for RD repairs, with a maximal 59.4% decrease (from a mean [SD] of 3.5 [4.0] to 1.6 [2.2] repairs) from April 13 to 19, 2020 (95% CI, -2.7 to -1.4 repairs; P < .001), and for other vitrectomies, with a maximal 84.3% decrease (from a mean [SD] of 3.0 [3.1] to 0.4 [0.8] other vitrectomies) from April 6 to 12, 2020 (95% CI, -3.3 to -1.8 other vitrectomies; P < .001). No differences were identified by region, setting, or state-level stay-at-home order adjustment. Conclusions and Relevance: Although the AAO endorsed the continued performance of urgent or emergent vitreoretinal surgical procedures, the frequency of such procedures throughout the country experienced a substantial decrease that may persist after the COVID-19 pandemic's initial exponential growth phase. This decrease appears independent of region, setting, and state-level stay-at-home orders. It is unknown to what extent vitreoretinal intervention would have decreased without AAO recommendations, and how the decrease is associated with outcomes. Although safety is paramount during the COVID-19 pandemic, practices should consider prioritizing availability for managing high-acuity conditions until underlying reasons for the reduction are fully appreciated.
Sobrin L, Yu Y, Han S, Susarla G, Kempen JH, Hubbard RA, VanderBeek BL. Risk of Non-infectious Uveitis with Metformin Therapy in a Large Healthcare Claims Database. Ocul Immunol Inflamm 2021;:1-7.Abstract
PURPOSE: To determine if metformin is associated with noninfectious uveitis (NIU). METHODS: Patients in an insurance claims database who initiated metformin (n = 359,139) or other oral anti-diabetic medications (n = 162,847) were followed for NIU development. Both cohort and case-control analyses were performed to assess differing exposure lengths using Cox and conditional logistic regression, respectively. RESULTS: The hazard ratio (HR) for incident NIU was not significantly different between the metformin and non-metformin cohorts [HR = 1.19, 95% Confidence Interval (CI): 0.92-1.54, = .19]. The case control analysis similarly showed no association between any metformin use 2 years before the outcome date and NIU [odds ratio (OR) = 0.64, 95% CI: 0.39-1.04, = .07]. However, there was a protective 20 association between cumulative metformin duration [(445-729 days) adjusted OR (aOR) = 0.49, 95% CI: 0.27-0.90, = .02] and dosage (>390,000 mg aOR = 0.44, 95% CI: 0.25-0.78, = .001) compared with no metformin use. CONCLUSIONS: Our results suggest metformin use for longer durations may be protective of NIU onset.
Vinken K, Op de Beeck H. Using deep neural networks to evaluate object vision tasks in rats. PLoS Comput Biol 2021;17(3):e1008714.Abstract
In the last two decades rodents have been on the rise as a dominant model for visual neuroscience. This is particularly true for earlier levels of information processing, but a number of studies have suggested that also higher levels of processing such as invariant object recognition occur in rodents. Here we provide a quantitative and comprehensive assessment of this claim by comparing a wide range of rodent behavioral and neural data with convolutional deep neural networks. These networks have been shown to capture hallmark properties of information processing in primates through a succession of convolutional and fully connected layers. We find that performance on rodent object vision tasks can be captured using low to mid-level convolutional layers only, without any convincing evidence for the need of higher layers known to simulate complex object recognition in primates. Our approach also reveals surprising insights on assumptions made before, for example, that the best performing animals would be the ones using the most abstract representations-which we show to likely be incorrect. Our findings suggest a road ahead for further studies aiming at quantifying and establishing the richness of representations underlying information processing in animal models at large.
Lin LY, Jochym N, Merz JF. Refusal rates and waivers of informed consent in pragmatic and comparative effectiveness RCTs: A systematic review. Contemp Clin Trials 2021;104:106361.Abstract
BACKGROUND: Pragmatic and comparative effectiveness randomized controlled trials (RCTs) aim to be highly generalizable studies, with broad applicability and flexibility in methods. These trials also address recruitment issues by minimizing exclusions. The trials may also appeal to potential subjects because of lower risk and lower burdens of participation. We sought to examine rates of refusal and uses of waivers of informed consent in pragmatic and comparative effectiveness RCTs. METHODS: A systematic review of pragmatic and comparative effectiveness RCTs performed wholely or in part in the United States and first published in 2014 and 2017. RESULTS: 103 studies involving 105 discrete populations were included for review. Refusal data was collected for 71 RCTs. Overall, studies reported an average rate of 31.9% of potential subjects refused participation; on an individual basis, 38.4% of people asked to take part refused at some point during recruitment. 23 trials (22%) were performed, at least in part, with a waiver of informed consent, 7 (30%) of which provided any form of notice to subjects. CONCLUSIONS: Overall refusal rates for pragmatic and comparative effectiveness RCTs appear roughly the same as other types of research, with studies reporting about a third of people solicited for participation refuse. Moreover, informed consent was waived in 22% (95% Binomial exact Confidence Interval 13.9-30.5%) of the trials, and further study is needed to understand when waivers are justified and when notice should be provided.
Perepelkina T, Fulton AB. Artificial Intelligence (AI) Applications for Age-Related Macular Degeneration (AMD) and Other Retinal Dystrophies. Semin Ophthalmol 2021;36(4):304-309.Abstract
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.
Dohlman TH, Singh RB, Dana R. Advances in the Medical Management of Neurotrophic Keratitis. Semin Ophthalmol 2021;36(4):335-340.Abstract
Neurotrophic Keratitis (NK) is a degenerative disorder of the cornea characterized by decreased or absent sensory corneal innervation, corneal epitheliopathy and impaired healing.The clinical presentation of NK can range from persistent epithelial defects to corneal perforation and management is often both challenging and protracted. Historically, the management of NK has consisted of non-specific strategies to facilitate corneal epithelial healing such as lubrication, bandage contact lenses and tarsorrhaphy. Recent advances in the development of therapeutics for NK have provided new and efficacious targeted strategies for its management.In this article, we review recombinant human nerve growth factor (Cenegermin), currently approved for clinical use in the United States and Europe, as well as other promising therapeutic options that are in pre-clinical development such as thymosine β4, connexin43 inhibitors, and artificial extracellular matrix components.

Pages