2021

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Ou J, Zhou Z, Dai R, Zhang J, Zhao S, Wu X, Lan W, Ren Y, Cui L, Lan Q, Lu L, Seto D, Chodosh J, Wu J, Zhang G, Zhang Q. V367F Mutation in SARS-CoV-2 Spike RBD Emerging during the Early Transmission Phase Enhances Viral Infectivity through Increased Human ACE2 Receptor Binding Affinity. J Virol 2021;95(16):e0061721.Abstract
The current pandemic of COVID-19 is caused by a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The SARS-CoV-2 spike protein receptor-binding domain (RBD) is the critical determinant of viral tropism and infectivity. To investigate whether naturally occurring RBD mutations during the early transmission phase have altered the receptor binding affinity and infectivity, we first analyzed in silico the binding dynamics between SARS-CoV-2 RBD mutants and the human angiotensin-converting enzyme 2 (ACE2) receptor. Among 32,123 genomes of SARS-CoV-2 isolates (December 2019 through March 2020), 302 nonsynonymous RBD mutants were identified and clustered into 96 mutant types. The six dominant mutations were analyzed applying molecular dynamics simulations (MDS). The mutant type V367F continuously circulating worldwide displayed higher binding affinity to human ACE2 due to the enhanced structural stabilization of the RBD beta-sheet scaffold. The MDS also indicated that it would be difficult for bat SARS-like CoV to infect humans. However, the pangolin CoV is potentially infectious to humans. The increased infectivity of V367 mutants was further validated by performing receptor-ligand binding enzyme-linked immunosorbent assay (ELISA), surface plasmon resonance, and pseudotyped virus assays. Phylogenetic analysis of the genomes of V367F mutants showed that during the early transmission phase, most V367F mutants clustered more closely with the SARS-CoV-2 prototype strain than the dual-mutation variants (V367F+D614G), which may derivate from recombination. The analysis of critical RBD mutations provides further insights into the evolutionary trajectory of early SARS-CoV-2 variants of zoonotic origin under negative selection pressure and supports the continuing surveillance of spike mutations to aid in the development of new COVID-19 drugs and vaccines. IMPORTANCE A novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused the pandemic of COVID-19. The origin of SARS-CoV-2 was associated with zoonotic infections. The spike protein receptor-binding domain (RBD) is identified as the critical determinant of viral tropism and infectivity. Thus, whether mutations in the RBD of the circulating SARS-CoV-2 isolates have altered the receptor binding affinity and made them more infectious has been the research hot spot. Given that SARS-CoV-2 is a novel coronavirus, the significance of our research is in identifying and validating the RBD mutant types emerging during the early transmission phase and increasing human angiotensin-converting enzyme 2 (ACE2) receptor binding affinity and infectivity. Our study provides insights into the evolutionary trajectory of early SARS-CoV-2 variants of zoonotic origin. The continuing surveillance of RBD mutations with increased human ACE2 affinity in human or other animals is critical to the development of new COVID-19 drugs and vaccines against these variants during the sustained COVID-19 pandemic.
Ozawa H, Usui Y, Takano Y, Horiuchi N, Kuribayashi T, Kurihara T, Smith LEH, Tsubota K, Tomita Y. Iris metastasis as the initial presentation of metastatic esophageal cancer diagnosed by fine needle aspiration biopsy: A case report. Medicine (Baltimore) 2021;100(22):e26232.Abstract
RATIONALE: Metastasis of neoplasms to the eye is quite uncommon. In this case report, we describe a patient where primary esophageal cancer was diagnosed by fine needle aspiration biopsy (FNAB) of an iris tumor. PATIENT CONCERNS: A 70-year-old male complained of redness and discomfort in the right eye. DIAGNOSIS AND INTERVENTIONS: The patient's right eye was diagnosed as idiopathic uveitis, and a topical steroid was administered. As vitreous opacities were observed even after topical therapy, oral prednisolone was administered. On slit-lamp examination of the right eye, an iris mass with neovascularization was seen in the anterior chamber. A metastatic tumor was suspected, and FNAB was performed. Histology revealed squamous cell carcinoma. Systemic workup revealed esophageal cancer with several metastases. Best-corrected visual acuity decreased to 20/400, and intraocular pressure was 40 mmHg in the right eye. Two iris tumors with neovascularization were present extending into the anterior chamber with posterior iris synechiae and 360 degree peripheral anterior synechiae. Intraocular pressure in the right eye was medically managed with hypotensive eye drops and oral acetazolamide. Iris metastases were treated with 40 Gray of radiation therapy and concurrent chemotherapy. OUTCOMES: The tumor regressed, but intraocular pressure was refractory to treatment because of 360 degree goniosynechial closure. The right eye lost light perception six months after treatment commenced, and the patient died 9 months after the onset of therapy due to multiple systemic metastases. LESSONS: This is a rare case of masquerade syndrome without systemic symptoms in which FNAB of an iris tumor led to a diagnosis of metastatic esophageal squamous cell carcinoma. Although the patient lost his sight due to uncontrollable ocular hypertension, systemic chemotherapy, and radiation therapy were initially effective in the treatment of the metastatic iris tumor. As the prognosis of patients with metastatic iris tumors is poor, it is important for ophthalmologists to consider such diagnoses and conduct systemic investigations when necessary.
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da Palma MM, Igelman AD, Ku C, Burr A, You JY, Place EM, Wang N-K, Oh JK, Branham KE, Zhang X, Ahn J, Gorin MB, Lam BL, Ronquillo CC, Bernstein PS, Nagiel A, Huckfeldt R, Cabrera MT, Kelly JP, Bakall B, Iannaccone A, Hufnagel RB, Zein WM, Koenekoop RK, Birch DG, Yang P, Fahim AT, Pennesi ME. Characterization of the Spectrum of Ophthalmic Changes in Patients With Alagille Syndrome. Invest Ophthalmol Vis Sci 2021;62(7):27.Abstract
Purpose: The purpose of this study was to characterize the phenotypic spectrum of ophthalmic findings in patients with Alagille syndrome. Methods: We conducted a retrospective, observational, multicenter, study on 46 eyes of 23 subjects with Alagille syndrome. We reviewed systemic and ophthalmologic data extracted from medical records, color fundus photography, fundus autofluorescence, optical coherence tomography, visual fields, electrophysiological assessments, and molecular genetic findings. Results: Cardiovascular abnormalities were found in 83% of all cases (of those, 74% had cardiac murmur), whereas 61% had a positive history of hepatobiliary issues, and musculoskeletal anomalies were present in 61% of all patients. Dysmorphic facies were present in 16 patients, with a broad forehead being the most frequent feature. Ocular symptoms were found in 91%, with peripheral vision loss being the most frequent complaint. Median (range) Snellen visual acuity of all eyes was 20/25 (20/20 to hand motion [HM]). Anterior segment abnormalities were present in 74% of the patients; of those, posterior embryotoxon was the most frequent finding. Abnormalities of the optic disc were found in 52%, and peripheral retinal abnormalities were the most frequent ocular finding in this series, found in 96% of all patients. Fifteen JAG1 mutations were identified in 16 individuals; of those, 6 were novel. Conclusions: This study reports a cohort of patients with Alagille syndrome in which peripheral chorioretinal changes were more frequent than posterior embryotoxon, the most frequent ocular finding according to a number of previous studies. We propose that these peripheral chorioretinal changes are a new hallmark to help diagnose this syndrome.
Pamir Z, Bauer CM, Bennett CR, Kran BS, Merabet LB. Visual perception supported by verbal mediation in an individual with cerebral visual impairment (CVI). Neuropsychologia 2021;160:107982.Abstract
Cerebral visual impairment (CVI) often presents with deficits associated with higher order visual processing. We report a case of an individual with CVI who uses a verbal mediation strategy to perceive and interact with his visual surroundings. Visual perceptual performance was assessed using a virtual reality based visual search task combined with eye tracking. Functional magnetic resonance imaging (fMRI) was employed to identify the neural correlates associated with this strategy. We found that when using verbal mediation, the individual could readily detect and track the target within the visual scene which was associated with robust activation within a network of occipito-parieto-temporal visual cortical areas. In contrast, when not using verbal mediation, the individual was completely unable to perform the task, and this was associated with dramatically reduced visual cortical activation. This unique compensatory strategy may be related to the individual's use of verbal working memory for the purposes of understanding complex visual information.
Papageorgiou GI, Symeonidis DG, Tsakatikas SA, Liatsos AD, Douglas KA, Douglas VP, Moschos MM, Kosmas C. Central neurotoxicity induced by trastuzumab emtansine (T-DM1): a case report. Anticancer Drugs 2021;Abstract
Trastuzumab emtansine (T-DM1) is a human epidermal growth factor receptor 2 (Her2) - targeted antibody-drug conjugate that is approved for patients previously treated with trastuzumab and a taxane for Her2-positive advanced breast cancer and those who have progressed within 6 months of completion of adjuvant chemotherapy, as well as for patients with residual invasive Her2-positive disease after the completion of adjuvant chemotherapy. Peripheral neuropathy is a common adverse event; however, ocular events have also been described. With the current report we present the case of a 67-year old woman who developed transient grade 2-3 blurred vision after the first T-DM1 infusion, which was complicated with grade 2 diplopia causing vertigo after the second infusion. After extended investigation, this symptomatology was attributed to central neurotoxicity, and gradually resolved after T-DM1 discontinuation.
of Partnership GES, Li Z, Wang Z, Lee MC, Zenkel M, Peh E, Ozaki M, Topouzis F, Nakano S, Chan A, Chen S, Williams SEI, Orr A, Nakano M, Kobakhidze N, Zarnowski T, Popa-Cherecheanu A, Mizoguchi T, Manabe S-I, Hayashi K, Kazama S, Inoue K, Mori Y, Miyata K, Sugiyama K, Higashide T, Chihara E, Ideta R, Ishiko S, Yoshida A, Tokumo K, Kiuchi Y, Ohashi T, Sakurai T, Sugimoto T, Chuman H, Aihara M, Inatani M, Mori K, Ikeda Y, Ueno M, Gaston D, Rafuse P, Shuba L, Saunders J, Nicolela M, Chichua G, Tabagari S, Founti P, Sim KS, Meah WY, Soo HM, Chen XY, Chatzikyriakidou A, Keskini C, Pappas T, Anastasopoulos E, Lambropoulos A, Panagiotou ES, Mikropoulos DG, Kosior-Jarecka E, Cheong A, Li Y, Lukasik U, Nongpiur ME, Husain R, Perera SA, Álvarez L, García M, González-Iglesias H, Cueto AFV, Cueto LFV, Martinón-Torres F, Salas A, Oguz Ç, Tamcelik N, Atalay E, Batu B, Irkec M, Aktas D, Kasim B, Astakhov YS, Astakhov SY, Akopov EL, Giessl A, Mardin C, Hellerbrand C, Cooke Bailey JN, Igo RP, Haines JL, Edward DP, Heegaard S, Davila S, Tan P, Kang JH, Pasquale LR, Kruse FE, Reis A, Carmichael TR, Hauser M, Ramsay M, Mossböck G, Yildirim N, Tashiro K, Konstas AGP, Coca-Prados M, Foo JN, Kinoshita S, Sotozono C, Kubota T, Dubina M, Ritch R, Wiggs JL, Pasutto F, Schlötzer-Schrehardt U, Ho YS, Aung T, Tam WL, Khor CC. Association of Rare CYP39A1 Variants With Exfoliation Syndrome Involving the Anterior Chamber of the Eye. JAMA 2021;325(8):753-764.Abstract
Importance: Exfoliation syndrome is a systemic disorder characterized by progressive accumulation of abnormal fibrillar protein aggregates manifesting clinically in the anterior chamber of the eye. This disorder is the most commonly known cause of glaucoma and a major cause of irreversible blindness. Objective: To determine if exfoliation syndrome is associated with rare, protein-changing variants predicted to impair protein function. Design, Setting, and Participants: A 2-stage, case-control, whole-exome sequencing association study with a discovery cohort and 2 independently ascertained validation cohorts. Study participants from 14 countries were enrolled between February 1999 and December 2019. The date of last clinical follow-up was December 2019. Affected individuals had exfoliation material on anterior segment structures of at least 1 eye as visualized by slit lamp examination. Unaffected individuals had no signs of exfoliation syndrome. Exposures: Rare, coding-sequence genetic variants predicted to be damaging by bioinformatic algorithms trained to recognize alterations that impair protein function. Main Outcomes and Measures: The primary outcome was the presence of exfoliation syndrome. Exome-wide significance for detected variants was defined as P < 2.5 × 10-6. The secondary outcomes included biochemical enzymatic assays and gene expression analyses. Results: The discovery cohort included 4028 participants with exfoliation syndrome (median age, 78 years [interquartile range, 73-83 years]; 2377 [59.0%] women) and 5638 participants without exfoliation syndrome (median age, 72 years [interquartile range, 65-78 years]; 3159 [56.0%] women). In the discovery cohort, persons with exfoliation syndrome, compared with those without exfoliation syndrome, were significantly more likely to carry damaging CYP39A1 variants (1.3% vs 0.30%, respectively; odds ratio, 3.55 [95% CI, 2.07-6.10]; P = 6.1 × 10-7). This outcome was validated in 2 independent cohorts. The first validation cohort included 2337 individuals with exfoliation syndrome (median age, 74 years; 1132 women; n = 1934 with demographic data) and 2813 individuals without exfoliation syndrome (median age, 72 years; 1287 women; n = 2421 with demographic data). The second validation cohort included 1663 individuals with exfoliation syndrome (median age, 75 years; 587 women; n = 1064 with demographic data) and 3962 individuals without exfoliation syndrome (median age, 74 years; 951 women; n = 1555 with demographic data). Of the individuals from both validation cohorts, 5.2% with exfoliation syndrome carried CYP39A1 damaging alleles vs 3.1% without exfoliation syndrome (odds ratio, 1.82 [95% CI, 1.47-2.26]; P < .001). Biochemical assays classified 34 of 42 damaging CYP39A1 alleles as functionally deficient (median reduction in enzymatic activity compared with wild-type CYP39A1, 94.4% [interquartile range, 78.7%-98.2%] for the 34 deficient variants). CYP39A1 transcript expression was 47% lower (95% CI, 30%-64% lower; P < .001) in ciliary body tissues from individuals with exfoliation syndrome compared with individuals without exfoliation syndrome. Conclusions and Relevance: In this whole-exome sequencing case-control study, presence of exfoliation syndrome was significantly associated with carriage of functionally deficient CYP39A1 sequence variants. Further research is needed to understand the clinical implications of these findings.
Pasquale LR, Gong L, Wiggs JL, Pan L, Yang Z, Wu M, Yang Z, Chen DF, Zeng W. Development of Primary Open Angle Glaucoma-Like Features in a Rhesus Macaque Colony From Southern China. Transl Vis Sci Technol 2021;10(9):20.Abstract
Purpose: To describe the ocular phenotype of spontaneous glaucoma in a non-human primate colony. Methods: In total, 722 Rhesus macaque monkeys aged 10 to 25 years underwent optical coherence tomography (OCT), fundus photography (FP), and intraocular pressure (IOP) measurements. Monkeys with baseline cup-to-disc ratio (CDR) <0.5 were used to establish baseline ocular features. A subset was followed longitudinally for three years and compared to glaucoma suspects on the basis of OCT/FP criteria. Results: The average IOP under ketamine sedation and average CDR for the entire colony was 13.0 ± 4.3 mm Hg and 0.38 ± 0.07, respectively. The mean baseline conscious IOP of glaucoma suspects (N = 18) versus controls (N = 108) was 16.2 ± 3.5 mm Hg and 13.9 ± 2.3 mm Hg, respectively (P = 0.001). All glaucoma suspects had unremarkable slit lamp examinations and open angles based on anterior segment OCT. Baseline global circumpapillary retinal nerve fiber layer (RNFL) thickness was 91.5 ± 11.0 µM versus 102.7 ± 8.5 µM in suspects and controls, respectively (P < 0.0001). All sectors on the baseline circumpapillary OCT showed a significant reduction in RNFL thickness versus controls (P ≤ 0.0022) except for the temporal sector (P ≥ 0.07). In three-year longitudinal analysis, neither CDR nor OCT parameters changed in controls (N = 40; P ≥ 0.16), whereas significant increase in CDR (P = 0.018) and nominally significant decreases in two OCT sectors (nasal, P = 0.023 and nasal inferior, P = 0.046) were noted in suspects. Conclusions: Members of a nonhuman primate colony exhibit important ophthalmic features of human primary open-angle glaucoma. Translational Relevance: Identification of a spontaneous model of glaucoma in nonhuman primates represents an unprecedented opportunity to elucidate the natural history, pathogenesis and effective therapeutic strategies for the disease.
Patel NA, Yannuzzi NA, Lin J, Smiddy WE. A Cost Effectiveness Analysis of Intravitreal Aflibercept for the Prevention of Progressive Diabetic Retinopathy. Ophthalmol Retina 2021;Abstract
PURPOSE: To calculate costs required to prevent center-involved diabetic macular edema (CI-DME) or proliferative diabetic retinopathy (PDR), and to improve the diabetic retinopathy severity score (DRSS) with intravitreal anti-VEGF injections as reported for aflibercept in two randomized control trials. DESIGN: Cost-effectiveness analysis modeling based on published data SUBJECTS: None METHODS: Results from PANORAMA and the Diabetic Retinopathy Clinical Research Network (DRCR.net) Protocol W were analyzed. Parameters collected included DRSS score, risk reduction of PDR, risk reduction of CI-DME, and number of treatments required. Costs were modeled based on 2020 Medicare reimbursement data practice settings of hospital-based facility and non-facility. MAIN OUTCOME MEASURE: Cost to prevent case of PDR and CI-DME, and to improve DRSS stage RESULTS: Over 2 years in Protocol W, the cost required to prevent 1 case of PDR was $83,000 ($72,400) in the facility (non-facility) setting; in PANORAMA, the corresponding 2 year costs were $89,400 ($75,000) for the 2Q16 arm, and $91,200 ($89,900) for the 2Q8PRN arm. To prevent 1 case of CI-DME with vision loss in Protocol W, the cost was $154,000 ($133,000). For all CI-DME, with and without vision loss; in PANORAMA, the costs to prevent a case were $70,900 ($59,500) for the 2Q16 arm, and $90,000 ($88,800) for the 2Q8PRN arm. In Protocol W, the overall accumulated total for cost /DRSS unit change at the 2 year point for facility (non-facility) setting was $2700 ($2400)/DRSS. In the first year alone, it was $2100 ($1800)/DRSS and in the second year alone, $6100 ($5300)/DRSS. CONCLUSION: There is a considerable cost associated with the prevention of PDR and CI-DME with intravitreal aflibercept injections. A price per unit of change in diabetic retinopathy severity score is a new parameter which might serve as a benchmark in future utility analyses that could be used to bring perspective to cost-utility considerations.
Patel S, Yuan A, Pineda R. Acute Benign Paroxysmal Positional Vertigo After Endothelial Keratoplasty-A Unique Cause of Postoperative Nausea and Headache. Cornea 2021;40(7):926-929.Abstract
PURPOSE: To describe a case of new-onset benign paroxysmal positional vertigo (BPPV) after uncomplicated Descemet stripping automated endothelial keratoplasty. METHODS: Case report and review of literature. RESULTS: A 61-year-old woman with a history of steroid-induced glaucoma and penetrating keratoplasty for Fuchs endothelial dystrophy, and no history of BPPV or other vertigo, underwent Descemet stripping automated endothelial keratoplasty for penetrating keratoplasty graft failure. On the third postoperative day, she developed acute spinning vertigo, nausea, and headache on sitting up after 3 days of strict supine positioning. Her ophthalmic examination was benign, with no evidence of a pupillary block, and she was diagnosed by an otologist with BPPV. Her symptoms resolved after 1 week without further intervention. CONCLUSIONS: BPPV is a benign but rare complication of nonotologic surgery and has not been previously reported with ophthalmic surgery. The overlap in symptomatology between BPPV and other serious and potentially vision-threatening causes of postoperative nausea and headache, such as pupillary block glaucoma, makes this a relevant etiology to consider in the spectrum of postendothelial keratoplasty complications.
Peiris TJ, El Rami HE, Sun JK. CENTRAL SEROUS CHORIORETINOPATHY ASSOCIATED WITH STEROID ENEMA. Retin Cases Brief Rep 2021;15(1):15-17.Abstract
BACKGROUND/PURPOSE: To report a case of acute recurrent central serous chorioretinopathy that developed after a regimen of corticosteroid enemas and suppositories. METHODS: Observational case report. Fluorescein angiography and spectral domain optical coherence tomography. RESULTS: A 47-year-old male patient with ulcerative colitis managed through hydrocortisone enemas presented to clinic with a 1-day history of blurry vision of his left eye. Posterior segment examination revealed subretinal fluid in the superotemporal macula of the left eye extending centrally. After diagnosis of acute central serous chorioretinopathy, the patient was advised to taper steroid enemas and his visual symptoms and subretinal fluid resolved within the month. Seven years later, several months after using steroid suppositories for the first time since the original central serous chorioretinopathy episode, asymptomatic subretinal fluid accumulation with foveal sparing was found on routine ophthalmic examination. Three months later, most of this fluid had resolved with minimal residual subretinal fluid on clinical examination. CONCLUSION: Acute central serous chorioretinopathy may develop after corticosteroid enema or suppository use, a route of administration that has not been previously reported in association with the disease.
Peng C, Wang Y, Ji L, Kuang L, Yu Z, Li H, Zhang J, Zhao J. LncRNA-MALAT1/miRNA-204-5p/Smad4 Axis Regulates Epithelial-Mesenchymal Transition, Proliferation and Migration of Lens Epithelial Cells. Curr Eye Res 2021;46(8):1137-1147.Abstract
MATERIALS AND METHODS: LECs were cultured and induced with TGF-β2 (10 ng/mL). SiRNA against MALAT1 (Si-MALAT1) was transfected into LECs to knockdown the expression of MALAT1. To overexpress or knockdown miR-204-5p, miR-204-5p mimics (miR-204-5p mimics) and anti-miR-204-5p (miR-204-5p inhibitor) were transfected into LECs. We used RNA FISH to identify the location of MALAT1. RNA levels of MALAT1 and miR-204-5p were analyzed by RT-qPCR. Additionally, target protein levels of Smad4, epithelial differentiation and mesenchymal markers were analyzed with Western blot. We employed EdU Labeling to measured cell proliferation and performed Transwell Assay to analyze the cell migration. Dual-luciferase reporter assays in LECs were conducted to verify whether miRNA-204-5p was negatively regulated by MALAT1 and Smad4 was a direct target of miR-204-5p. RESULTS: The expression of MALAT1 was upregulated in PCO specimens. MALAT1 was overexpressed in TGF-β2 induced LECs, and the knockdown of MALAT1 could attenuate TGF-β2 induced EMT. Besides, the upregulation of MALAT1 was correlated with the downregulation of miR-204-5p and upregulation of Smad4. Importantly, MALAT1 was revealed to be located in the cytoplasm of LECs. Furthermore, luciferase reporter assays confirmed that MALAT1 could negatively regulate the expression of miR-204-5p and then regulate its direct target Smad4. Finally, the knockdown of MALAT1 could inhibit the EMT, proliferation, and migration of LECs; however, those can be reversed by anti-miR-204-5p. CONCLUSIONS: Our findings reveal that MALAT1 may regulate EMT, proliferation, and migration of LECs as a ceRNA by "sponging" miR-204-5p and targeting Smad4, and serve as a promising therapeutic target in preventing PCO.
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.
Peterson SL, Li Y, Sun CJ, Wong KA, Leung KS, de Lima S, Hanovice NJ, Yuki K, Stevens B, Benowitz LI. Retinal Ganglion Cell Axon Regeneration Requires Complement and Myeloid Cell Activity within the Optic Nerve. J Neurosci 2021;Abstract
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 optic nerve injury, 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 neuro-immune role for complement and microglia/monocytes in CNS repair.SIGNIFICANCE STATEMENTDespite 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.
Pistilli M, Gangaputra SS, Pujari SS, Jabs DA, Levy-Clarke GA, Nussenblatt RB, Rosenbaum JT, Sen NH, Suhler EB, Thorne JE, Bhatt NP, Foster SC, Begum H, Fitzgerald TD, Dreger KA, Kempen JH. Contemporaneous Risk Factors for Visual Acuity in Non-Infectious Uveitis. Ocul Immunol Inflamm 2021;:1-8.Abstract
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.
Pivodic A, Johansson H, Smith LEH, Hård A-L, Löfqvist C, Yoder BA, Hartnett EM, Wu C, Bründer M-C, Lagrèze WA, Stahl A, Al-Hawasi A, Larsson E, Lundgren P, Gränse L, Sunnqvist B, Tornqvist K, Wallin A, Holmström G, Albertsson-Wikland K, Nilsson S, Hellström A. Development and validation of a new clinical decision support tool to optimize screening for retinopathy of prematurity. Br J Ophthalmol 2021;Abstract
BACKGROUND/AIMS: Prematurely born infants undergo costly, stressful eye examinations to uncover the small fraction with retinopathy of prematurity (ROP) that needs treatment to prevent blindness. The aim was to develop a prediction tool (DIGIROP-Screen) with 100% sensitivity and high specificity to safely reduce screening of those infants not needing treatment. DIGIROP-Screen was compared with four other ROP models based on longitudinal weights. METHODS: Data, including infants born at 24-30 weeks of gestational age (GA), for DIGIROP-Screen development (DevGroup, N=6991) originate from the Swedish National Registry for ROP. Three international cohorts comprised the external validation groups (ValGroups, N=1241). Multivariable logistic regressions, over postnatal ages (PNAs) 6-14 weeks, were validated. Predictors were birth characteristics, status and age at first diagnosed ROP and essential interactions. RESULTS: ROP treatment was required in 287 (4.1%)/6991 infants in DevGroup and 49 (3.9%)/1241 in ValGroups. To allow 100% sensitivity in DevGroup, specificity at birth was 53.1% and cumulatively 60.5% at PNA 8 weeks. Applying the same cut-offs in ValGroups, specificities were similar (46.3% and 53.5%). One infant with severe malformations in ValGroups was incorrectly classified as not needing screening. For all other infants, at PNA 6-14 weeks, sensitivity was 100%. In other published models, sensitivity ranged from 88.5% to 100% and specificity ranged from 9.6% to 45.2%. CONCLUSIONS: DIGIROP-Screen, a clinical decision support tool using readily available birth and ROP screening data for infants born GA 24-30 weeks, in the European and North American populations tested can safely identify infants not needing ROP screening. DIGIROP-Screen had equal or higher sensitivity and specificity compared with other models. DIGIROP-Screen should be tested in any new cohort for validation and if not validated it can be modified using the same statistical approaches applied to a specific clinical setting.
Pivodic A, Nilsson S, Stahl A, Smith LEH, Hellström A. Validation of the Retinopathy of Prematurity Activity Scale (ROP-ActS) using retrospective clinical data. Acta Ophthalmol 2021;99(2):201-206.Abstract
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.
Porporato N, Baskaran M, Perera S, Tun TA, Sultana R, Tan M, Quah JHM, Allen JC, Friedman D, Cheng CY, Aung T. Evaluation of meridional scans for angle closure assessment with anterior segment swept-source optical coherence tomography. Br J Ophthalmol 2021;105(1):131-134.Abstract
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.
Pundlik S, Baliutaviciute V, Moharrer M, Bowers AR, Luo G. Home-Use Evaluation of a Wearable Collision Warning Device for Individuals With Severe Vision Impairments: A Randomized Clinical Trial. JAMA Ophthalmol 2021;139(9):998-1005.Abstract
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.
Pundlik S, Nigalye A, Laíns I, Mendez KM, Katz R, Kim J, Kim IK, Miller JB, Vavvas D, Miller JW, Luo G, Husain D. Area under the dark adaptation curve as a reliable alternate measure of dark adaptation response. Br J Ophthalmol 2021;Abstract
PURPOSE: Quantification of dark adaptation (DA) response using the conventional rod intercept time (RIT) requires very long testing time and may not be measurable in the presence of impairments due to diseases such as age-related macular degeneration (AMD). The goal of this study was to investigate the advantages of using area under the DA curve (AUDAC) as an alternative to the conventional parameters to quantify DA response. METHODS: Data on 136 eyes (AMD: 98, normal controls: 38) from an ongoing longitudinal study on AMD were used. DA was measured using the AdaptDx 20 min protocol. AUDAC was computed from the raw DA characteristic curve at different time points, including 6.5 min and 20 min (default). The presence of AMD in the given eye was predicted using a logistic regression model within the leave-one-out cross-validation framework, with DA response as the predictor while adjusting for age and gender. The DA response variable was either the AUDAC values computed at 6.5 min (AUDAC6.5) or at 20 min (AUDAC20) cut-off, or the conventional RIT. RESULTS: AUDAC6.5 was strongly correlated with AUDAC20 (β=86, p<0.001, R=0.87). The accuracy of predicting the presence of AMD using AUDAC20 was 76%, compared with 79% when using RIT, the current gold standard. In addition, when limiting AUDAC calculation to 6.5 min cut-off, the predictive accuracy of AUDAC6.5 was 80%. CONCLUSIONS: AUDAC can be a valuable measure to quantify the overall DA response and can potentially facilitate shorter testing duration while maintaining diagnostic accuracy.
Putra I, Shen X, Anwar KN, Rabiee B, Samaeekia R, Almazyad E, Giri P, Jabbehdari S, Hayat MR, Elhusseiny AM, Ghassemi M, Mahmud N, Edward DP, Joslin CE, Rosenblatt MI, Dana R, Eslani M, Hematti P, Djalilian AR. Preclinical Evaluation of the Safety and Efficacy of Cryopreserved Bone Marrow Mesenchymal Stromal Cells for Corneal Repair. Transl Vis Sci Technol 2021;10(10):3.Abstract
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.

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