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Lei F, Cui N, Zhou C, Chodosh J, Vavvas DG, Paschalis EI. CSF1R inhibition by a small-molecule inhibitor is not microglia specific; affecting hematopoiesis and the function of macrophages. Proc Natl Acad Sci U S A 2020;117(38):23336-23338.Abstract
Colony-stimulating factor 1 receptor (CSF1R) inhibition has been proposed as a method for microglia depletion, with the assumption that it does not affect peripheral immune cells. Here, we show that CSF1R inhibition by PLX5622 indeed affects the myeloid and lymphoid compartments, causes long-term changes in bone marrow-derived macrophages by suppressing interleukin 1β, CD68, and phagocytosis but not CD208, following exposure to endotoxin, and also reduces the population of resident and interstitial macrophages of peritoneum, lung, and liver but not spleen. Thus, small-molecule CSF1R inhibition is not restricted to microglia, causing strong effects on circulating and tissue macrophages that perdure long after cessation of the treatment. Given that peripheral monocytes repopulate the central nervous system after CSF1R inhibition, these changes have practical implications for relevant experimental data.
Anand N, Klug E, Nirappel A, Solá-Del Valle D. A Review of Cyclodestructive Procedures for the Treatment of Glaucoma. Semin Ophthalmol 2020;:1-15.Abstract
Cyclodestruction aims to reduce aqueous humor production through the coagulation or destruction of the ciliary body and has been an important treatment choice for glaucoma since the 1930s. The purpose of the current review is to highlight the evidence regarding the safety and efficacy of various cyclodestructive modalities, emphasizing peer-reviewed articles from the last 20 years and the most common variants of these procedures. The review focuses primarily on the two most common variants of transscleral cyclophotocoagulation (TS-CPC), continuous-wave diode cyclophotocoagulation (CW-TSCPC) and MicroPulse diode cyclophotocoagulation (MP-TSCPC) as well as endoscopic cyclophotocoagulation (ECP) and high-intensity focused ultrasound cyclodestruction (HIFU). We believe that the role of cyclodestruction in glaucoma treatment will only continue to expand given the advances in the field, particular with regards to targeted ciliary body destruction and improvement in the safety profile.
Bai J, Khajavi M, Sui L, Fu H, Krishnaji ST, Birsner AE, Bazinet L, Kamm RD, D'Amato RJ. Angiogenic responses in a 3D micro-engineered environment of primary endothelial cells and pericytes. Angiogenesis 2020;Abstract
Angiogenesis plays a key role in the pathology of diseases such as cancer, diabetic retinopathy, and age-related macular degeneration. Understanding the driving forces of endothelial cell migration and organization, as well as the time frame of these processes, can elucidate mechanisms of action of important pathological pathways. Herein, we have developed an organ-specific microfluidic platform recapitulating the in vivo angiogenic microenvironment by co-culturing mouse primary brain endothelial cells with brain pericytes in a three-dimensional (3D) collagen scaffold. As a proof of concept, we show that this model can be used for studying the angiogenic process and further comparing the angiogenic properties between two different common inbred mouse strains, C57BL/6J and 129S1/SvlmJ. We further show that the newly discovered angiogenesis-regulating gene Padi2 promotes angiogenesis through Dll4/Notch1 signaling by an on-chip mechanistic study. Analysis of the interplay between primary endothelial cells and pericytes in a 3D microfluidic environment assists in the elucidation of the angiogenic response.
Kras A, Celi LA, Miller JB. Accelerating ophthalmic artificial intelligence research: the role of an open access data repository. Curr Opin Ophthalmol 2020;31(5):337-350.Abstract
PURPOSE OF REVIEW: Artificial intelligence has already provided multiple clinically relevant applications in ophthalmology. Yet, the explosion of nonstandardized reporting of high-performing algorithms are rendered useless without robust and streamlined implementation guidelines. The development of protocols and checklists will accelerate the translation of research publications to impact on patient care. RECENT FINDINGS: Beyond technological scepticism, we lack uniformity in analysing algorithmic performance generalizability, and benchmarking impacts across clinical settings. No regulatory guardrails have been set to minimize bias or optimize interpretability; no consensus clinical acceptability thresholds or systematized postdeployment monitoring has been set. Moreover, stakeholders with misaligned incentives deepen the landscape complexity especially when it comes to the requisite data integration and harmonization to advance the field. Therefore, despite increasing algorithmic accuracy and commoditization, the infamous 'implementation gap' persists. Open clinical data repositories have been shown to rapidly accelerate research, minimize redundancies and disseminate the expertise and knowledge required to overcome existing barriers. Drawing upon the longstanding success of existing governance frameworks and robust data use and sharing agreements, the ophthalmic community has tremendous opportunity in ushering artificial intelligence into medicine. By collaboratively building a powerful resource of open, anonymized multimodal ophthalmic data, the next generation of clinicians can advance data-driven eye care in unprecedented ways. SUMMARY: This piece demonstrates that with readily accessible data, immense progress can be achieved clinically and methodologically to realize artificial intelligence's impact on clinical care. Exponentially progressive network effects can be seen by consolidating, curating and distributing data amongst both clinicians and data scientists.
Chen D, Wang J, Sullivan DA, Kam WR, Liu Y. Effects of Terpinen-4-ol on Meibomian Gland Epithelial Cells In Vitro. Cornea 2020;39(12):1541-1546.Abstract
PURPOSE: Infestation with demodex mites has been linked to the development of chalazion, meibomian gland dysfunction, and blepharitis. An effective treatment is the eyelid application of terpinen-4-ol (T4O), a tea tree oil component. However, T4O is also known to be toxic to nonocular epithelial cells. We hypothesize that T4O toxicity also extends to human meibomian gland epithelial cells (HMGECs). METHODS: Immortalized (I) HMGECs were cultured with varying concentrations (1.0%-0.001%) of T4O under proliferating or differentiating conditions up to 5 days. Experimental procedures included analyses of cell appearance, survival, P-Akt signaling, lysosome accumulation, and neutral lipid content. RESULTS: Our findings show that T4O causes a dose- and time-dependent decrease in the cell survival of IHMGECs. After 15 minutes of exposure to 1% T4O, IHMGECs exhibited rounding, atrophy, and poor adherence. Within 90 minutes of such treatment, almost all cells died. Reducing the T4O concentration to 0.1% also led to a marked decrease in P-Akt signaling and cell survival of IHMGECs. Decreasing the T4O amount to 0.01% caused a slight, but significant, reduction in the IHMGEC number after 5 days of culture and did not influence the ability of these cells to differentiate. CONCLUSIONS: T4O, even at levels 10-fold to 100-fold lower than demodicidal concentrations, is toxic to HMGECs in vitro.
Rossato FA, Su Y, Mackey A, Ng YSE. Fibrotic Changes and Endothelial-to-Mesenchymal Transition Promoted by VEGFR2 Antagonism Alter the Therapeutic Effects of VEGFA Pathway Blockage in a Mouse Model of Choroidal Neovascularization. Cells 2020;9(9)Abstract
Many patients with wet age-related macular degeneration do not respond well to anti- vascular endothelial growth factor A (VEGFA) therapy for choroidal neovascularization (CNV), and the efficacy of anti-VEGFA decreases over time. We investigated the hypothesis that fibrotic changes, in particular via endothelial-to-mesenchymal transition (EndoMT), play a role in CNV and alter the therapeutic effects of VEGFA pathway blockage. Induction of EndoMT of primary human retinal endothelial cells led to a significantly reduced response to VEGFA at the level of gene expression, cellular proliferation, migration, and tube formation. Suppression of EndoMT restored cell responsiveness to VEGFA. In a mouse model of spontaneous CNV, fibrotic changes and EndoMT persisted as the CNV lesions became more established over time. VEGFA receptor-2 (VEGFR2) antagonism further induced fibrosis and EndoMT in the CNV. The combination of VEGFR2 antagonism and fibrosis/EndoMT inhibition was more effective than either individual treatment in reducing CNV. Our data indicate that fibrosis and EndoMT are involved in the progression of CNV, are exacerbated by VEGFR2 inhibition, and could provide an explanation for the reduced efficacy of anti-VEGFA treatment over time.
Jakobiec FA, Barrantes PC, Yonekawa Y, Lad EM, Proia AD. Subretinal Mononuclear Cells in Coats' Disease Studied with RPE65 and CD163: Evidence for Histiocytoid Pigment Epithelial Cells. Am J Ophthalmol 2020;Abstract
PURPOSE: To evaluate the mononuclear cells in the subretinal exudate in Coats' disease. DESIGN: Retrospective case series. METHODS: Five enucleated globes and one cytology sample with Coats' disease and one case of chronic retinal detachment following repair of an open globe injury were examined immunohistochemically to identify the intraretinal and subretinal exudative cells. The two biomarkers were RPE65 for retinal pigment epithelium and CD163 for histiocytes, each tagged with different chromogens, yellow for pigment epithelium and purple for CD163+ monocytes/histiocytes. Expressions were sought of both biomarkers together or singly. A color shift to red in the cells' chromogenic reaction indicated the simultaneous presence of the two biomarkers. RESULTS: The majority of the mononuclear cells in Coats' disease were CD163 (purple) positive, and a minority were RPE65 (yellow) positive. An intermediate number of cells were RPE65/CD163 positive (orange-red). The eye with a chronic retinal detachment had an equal distribution of CD163 positive and RPE65/CD163 positive cells. CONCLUSIONS: The retinal pigment epithelium has several well-delineated phenotypes and functions. In normal visual physiology, the pigment epithelium supports the photoreceptors and participates in their renewal by phagocytosis of the tips of the photoreceptors. The expression of CD163, a feature of hematopoietically derived monocytes, together with RPE65 in the retinal pigment epithelium, supports differentiation toward histiocytes. Yellow staining detached pigment epithelial cells were rare. The presence of histiocytoid pigment epithelium at the level of Bruch's membrane probably also has implications for macular degeneration.
Testi I, Agrawal R, Mahajan S, Agarwal A, Gunasekeran DV, Raje D, Aggarwal K, Murthy SI, Westcott M, Chee S-P, McCluskey P, Ho SL, Teoh S, Cimino L, Biswas J, Narain S, Agarwal M, Mahendradas P, Khairallah M, Jones N, Tugal-Tutkun I, Babu K, Basu S, Carreño E, Lee R, Al-Dhibi H, Bodaghi B, Invernizzi A, Goldstein DA, Herbort CP, Barisani-Asenbauer T, González-López JJ, Androudi S, Bansal R, Moharana B, Esposti SD, Tasiopoulou A, Nadarajah S, Agarwal M, Abraham S, Vala R, Singh R, Sharma A, Sharma K, Zierhut M, Kon OM, Cunningham ET, Kempen JH, Nguyen QD, Pavesio C, Gupta V. The Collaborative Ocular Tuberculosis Study (COTS)-1: A Multinational Descriptive Review of Tubercular Uveitis in Paediatric Population. Ocul Immunol Inflamm 2020;:1-7.Abstract
PURPOSE: To examine disease profile of tubercular uveitis (TBU) in Paediatric population. METHODS: Among 945 patients of the retrospective multinational study by the Collaborative Ocular Tuberculosis Study (COTS)-1, 29 Paediatric patients diagnosed with TBU were analyzed. RESULTS: Mean age of disease presentation was 12.8 (range 4-18 years), with predominance of males (n = 14/20; 70.0%) and Asian ethnicity (n = 25/29; 86.2%). Posterior uveitis (n = 14/28; 50%) was the most frequent uveitis phenotype, with choroidal involvement occurring in 64.7% (n = 11/17). Incidence of optic disc edema and macular edema was higher in children (n = 8/18; 44.4% and n = 5/18; 27.8%, respectively) than in adults (n = 160/942; 16.9% and n = 135/942; 14.3%, respectively). Comparison of optic disc edema between subgroups showed a significant difference (). All patients received oral corticosteroids, most of them with antitubercular therapy. Treatment failure developed in 4.8% (n = 1/21). CONCLUSIONS: Children have a more severe inflammatory response to the disease, and an intensive anti-inflammatory therapeutic regimen is required to achieve a positive treatment outcome.
Lee JS, Mukherjee S, Lee JY, Saha A, Chodosh J, Painter DF, Rajaiya J. Entry of Epidemic Keratoconjunctivitis-Associated Human Adenovirus Type 37 in Human Corneal Epithelial Cells. Invest Ophthalmol Vis Sci 2020;61(10):50.Abstract
Purpose: Ocular infection by human adenovirus species D type 37 (HAdV-D37) causes epidemic keratoconjunctivitis, a severe, hyperacute condition. The corneal component of epidemic keratoconjunctivitis begins upon infection of corneal epithelium, and the mechanism of viral entry dictates subsequent proinflammatory gene expression. Therefore, it is important to understand the specific pathways of adenoviral entry in these cells. Methods: Transmission electron microscopy of primary and tert-immortalized human corneal epithelial cells infected with HAdV-D37 was performed to identify the means of viral entry. Confocal microscopy was used to determine intracellular trafficking. The results of targeted small interfering RNA and specific chemical inhibitors were analyzed by quantitative PCR, and Western blot. Results: By transmission electron microscopy, HAdV-D37 was seen to enter by both clathrin-coated pits and macropinocytosis; however, entry was both pH and dynamin 2 independent. Small interfering RNA against clathrin, AP2A1, and lysosome-associated membrane protein 1, but not early endosome antigen 1, decreased early viral gene expression. Ethyl-isopropyl amiloride, which blocks micropinocytosis, did not affect HAdV-D37 entry, but IPA, an inhibitor of p21-activated kinase, and important to actin polymerization, decreased viral entry in a dose-dependent manner. Conclusions: HAdV-D37 enters human corneal epithelial cells by a noncanonical clathrin-mediated pathway involving lysosome-associated membrane protein 1 and PAK1, independent of pH, dynamin, and early endosome antigen 1. We showed earlier that HAdV-D37 enters human keratocytes through caveolae. Therefore, epidemic keratoconjunctivitis-associated viruses enter different corneal cell types via disparate pathways, which could account for a relative paucity of proinflammatory gene expression upon infection of corneal epithelial cells compared with keratocytes, as seen in prior studies.
Molinaro A, Micheletti S, Rossi A, Gitti F, Galli J, Merabet LB, Fazzi EM. Autistic-Like Features in Visually Impaired Children: A Review of Literature and Directions for Future Research. Brain Sci 2020;10(8)Abstract
There remains great interest in understanding the relationship between visual impairment (VI) and autism spectrum disorder (ASD) due to the extraordinarily high prevalence of ASD in blind and visually impaired children. The broad variability across individuals and assessment methodologies have made it difficult to understand whether autistic-like symptoms shown by some children with VI might reflect the influence of the visual deficit, or represent a primary neurodevelopmental condition that occurs independently of the VI itself. In the absence of a valid methodology adapted for the visually impaired population, diagnosis of ASD in children with VI is often based on non-objective clinical impression, with inconclusive prevalence data. In this review, we discuss the current state of knowledge and suggest directions for future research.
Inomata T, Kitazawa K, Kuno T, Sung J, Nakamura M, Iwagami M, Takagi H, Midorikawa-Inomata A, Zhu J, Fujimoto K, Okumura Y, Miura M, Fujio K, Hirosawa K, Akasaki Y, Kuwahara M, Dana R, Murakami A. Clinical and Prodromal Ocular Symptoms in Coronavirus Disease: A Systematic Review and Meta-Analysis. Invest Ophthalmol Vis Sci 2020;61(10):29.Abstract
Purpose: This systematic review aimed to determine currently reported clinical and prodromal ocular symptoms in patients with coronavirus disease 2019 (COVID-19). Methods: An online article search was performed in PubMed and EMBASE. Altogether 15 studies (retrospective, prospective, or case studies) involving 1533 patients with COVID-19, reporting on ocular symptoms, and with outcome data available were identified. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses reporting guidelines were followed. Study-specific estimates (incidence rates of ocular symptoms in patients with COVID-19) of cases were combined using one-group meta-analysis in a random-effects model. Results: Of all included studies, 11.2% (95% confidence interval, 5.5-16.9; 78/1526 cases) reported ocular symptoms. The most common ocular finding was conjunctivitis. Prodromal ocular symptoms occurred in 12.5% (13/104 cases) of patients with COVID-19. Positive real-time polymerase chain reaction results were obtained for 16.7% (10/60 cases) of conjunctival samples and 0% (0/17 cases) of tear samples. Twelve ocular conjunctival swab samples tested positive for SARS-CoV-2. Ten cases were from subjects showing ocular symptoms (16.7%, 10/60 cases), and the remaining two cases were from subjects without ocular manifestation (1.8%, 2/113 cases). Limitations included the short study period, small sample size, findings were limited to the Asian population, only seven articles included ophthalmologic examination details, and there is currently no consensus on COVID-19 management. Conclusions: Ocular symptoms may occur in the presymptomatic phase as a prodromal symptom (12.5%, 13/104 cases), suggesting the possibility of viral transmission from the conjunctiva.
Barrero-Castillero A, Corwin BK, VanderVeen DK, Wang JC. Workforce Shortage for Retinopathy of Prematurity Care and Emerging Role of Telehealth and Artificial Intelligence. Pediatr Clin North Am 2020;67(4):725-733.Abstract
Retinopathy of prematurity (ROP) is the leading cause of childhood blindness in very-low-birthweight and very preterm infants in the United States. With improved survival of smaller babies, more infants are at risk for ROP, yet there is an increasing shortage of providers to screen and treat ROP. Through a literature review of new and emerging technologies, screening criteria, and analysis of a national survey of pediatric ophthalmologists and retinal specialists, the authors found the shortage of ophthalmology workforce for ROP a serious and growing concern. When used appropriately, emerging technologies have the potential to mitigate gaps in the ROP workforce.

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