Proliferative vitreoretinopathy (PVR) exemplifies a disease that is difficult to predict, lacks effective treatment options, and substantially reduces the quality of life of an individual. Surgery to correct a rhegmatogenous retinal detachment fails primarily because of PVR. Likely mediators of PVR are growth factors in vitreous, which stimulate cells within and behind the retina as an inevitable consequence of a breached retina. Three classes of growth factors [vascular endothelial growth factor A (VEGF-A), platelet-derived growth factors (PDGFs), and non-PDGFs (growth factors outside of the PDGF family)] are relevant to PVR pathogenesis because they act on PDGF receptor α, which is required for experimental PVR and is associated with this disease in humans. We discovered that ranibizumab (a clinically approved agent that neutralizes VEGF-A) reduced the bioactivity of vitreous from patients and experimental animals with PVR, and protected rabbits from developing disease. The apparent mechanism of ranibizumab action involved derepressing PDGFs, which, at the concentrations present in PVR vitreous, inhibited non–PDGF-mediated activation of PDGF receptor α. These preclinical findings suggest that available approaches to neutralize VEGF-A are prophylactic for PVR, and that anti–VEGF-based therapies may be effective for managing more than angiogenesis- and edema-driven pathological conditions. Proliferative vitreoretinopathy (PVR) exemplifies a disease that is difficult to predict, lacks effective treatment options, and substantially reduces the quality of life of an individual. Surgery to correct a rhegmatogenous retinal detachment fails primarily because of PVR. Likely mediators of PVR are growth factors in vitreous, which stimulate cells within and behind the retina as an inevitable consequence of a breached retina. Three classes of growth factors [vascular endothelial growth factor A (VEGF-A), platelet-derived growth factors (PDGFs), and non-PDGFs (growth factors outside of the PDGF family)] are relevant to PVR pathogenesis because they act on PDGF receptor α, which is required for experimental PVR and is associated with this disease in humans. We discovered that ranibizumab (a clinically approved agent that neutralizes VEGF-A) reduced the bioactivity of vitreous from patients and experimental animals with PVR, and protected rabbits from developing disease. The apparent mechanism of ranibizumab action involved derepressing PDGFs, which, at the concentrations present in PVR vitreous, inhibited non–PDGF-mediated activation of PDGF receptor α. These preclinical findings suggest that available approaches to neutralize VEGF-A are prophylactic for PVR, and that anti–VEGF-based therapies may be effective for managing more than angiogenesis- and edema-driven pathological conditions. Proliferative vitreoretinopathy (PVR) is an example of a disease that remains difficult to manage despite multidecade efforts to improve treatment options.1Han D: Proliferative Vitreoretinopathy. In: Albert D, JW M, DT A, BA B editor. Philadelphia, PA: Elsevier Saunders; 2008;p. 2315–2324.Google Scholar, 2Michels R.G. Wilkinson C.P. Rice T.A. Proliferative Retinopathy. Mosby, St. Louis1990Google Scholar, 3Pastor J.C. Proliferative vitreoretinopathy: an overview.Surv Ophthalmol. 1998; 43: 3-18Abstract Full Text Full Text PDF PubMed Scopus (321) Google Scholar, 4Patel N.N. Bunce C. Asaria R.H. Charteris D.G. 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Vitrectomy with silicone oil or long-acting gas in eyes with severe proliferative vitreoretinopathy: results of additional and long-term follow-up: Silicone Study report 11.Arch Ophthalmol. 1997; 115: 335-344Crossref PubMed Scopus (171) Google Scholar Vision loss is permanent and thereby substantially reduces the quality of life for these patients. By using 2010 census data, an estimated 55,000 individuals in the United States experience an RRD annually, and by extrapolation, 2750 to 5550 people will develop PVR.5Asaria R.H. Charteris D.G. Proliferative vitreoretinopathy: developments in pathogenesis and treatment.Compr Ophthalmol Update. 2006; 7: 179-185PubMed Google Scholar Both the small size of this population and the difficulty in predicting which patient will succumb to this affliction make PVR a low priority for the pharmaceutical industry. Consequently, efforts to develop new therapies for PVR and evaluate them in clinical trials have languished. 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Pathological signaling via platelet-derived growth factor receptor {alpha} involves chronic activation of Akt and suppression of p53.Mol Cell Biol. 2011; 31: 1788-1799Crossref PubMed Scopus (53) Google Scholar Vitreous abounds with non-PDGFs that activate PDGFRα in the way that reduces p53.29Pennock S. Rheaume M.A. Mukai S. Kazlauskas A. A novel strategy to develop therapeutic approaches to prevent proliferative vitreoretinopathy.Am J Pathol. 2011; 179: 2931-2940Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar, 39Lei H. Velez G. Kazlauskas A. Pathological signaling via platelet-derived growth factor receptor {alpha} involves chronic activation of Akt and suppression of p53.Mol Cell Biol. 2011; 31: 1788-1799Crossref PubMed Scopus (53) Google Scholar Although PDGFs are also present, their level in vitreous of patients and rabbits with PVR is insufficient to cause a substantial decline in the level of p53.38Lei H. Rheaume M.A. Cui J. Mukai S. Maberley D. Samad A. Matsubara J. Kazlauskas A. A novel function of p53: a gatekeeper of retinal detachment.Am J Pathol. 2012; 181: 866-874Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar, 39Lei H. Velez G. Kazlauskas A. Pathological signaling via platelet-derived growth factor receptor {alpha} involves chronic activation of Akt and suppression of p53.Mol Cell Biol. 2011; 31: 1788-1799Crossref PubMed Scopus (53) Google Scholar Furthermore, PDGFs antagonize the ability of non-PDGFs to reduce the p53 level.37Pennock S. Kazlauskas A. Vascular endothelial growth factor A competitively inhibits platelet-derived growth factor (PDGF)-dependent activation of PDGF receptor and subsequent signaling events and cellular responses.Mol Cell Biol. 2012; 32: 1955-1966Crossref PubMed Scopus (49) Google Scholar, 39Lei H. Velez G. Kazlauskas A. Pathological signaling via platelet-derived growth factor receptor {alpha} involves chronic activation of Akt and suppression of p53.Mol Cell Biol. 2011; 31: 1788-1799Crossref PubMed Scopus (53) Google Scholar The underlying mechanism appears to involve PDGF-mediated reduction in the amount of PDGFRα available to non-PDGFs.39Lei H. Velez G. Kazlauskas A. Pathological signaling via platelet-derived growth factor receptor {alpha} involves chronic activation of Akt and suppression of p53.Mol Cell Biol. 2011; 31: 1788-1799Crossref PubMed Scopus (53) Google Scholar The results of these biochemical studies indicate that the key agent in vitreous that drives PVR is non-PDGFs, whereas PDGFs protect from PVR. In vivo studies confirmed some, but not all, of these concepts. Neutralizing vitreal non-PDGFs protected rabbits from developing PVR, and thereby confirmed the idea that non-PDGFs were required for experimental PVR.29Pennock S. Rheaume M.A. Mukai S. Kazlauskas A. A novel strategy to develop therapeutic approaches to prevent proliferative vitreoretinopathy.Am J Pathol. 2011; 179: 2931-2940Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar In contrast, inhibiting vitreal PDGFs had no effect.36Lei H. Velez G. Hovland P. Hirose T. Gilbertson D. Kazlauskas A. Growth factors outside the PDGF family drive experimental PVR.Invest Ophthalmol Vis Sci. 2009; 50: 3394-3403Crossref PubMed Scopus (53) Google Scholar In light of the fact that PDGFs antagonize non-PDGFs, one would have expected that neutralizing PDGFs should have promoted PVR. Although these findings indicated a requirement for non-PDGFs in experimental PVR, they also indicated that there were additional concepts that needed to be considered. For instance, VEGF, which is also present in patients and experimental animals with PVR,16Banerjee S. Savant V. Scott R.A. Curnow S.J. Wallace G.R. Murray P.I. Multiplex bead analysis of vitreous humor of patients with vitreoretinal disorders.Invest Ophthalmol Vis Sci. 2007; 48: 2203-2207Crossref PubMed Scopus (105) Google Scholar, 20Citirik M. Kabatas E.U. Batman C. Akin K.O. Kabatas N. Vitreous vascular endothelial growth factor concentrations in proliferative diabetic retinopathy versus proliferative vitreoretinopathy.Ophthalmic Res. 2012; 47: 7-12Crossref PubMed Scopus (23) Google Scholar, 29Pennock S. Rheaume M.A. Mukai S. Kazlauskas A. A novel strategy to develop therapeutic approaches to prevent proliferative vitreoretinopathy.Am J Pathol. 2011; 179: 2931-2940Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar, 40Dieudonne S.C. La Heij E.C. Diederen R.M. Kessels A.G. Liem A.T. Kijlstra A. Hendrikse F. Balance of vascular endothelial growth factor and pigment epithelial growth factor prior to development of proliferative vitreoretinopathy.Ophthalmic Res. 2007; 39: 148-154Crossref PubMed Scopus (31) Google Scholar competitively inhibited PDGF from binding and activating PDGFRα.37Pennock S. Kazlauskas A. Vascular endothelial growth factor A competitively inhibits platelet-derived growth factor (PDGF)-dependent activation of PDGF receptor and subsequent signaling events and cellular responses.Mol Cell Biol. 2012; 32: 1955-1966Crossref PubMed Scopus (49) Google Scholar Thus, a plausible explanation for why neutralizing PDGFs had no impact on PVR was because VEGF was already eliminating their contribution. Furthermore, because PDGFs antagonize non-PDGFs, then VEGF (by inhibiting PDGF) should promote the action of non-PDGFs (Figure 1A). This reasoning led to the prediction that neutralizing VEGF would inhibit PVR because it would allow PDGF-mediated inhibition of non-PDGFs, which activate PDGFRα in the way that leads to PVR. In the course of investigating this possibility, we discovered that ranibizumab, an anti–VEGF-A monoclonal antibody fragment, reduced the pathogenic bioactivity of vitreous from patients and experimental animals with PVR and protected rabbits from developing this disease. These preclinical findings suggest that one or more of the clinically approved approaches to neutralize VEGF-A are prophylactic for PVR. In addition, anti–VEGF-based therapies may be effective for managing more than the angiogenesis and vascular permeability-driven pathological conditions. Recombinant human PDGF-A, PDGF-AB, and PDGF-B were purchased from Peprotech Inc. (Rocky Hill, NJ). The following antibodies were raised in the laboratory, as referenced: anti-PDGFRα,41Lei H. Hovland P. Velez G. Haran A. Gilbertson D. Hirose T. Kazlauskas A. A potential role for PDGF-C in experimental and clinical proliferative vitreoretinopathy.Invest Ophthalmol Vis Sci. 2007; 48: 2335-2342Crossref PubMed Scopus (62) Google Scholar, 42Robbins S.G. Mixon R.N. Wilson D.J. Hart C.E. Robertson J.E. Westra I. Planck S.R. Rosenbaum J.T. Platelet-derived growth factor ligands and receptors immunolocalized in proliferative retinal diseases.Invest Ophthalmol Vis Sci. 1994; 35: 3649-3663PubMed Google Scholar anti–phospho-PDGFRα (Y742),43Lei H. Velez G. Cui J. Samad A. Maberley D. Matsubara J. Kazlauskas A. N-acetylcysteine suppresses retinal detachment in an experimental model of proliferative vitreoretinopathy.Am J Pathol. 2010; 177: 132-140Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar and anti-RasGAP.44Klinghoffer R.A. Duckworth B. Valius M. Cantley L. Kazlauskas A. Platelet-derived growth factor-dependent activation of phosphatidylinositol 3-kinase is regulated by receptor binding of SH2-domain-containing proteins which influence Ras activity.Mol Cell Biol. 1996; 16: 5905-5914Crossref PubMed Scopus (124) Google Scholar Anti-Akt (9272S) and anti–phospho-Akt (pS473 and 9271L) were purchased from Cell Signaling (Danvers, MA). Anti–phospho-PDGFRα (pY720), anti-p53 (sc-126), PrA-agarose beads (sc-2001), and horseradish peroxidase–conjugated goat anti-rabbit and goat anti-mouse IgG secondary antibodies were purchased from Santa Cruz Biotechnology (Santa Cruz, CA). Enhanced chemiluminescent substrate for horseradish peroxidase detection was purchased from Pierce (Rockford, IL). PDGF TRAP (which binds to and sequesters PDGF) is a chimera consisting of the extracellular domain of PDGFRα fused to human IgG Fc5, was provided by Dr. Debra Gilbertson at ZymoGenetics.42Robbins S.G. Mixon R.N. Wilson D.J. Hart C.E. Robertson J.E. Westra I. Planck S.R. Rosenbaum J.T. Platelet-derived growth factor ligands and receptors immunolocalized in proliferative retinal diseases.Invest Ophthalmol Vis Sci. 1994; 35: 3649-3663PubMed Google Scholar The anti–VEGF-A Fab fragment, ranibizumab (GENENTECH, South San Francisco, CA), was a generous gift from Dr. Patricia D'Amore (Schepens Eye Research Institute, Boston, MA). Primary rabbit conjunctival fibroblasts (RCFs) were isolated as described previously.45Nakagawa M. Refojo M.F. Marin J.F. Doi M. Tolentino F.I. Retinoic acid in silicone and silicone-fluorosilicone copolymer oils in a rabbit model of proliferative vitreoretinopathy.Invest Ophthalmol Vis Sci. 1995; 36: 2388-2395PubMed Google Scholar These cells were used for analysis of rabbit vitreous bioactivity and for injection into rabbit eyes in the experimental PVR model. Primary mouse embryonic fibroblasts (MEFs) were obtained at third passage from ATCC (Manassas, VA) and used for the shRNA knockdown and receptor activation threshold experiments. R627 cells are immortalized fibroblasts derived from mouse embryos nullizygous for both PDGFR isoforms, in which a full-length kinase-inactive mutant PDGFRα is re-expressed.15Andrews A. Balciunaite E. Leong F.L. Tallquist M. Soriano P. Refojo M. Kazlauskas A. Platelet-derived growth factor plays a key role in proliferative vitreoretinopathy.Invest Ophthalmol Vis Sci. 1999; 40: 2683-2689PubMed Google Scholar, 46Rosenkranz S. DeMali K.A. Gelderloos J.A. Bazenet C. Kazlauskas A. Identification of the receptor-associated signaling enzymes that are required for platelet-derived growth factor-AA-dependent chemotaxis and DNA synthesis.J Biol Chem. 1999; 274: 28335-28343Crossref PubMed Scopus (76) Google Scholar R627 cells were used in experiments to ascertain the role of PDGF-induced dimerization of PDGFRα in reducing the bioactivity of vitreous. ARPE-19α cells, derived from the human retinal pigment epithelial (RPE) cell line, ARPE-19 (ATCC), overexpress human PDGFRα.41Lei H. Hovland P. Velez G. Haran A. Gilbertson D. Hirose T. Kazlauskas A. A potential role for PDGF-C in experimental and clinical proliferative vitreoretinopathy.Invest Ophthalmol Vis Sci. 2007; 48: 2335-2342Crossref PubMed Scopus (62) Google Scholar These cells were used to investigate the PDGFRα-inhibitory activity of human PVR vitreous. RPE cells from human PVR membranes (RPEM cells) were isolated from a surgically removed patient PVR membrane.47Wong C.A. Potter M.J. Cui J.Z. Chang T.S. Ma P. Maberley A.L. Ross W.H. White V.A. Samad A. Jia W. Hornan D. Matsubara J.A. Induction of proliferative vitreoretinopathy by a unique line of human retinal pigment epithelial cells.Can J Ophthalmol. 2002; 37: 211-220PubMed Scopus (31) Google Scholar RPEM cells (at passages 4 to 7) were used in experiments to assess human vitreous bioactivity. PAE-KDR cells are pig aortic endothelial (PAE) cells that overexpress human VEGF receptor 2 (VEGFR2), as previously described48Waltenberger J. Claesson-Welsh L. Siegbahn A. Shibuya M. Heldin C.H. Different signal transduction properties of KDR and Flt1, two receptors for vascular endothelial growth factor.J Biol Chem. 1994; 269: 26988-26995Abstract Full Text PDF PubMed Google Scholar; these cells were used to test whether heat functionally inactivates VEGF-A in PVR vitreous. RCFs, MEFs, and R627 cells were maintained in high-glucose–containing Dulbecco's modified Eagle's medium (DMEM; Gibco BRL, NY). ARPE-19α, RPEM, and PAE-KDR cells were maintained in a 1:1 mixture of high-glucose DMEM and Ham's F12 medium (Gibco BRL). Cells were cultured in media supplemented with 10% fetal bovine serum (FBS), 500 U/mL penicillin, and 500 μg/mL streptomycin, and incubated at 37°C in a humidified 5% CO2 atmosphere. Cells were grown to near confluence, serum starved overnight in DMEM with 0.1% FBS, and treated the next morning. Vitreous (RV-PVR or HV-PVR) that was used to stimulate cells consisted of an equal-volume pool of several individual samples. Vitreous or DMEM, supplemented with the indicated treatments, was added directly to cells after removal of media and rinsing with PBS. Treatments were performed under the same conditions as cells that were incubated (37°C in a humidified 5% CO2 atmosphere). Vitreous was extracted from either PVR-positive rabbit eyes (RV-PVR) or healthy control rabbits eyes (RV) that were enucleated and frozen at −80°C. While still frozen, vitreous was removed, allowed to thaw to room temperature, and then centrifuged at 4°C for 5 minutes at 10,000 × g. The resultant clarified vitreous was used for subsequent analysis. Vitreous used for treatment is an equal-volume mix from several rabbit eyes of comparable clinical status (ie, PVR stage). Cells were washed twice with ice-cold PBS after treatment, then lysed in sample buffer (50 mmol/L Tris-HCl, pH 6.8, 10% glycerol, 2% SDS, 1% β-mercaptoethanol, 10 mmol/L EDTA, and 0.02% bromophenol blue). Total cell lysates (TCLs) were incubated on ice for 15 minutes, heated to 95°C for 5 minutes, and clarified by centrifugation at 13,000 × g, 4°C for 15 minutes. Samples were then run on 8% or 10% acrylamide SDS-PAGE gels, and resolved proteins were transferred to polyvinylidene difluoride immunoblotting membranes by semidry transfer. Each immunoblot shown is representative of three independent experiments. Signal intensity was determined by densitometry using Quantity One software version 4.0 (Bio-Rad, Pinole, CA); signal quantities shown were standardized to background and normalized for loading. Cells were grown to near confluence and then preconditioned for 48 hours with the indicated treatment in DMEM before performing the contraction assay, as previously described.32Ikuno Y. Kazlauskas A. An in vivo gene therapy approach for experimental proliferative vitreoretinopathy using the truncated platelet-derived growth factor alpha receptor.Invest Ophthalmol Vis Sci. 2002; 43: 2406-2411PubMed Google Scholar, 49Grinnell F. Ho C.H. Lin Y.C. Skuta G. Differences in the regulation of fibroblast contraction of floating versus stressed collagen matrices.J Biol Chem. 1999; 274: 9
This paper presents the efficacy of fresh and fresh frozen plasma in disseminated intravascular coagulation (DIC) cases in dogs. DIC is common acquired coagulapathy in dogs. In the present study total 6 dogs were diagnosed on the basis of signs and increased CBCT, ACT, PT, aPTT, TT, FDPs and decreased plasma fibrinogen and presence of D-dimer. The therapeutic management of DIC by replacement of coagulation factors, proteins and fibrinogen was studied with the improvement in coagulation parameters. The before and after treatment values of CBCT was (9.01 ± 1.05 and 6.23 ± 0.34 min), ACT (140.83± 10.68 and 118.33 ±6.88 sec), PT (17.33 ± 4.17 and 14.16 ± 0.75 sec), aPTT (20.00 ± 3.46 and 15.50 ± 1.76 sec), TT (31.00 ± 8.27 and 20.66 ± 2.50 sec), FDPs (5–20 mg/dl), fibrinogen (193.00 ± 61.48 and 260.00 ±73.76 mg/dl) and presence of D-dimer. All coagulapathy tests were significantly improved after administration of fresh and fresh frozen plasma.
An anonymous survey was designed by the Canadian Retina Research Network coronavirus disease 2019 (COVID-19) Steering Committee to assess awareness of, confidence in, and adherence to recent guidelines released by the Canadian Ophthalmology Society (COS) and Canadian Retina Society (CRS) for ophthalmic care during the COVID-19 pandemic.1Canadian Ophthalmology Society and Association of Canadian University Professors of Ophthalmology. Guidelines for Ophthalmic Care during COVID-19 Pandemic. 2020. www.cosprc.ca/resource/guidelines-for-ophthalmic-care/ (accessed 14 May 2020).Google Scholar,2Canadian Retinal Society. Position Statement on Intravitreal Injections and the Management of Retinal Diseases during the COVID-19 Crisis. 2020. www.cosprc.ca/resource/canadian-retina-society-crs-position-statement-on-intravitreal-injections-and-the-management-of-retinal-diseases-during-the-covid-19-crisis/ (accessed 14 May 2020).Google Scholar The survey was pilot-tested and validated with 9 content experts. It was then distributed via email to physician members of the CRS in May 2020 with one reminder email to maximize response rate. Research ethics board approval was waived at our lead institution for this quality improvement study. In total, 44 of 118 retinal specialists completed the survey, yielding a response rate of 41%. Response rates above 40% have previously been deemed adequate for surveys of high importance and for which only a short period is available to conduct fieldwork.3Public Services and Procurement Canada. Standards and Guidelines for: Response Rate. 2014. www.tpsgc-pwgsc.gc.ca/rop-por/rapports-reports/comitephone-panelphone/page-06-eng.html (accessed 15 May 2020).Google Scholar All but 2 respondents were aware of national personal protective equipment (PPE) and practice management guidelines from the COS and the CRS. Eighty-three percent expressed that they were "somewhat confident" or "very confident" in the proposed guidance. All respondents were aware of the importance of hand hygiene, and over 90% were aware of guidance on eye protection and the use of slit-lamp breath shields. Almost 70% of respondents were aware of guidance on the regular use of a fluid-resistant surgical facemask, gloves, or an N95 respirator when indicated. Notably, 30% of respondents believed that the routine use of long-sleeved disposable gowns was recommended in COS and CRS guidance. Nearly 20% of respondents claimed to have adopted use of such gowns, even though this is not currently advised by either society at the time of writing (Fig. 1). All respondents stated that they implemented strategies to defer care for nonurgent cases, to enforce cleaning of equipment between each patient encounter, to decrease patients' time spent in the waiting room, and to restrict accompanying persons from entry into the clinic to promote optimal physical distancing. Respondents were less likely to adhere to guidance recommending the instillation of single-use eye drops (50%), asking patients to limit or decrease conversation (66%), and the lengthening of treatment intervals for eligible patients receiving intravitreal injections for retinal disease (73%). The survey results demonstrated strong awareness among CRS members of the guidelines recently released by COS and CRS in response to the COVID-19 crisis, suggesting that the mechanisms of dissemination used by these governing bodies were successful at reaching their physician members in a timely manner. These mechanisms could be adopted effectively in future events of similar magnitude and importance. Nevertheless, the present study did also reveal suboptimal understanding of, and adherence to, specific aspects of this guidance. For example, the fact that over 30% of specialists endorsed awareness of guidance never proposed by COS and CRS indicates some confusion with the guidance released. Presumably this resulted from being inundated with messaging from a myriad of other sources, as 32.6% of respondents claimed to have consulted web sites, academic rounds, hospitals, and other local and regional health regulatory authorities for PPE-related guidance during the COVID-19 crisis. Likewise, the proportion of physicians without a recent N95 respirator fit test (18%) or recent PPE training (25%) demonstrates a lack of preparedness to adopt such guidelines (Fig. 2). Minocha et al. published a similar survey in the United Kingdom, in which they observed that a lack of coordination and agreement between federal guidelines and those released by local health units and hospitals risked confusion for practitioners and patients alike.4Minocha A. Sim S.Y. Than J. Vakros G. Survey of ophthalmology practitioners in A&E on current COVID-19 guidance at three major UK eye hospitals [e-pub ahead of print].Eye (Lond). 2020; (Accessed)https://doi.org/10.1038/s41433-020-0857-5Crossref PubMed Scopus (33) Google Scholar Thus, in response to COVID-19, we suggest that future mechanisms be refined to coordinate clear, standardized, uniform, and evidence-based guidance for best-practice clinical management and the use of PPE in ophthalmic care. Dr. Varun Chaudhary has investigator-sponsored research grants and participates in clinical trials funded by Novartis, Bayer, and Allergan; Dr. Chaudhary has also served on the advisory board and is consultant for Novartis and Bayer. Dr. Cynthia Qian has served as consultant for Novartis, Bayer, Allergan, and Bausch and Lomb. Dr. Alan Berger serves as consultant and receives honoraria from Novartis, Bayer, Allergan, and Roche. Dr. James Whelan has received honoraria from Alcon, Novartis, and Bayer, and has investigator-sponsored research grants from Novartis. Dr. Amin Kherani participates in clinical trials funded by Novartis, Bayer, Allergan, Alcon, and Bausch and Lomb. Dr. Arif Samad participates in clinical trials funded by, and is consultant with, Novartis and Bayer. Dr. Jason Noble serves on the advisory board of Novartis and Bayer, and is a speaker for Novartis. None of these have any bearing on the current study. The remaining authors have no financial disclosures to declare. This research did not receive any funding or grants from agencies in the public, commercial, or not-for-profit sectors.
