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Shoji MK, Shishido S, Freitag SK. The Use of Sirolimus for Treatment of Orbital Lymphatic Malformations: A Systematic Review. Ophthalmic Plast Reconstr Surg 2020;36(3):215-221.Abstract
PURPOSE: Orbital lymphatic malformations are rare congenital choristomas associated with pain, proptosis, exposure keratopathy, and vision loss. Current treatments of surgery, drainage, and sclerotherapy may have adverse effects including risk of damage to surrounding structures, swelling, and malformation persistence or recrudescence. Sirolimus, which inhibits mammalian target of rapamycin, a regulator of cell growth and vascular endothelial growth factor expression, has successfully treated systemic vascular malformations. However, its efficacy and safety have not yet been well established for orbital lymphatic malformations. METHODS: Systematic review and analysis of relevant published literature were performed. PubMed, Embase, and World of Science searches were conducted for studies involving sirolimus treatment of orbital lymphatic malformations through July 2019. RESULTS: Nine case series and reports with 10 total patients who received sirolimus for treatment of orbital lymphatic malformations were included. The age at sirolimus initiation ranged from 1 week to 23 years. The malformation was lymphatic in 6 patients, lymphaticovenous in 3 patients, and lymphatic-arteriovenous in 1 patient. Six patients underwent ineffective prior therapy including sclerotherapy, surgery, or medical therapy. Initial sirolimus dosage ranged from 0.05 mg/kg twice a day to 1 mg twice a day, and duration ranged from 6 months to 53 months. Seven patients had partial response, and 3 patients, all of whom had a microcystic malformation component, experienced complete response. Adverse effects included mild reversible leukopenia, hypertriglyceridemia, hypercholesterolemia, and transaminitis with adverse effects denied or not specified for 6 patients. CONCLUSIONS: Sirolimus may be a safe and effective treatment for orbital lymphatic malformations, especially microcystic malformations.
Yang J, LeBlanc ME, Cano I, Saez-Torres KL, Saint-Geniez M, Ng Y-S, D'Amore PA. ADAM10 and ADAM17 proteases mediate proinflammatory cytokine-induced and constitutive cleavage of endomucin from the endothelial surface. J Biol Chem 2020;295(19):6641-6651.Abstract
Contact between inflammatory cells and endothelial cells (ECs) is a crucial step in vascular inflammation. Recently, we demonstrated that the cell-surface level of endomucin (EMCN), a heavily -glycosylated single-transmembrane sialomucin, interferes with the interactions between inflammatory cells and ECs. We have also shown that, in response to an inflammatory stimulus, EMCN is cleared from the cell surface by an unknown mechanism. In this study, using adenovirus-mediated overexpression of a tagged EMCN in human umbilical vein ECs, we found that treatment with tumor necrosis factor α (TNF-α) or the strong oxidant pervanadate leads to loss of cell-surface EMCN and increases the levels of the C-terminal fragment of EMCN 3- to 4-fold. Furthermore, treatment with the broad-spectrum matrix metalloproteinase inhibitor batimastat (BB94) or inhibition of ADAM metallopeptidase domain 10 (ADAM10) and ADAM17 with two small-molecule inhibitors, GW280264X and GI254023X, or with siRNA significantly reduced basal and TNFα-induced cell-surface EMCN cleavage. Release of the C-terminal fragment of EMCN by TNF-α treatment was blocked by chemical inhibition of ADAM10 alone or in combination with ADAM17. These results indicate that cell-surface EMCN undergoes constitutive cleavage and that TNF-α treatment dramatically increases this cleavage, which is mediated predominantly by ADAM10 and ADAM17. As endothelial cell-surface EMCN attenuates leukocyte-EC interactions during inflammation, we propose that EMCN is a potential therapeutic target to manage vascular inflammation.
Xiao S, Gaier ED, Mazow ML, Stout AU, Travers DA, Angjeli E, Wu HC, Binenbaum G, Hunter DG. Improved adherence and treatment outcomes with an engaging, personalized digital therapeutic in amblyopia. Sci Rep 2020;10(1):8328.Abstract
Given the prevalence of poor adherence to therapy and the biases of self-reporting across healthcare, we hypothesized that an engaging, personalized therapy may improve adherence and treatment outcomes in the home. We tested this hypothesis in the initial indication of amblyopia, a neurodevelopmental disorder for which available treatments are limited by low adherence. We designed a novel digital therapeutic that modifies patient-selected cinematic content in real-time into therapeutic visual input, while objectively monitoring adherence. The therapeutic design integrated a custom-designed headset that delivers precise visual input to each eye, computational algorithms that apply real-time therapeutic modifications to source content, a cloud-based content management system that enables treatment in the home, and a broad library of licensed content. In a proof-of-concept human study on the therapeutic, we found that amblyopic eye vision improved significantly after 12 weeks of treatment, with higher adherence than that of available treatments. These initial results support the utility of personalized therapy in amblyopia and may have broader relevance for improving treatment outcomes in additional indications.
Peters RPH, Kestelyn PG, Zierhut M, Kempen JH. The Changing Global Epidemic of HIV and Ocular Disease. Ocul Immunol Inflamm 2020;28(7):1007-1014.Abstract
: Overview of the evolving epidemiology of human immunodeficiency virus (HIV)-related ocular disease over time. : Narrative review. : HIV enhances susceptibility to opportunistic eye infections, has direct pathogenic effects, and places patients at risk of immune recovery inflammatory syndromes in previously infected eyes after starting highly-active antiretroviral therapy (HAART). Widespread availability of HAART has resulted in a decrease of infectious ocular conditions such as cytomegalovirus retinitis, toxoplasmic retinitis, squamous cell carcinoma of the conjunctiva, and microvascular retinopathy. However, large coexisting burdens of tuberculosis, herpesvirus infection and syphilis (among others) continue to contribute to the burden of ocular disease, especially in low-resource settings. Growing risks of cataract, retinopathy and retinal nerve fiber thinning can affect patients with chronic HIV on HAART; thought due to chronic inflammation and immune activation. : The changing epidemic of ocular disease in HIV-infected patients warrants close monitoring and identification of interventions that can help reduce the imminent burden of disease.
Junk AK, Chang TC, Vanner E, Chen T. Current Trends in Tonometry and Tonometer Tip Disinfection. J Glaucoma 2020;29(7):507-512.Abstract
PRECIS: A survey among members of the American Glaucoma Society (AGS) and the American Optometry Association (AOA) on tonometer preference and tonometer disinfection indicates a shift to disposable tonometer tips compared with 1987. PURPOSE: This survey's purpose was to determine how eye care providers responded to the 2008 Centers of Disease Control (CDC) tonometer disinfection guidelines, which recommend 10% hypochlorite (dilute bleach) for reusable tonometers. Tonometers measure the eye pressure when they touch the cornea, an essential part of the eye examination. METHODS: AGS and AOA members were surveyed on tonometer preference, tonometer use, disinfection process, disinfectants, disinfection timing, and tonometer damage. RESULTS: Survey responses from 79 AOA members and 197 AGS members are included. The Goldmann tonometer is considered most accurate (70, 89% AOA and 161, 82% AGS). It is preferred by 54 (70%) AOA and 193 (98%) AGS members. Many providers (165) use reusable Goldmann tonometer tips (77, 79% AOA, 88, 45% AGS), and most clean with 70% isopropyl alcohol wipes 59 (77%) AOA and 54 (61%) AGS. In summary, 126 of 276 participants (8, 10% AOA and 118, 60% AGS) follow CDC guidelines by using disposable tips (2 AOA and 109 AGS) or disinfecting reusable tips with 10% hypochlorite (6 AOA and 9 AGS). CONCLUSIONS: The majority of AGS providers follow current CDC tonometer disinfection guidelines by shifting to disposable Goldmann tonometer tips. Only a minority of providers who use reusable tonometer tips disinfect with dilute bleach. Continued education on proper tonometer disinfection is critical to prevent eye-care related infection due to improper disinfection.
Orts-Vila P, Amparo F, Rodríguez-Prats JL, Tañá-Rivero P. Alport Syndrome and Femtosecond Laser-assisted Cataract Surgery. J Ophthalmic Vis Res 2020;15(2):264-269.Abstract
We report the surgical management of a patient with bilateral anterior lenticonus due to Alport syndrome using femtosecond laser-assisted cataract surgery (FLACS) and the Optiwave Refractive Analysis (ORA) system. A 38-year-old man with Alport syndrome presented to our department with visual loss due to anterior lenticonus in both eyes. Adjustments during bilateral FLACS were performed with the software's calipers to manually delineate the anterior capsulotomy. Multifocal toric intraocular lenses (IOLs) were selected and placed in the posterior chamber with the aid of intraoperative aberrometry. The intended postoperative positioning parameters for the IOL as well as the planned visual acuity and refraction were achieved. The implementation of FLACS and intraoperative wavefront aberrometry is a safe and useful surgical approach for the management of cataract in challenging cases such as patients with anterior lenticonus due to Alport syndrome.
Lu X, Kugadas A, Smith-Page K, Lamb J, Lin T, Ru Y, Morley SC, Fichorova R, Mittal SK, Chauhan SK, Littleton S, Saban D, Gadjeva M. Neutrophil L-Plastin Controls Ocular Paucibacteriality and Susceptibility to Keratitis. Front Immunol 2020;11:547.Abstract
Why ocular mucosa is paucibacterial is unknown. Many different mechanisms have been suggested but the comprehensive experimental studies are sparse. We found that a deficiency in L-plastin (LCP1), an actin bundling protein, resulted in an ocular commensal overgrowth, characterized with increased presence of conjunctival spp. The commensal overgrowth correlated with susceptibility to -induced keratitis. L-plastin knock-out (KO) mice displayed elevated bacterial burden in the -infected corneas, altered inflammatory responses, and compromised bactericidal activity. Mice with ablation of LPL under the LysM Cre ( ) and S100A8 Cre ( ) promoters had a similar phenotype to the LPL KOs mice. In contrast, infected mice did not display elevated susceptibility to infection, implicating the myeloid L-plastin-sufficient cells (e.g., macrophages and neutrophils) in maintaining ocular homeostasis. Mechanistically, the elevated commensal burden and the susceptibility to infection were linked to defects in neutrophil frequencies at steady state and during infection and compromised bactericidal activities upon priming. Macrophage exposure to commensal organisms primed neutrophil responses to , augmenting PMN bactericidal capacity in an L-plastin dependent manner. Cumulatively, our data highlight the importance of neutrophils in controlling ocular paucibacteriality, reveal molecular and cellular events involved in the process, and suggest a link between commensal exposure and resistance to infection.
Geffrey AL, Geenen KR, Abati E, Greenstein SH, VanderVeen DK, Levy RL, Davidson SL, McGarrey MP, Thiele EA, Aronow ME. Juvenile cataract in association with tuberous sclerosis complex. Ophthalmic Genet 2020;41(4):345-349.Abstract
BACKGROUND: Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder characterized by benign hamartomas occurring in multiple organ systems including the brain, kidneys, heart, lungs, liver, skin, and the eyes. Typical retinal findings associated with TSC include astrocytic hamartoma and achromic patch. While rare cases of cataract occurring in the setting of TSC have been reported, this is the first analysis of a large series of individuals with TSC that aims to quantify the frequency of this finding and to describe its clinical and genetic associations. MATERIALS AND METHODS: This is a retrospective chart review of 244 patients from the Herscot Center for Tuberous Sclerosis Complex at the Massachusetts General Hospital who underwent complete ophthalmic examination. We describe the clinical and genetic findings in five individuals with TSC and juvenile cataract. RESULTS: Four of five cases (80%) were unilateral. The cataract was described as having an anterior subcapsular component in 3 of 5 cases (60%). Three individuals (60%) underwent lensectomy with intraocular lens (IOL) implant and two individuals (40%) were observed. Genetic testing revealed a known disease-causing mutation in in 100% of cases. CONCLUSIONS: Recent evidence suggests that mTOR signaling may play a role in cataract formation which could explain the relatively high incidence of juvenile cataract in this population. Juvenile cataract is a potentially under-recognized ocular manifestation of TSC.
Agrawal R, Testi I, Mahajan S, Yuen YS, Agarwal A, Rousselot A, Raje D, Gunasekeran DV, Kon OM, Barisani-Asenbauer T, Kempen JH, Gupta A, Jabs DA, Smith JR, Bodaghi B, Zierhut M, DeSmet M, McCluskey P, Agarwal M, Agarwal M, Aggarwal K, Agrawal M, Al-Dhibi H, Androudi S, Asyari F, Balasundaram MB, Murthy KB, Baglivo E, Banker A, Bansal R, Basu S, Behera D, Biswas J, Carreño E, Caspers L, Chee SP, Chhabra R, Cimino L, Del Rio LEC, Cunningham ET, Curi ALL, Das D, Denisova E, Denniston AK, Errera M-H, Fonollosa A, George A, Goldstein DA, Crosier YG, Gurbaxani A, Invernizzi A, Isa HM, Md Islam S, Jones N, Katoch D, Khairallah M, Khosla A, Kramer M, Kumar A, Kumar A, Distia Nora RL, Lee R, Lowder C, Luthra S, Mahendradas P, Makhoul D, Mazumdar S, Mehta S, Miserocchi E, Mochizuki M, Mohamed OS, Muccioli C, Munk MR, Murthy S, Narain S, Nascimento H, Neri P, Nguyen M, Okada AA, Ozdal P, Palestine A, Pichi F, Rathinam SR, Schlaen A, Sehgal S, Sen NH, Sharma A, Sharma K, Shoughy SS, Singh N, Singh R, Soheilian M, Sridharan S, Thorne JE, Tappeiner C, Teoh S, Tognon MS, Tugal-Tutkun I, Tyagi M, Uy H, Santos DVV, Valentincic NV, Westcott M, Yanai R, Alvarez BY, Zahedur R, Nguyen QD, Pavesio C, Gupta V. The Collaborative Ocular Tuberculosis Study (COTS) Consensus (CON) Group Meeting Proceedings. Ocul Immunol Inflamm 2020;:1-11.Abstract
An international, expert led consensus initiative was set up by the Collaborative Ocular Tuberculosis Study (COTS) group to develop systematic, evidence, and experience-based recommendations for the treatment of ocular TB using a modified Delphi technique process. In the first round of Delphi, the group identified clinical scenarios pertinent to ocular TB based on five clinical phenotypes (anterior uveitis, intermediate uveitis, choroiditis, retinal vasculitis, and panuveitis). Using an interactive online questionnaires, guided by background knowledge from published literature, 486 consensus statements for initiating ATT were generated and deliberated amongst 81 global uveitis experts. The median score of five was considered reaching consensus for initiating ATT. The median score of four was tabled for deliberation through Delphi round 2 in a face-to-face meeting. This report describes the methodology adopted and followed through the consensus process, which help elucidate the guidelines for initiating ATT in patients with choroidal TB.
Vujosevic S, Aldington SJ, Silva P, Hernández C, Scanlon P, Peto T, Simó R. Screening for diabetic retinopathy: new perspectives and challenges. Lancet Diabetes Endocrinol 2020;8(4):337-347.Abstract
Although the prevalence of all stages of diabetic retinopathy has been declining since 1980 in populations with improved diabetes control, the crude prevalence of visual impairment and blindness caused by diabetic retinopathy worldwide increased between 1990 and 2015, largely because of the increasing prevalence of type 2 diabetes, particularly in low-income and middle-income countries. Screening for diabetic retinopathy is essential to detect referable cases that need timely full ophthalmic examination and treatment to avoid permanent visual loss. In the past few years, personalised screening intervals that take into account several risk factors have been proposed, with good cost-effectiveness ratios. However, resources for nationwide screening programmes are scarce in many countries. New technologies, such as scanning confocal ophthalmology with ultrawide field imaging and handheld mobile devices, teleophthalmology for remote grading, and artificial intelligence for automated detection and classification of diabetic retinopathy, are changing screening strategies and improving cost-effectiveness. Additionally, emerging evidence suggests that retinal imaging could be useful for identifying individuals at risk of cardiovascular disease or cognitive impairment, which could expand the role of diabetic retinopathy screening beyond the prevention of sight-threatening disease.
Furutani E, Shah AS, Zhao Y, Andorsky D, Dedeoglu F, Geddis A, Zhou Y, Libermann TA, Myers KC, Shimamura A. Inflammatory manifestations in patients with Shwachman-Diamond syndrome: A novel phenotype. Am J Med Genet A 2020;182(7):1754-1760.Abstract
Shwachman-Diamond syndrome (SDS) is an autosomal recessive multisystem disorder characterized by exocrine pancreatic dysfunction, bone marrow failure, and leukemia predisposition. Approximately 90% of cases are due to biallelic mutations in the Shwachman-Bodian-Diamond (SBDS) gene. Additional phenotypic features variably associated with SDS include skeletal, neurologic, hepatic, cardiac, endocrine, and dental abnormalities. We report five subjects with SDS who developed a range of inflammatory manifestations. Three patients developed inflammatory eye conditions. Single cases of juvenile idiopathic arthritis, chronic recurrent multifocal osteomyelitis, and scleroderma were also noted. Clinical presentation and treatment responses are described. Proteomic analysis revealed increased inflammatory signatures in SDS subjects as compared to controls. Treatment of inflammatory manifestations in patients with SDS may be complicated by potential myelosuppressive toxicities of anti-rheumatic medications. Further research is needed to better understand the potential link between inflammatory disorders and SDS to inform effective treatment strategies.
Almeida LM, Lebreton F, Gaca A, Bispo PM, Saavedra JT, Calumby RN, Grillo LM, Nascimento TG, Filsner PH, Moreno AM, Gilmore MS. Transferable Resistance Gene in Enterococcus faecalis from Swine in Brazil. Antimicrob Agents Chemother 2020;64(6)Abstract
OptrA is an ATP-binding cassette (ABC)-F protein that confers resistance to oxazolidinones and phenicols and can be either plasmid-encoded or chromosomally encoded. Here, we isolated 13 strains possessing a linezolid MIC of ≥4 mg/liter from nursery pigs in swine herds located across Brazil. Genome sequence comparison showed that these strains possess in different genetic contexts occurring in 5 different sequence type backgrounds. The gene invariably occurred in association with an regulator and a gene encoding a hypothetical protein. In some contexts, this genetic island was able to excise and form a covalently closed circle within the cell; this circle appeared to occur in high abundance and to be transmissible by coresident plasmids.
Foulsham W, Mittal SK, Taketani Y, Chen Y, Nakao T, Chauhan SK, Dana R. Aged Mice Exhibit Severe Exacerbations of Dry Eye Disease with an Amplified Memory Th17 Cell Response. Am J Pathol 2020;190(7):1474-1482.Abstract
The prevalence as well as the severity of dry eye disease increase with age. Memory T helper 17 (Th17) cells (CD4IL-17ACD44) drive the chronic and relapsing course of dry eye disease. Here, we investigated the contribution of memory Th17 cells to age-related dry eye disease, and evaluated memory Th17 cell depletion with anti-IL-15 antibody as a strategy to abrogate the severe exacerbations of dry eye disease observed in aged mice. After initial exposure to desiccating stress, aged mice maintained higher frequencies of memory Th17 cells in the draining lymph nodes relative to young mice. Upon secondary exposure to desiccating stress, aged mice developed more severe corneal epitheliopathy than young mice, which is associated with increased local frequencies of Th17 cells (CD4IL-17A). Treatment with anti-IL-15 antibody decreased the enlarged memory Th17 pool in aged mice to frequencies comparable with young mice. Furthermore, anti-IL-15-treated mice showed significantly reduced conjunctival infiltration of Th17 cells and lower corneal fluorescein staining scores compared with saline-treated control mice. Our data suggest that age-related increases in the memory Th17 compartment predispose aged mice toward the development of severe corneal epithelial disease after exposure to a dry environment. Selectively targeting memory Th17 cells may be a viable therapeutic approach in the treatment of age-related dry eye disease.
Wladis EJ, Aakalu VK, Foster JA, Freitag SK, Sobel RK, Tao JP, Yen MT. Intense Pulsed Light for Meibomian Gland Disease: A Report by the American Academy of Ophthalmology. Ophthalmology 2020;127(9):1227-1233.Abstract
PURPOSE: To review the literature on the efficacy of intense pulsed light (IPL) on the eyelids in the management of meibomian gland disease (MGD) and meibomian gland-related ocular surface disease. METHODS: A literature search was last conducted on May 15, 2019, in the PubMed and Cochrane Library databases for English-language original research that assessed the effect of IPL on MGD in adult patients. Thirty-three articles were identified, and 12 studies were determined to be relevant to the criteria outlined for assessment. The panel methodologist (V.K.A.) assigned a level of evidence rating to each study; 4 studies were rated level II, and 8 studies were rated level III. Five studies had potential conflicts of interest and design limitations that affected interpretation of results. RESULTS: All studies documented improvement in clinically meaningful metrics, including tear breakup time (TBUT), corneal staining and eyelid margin measurements, meibum quality, meibomian gland expressability, ocular surface disease index (OSDI), and standard patient evaluation of eye dryness (SPEED) questionnaire scores. Side effects were relatively uncommon but included discomfort, cutaneous erythema, blistering, eyelash loss, and floaters; these were uniformly self-limited. CONCLUSIONS: Although methodological limitations and potential conflicts of interest in some studies raised concern, the existing body of literature demonstrates improvements in the signs and symptoms of MGD after IPL therapy.

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