May 2020

Chilambi GS, Nordstrom HR, Evans DR, Ferrolino JA, Hayden RT, Marón GM, Vo AN, Gilmore MS, Wolf J, Rosch JW, Van Tyne D. Evolution of vancomycin-resistant during colonization and infection in immunocompromised pediatric patients. Proc Natl Acad Sci U S A 2020;117(21):11703-11714.Abstract
Patients with hematological malignancies or undergoing hematopoietic stem cell transplantation are vulnerable to colonization and infection with multidrug-resistant organisms, including vancomycin-resistant (VREfm). Over a 10-y period, we collected and sequenced the genomes of 110 VREfm isolates from gastrointestinal and blood cultures of 24 pediatric patients undergoing chemotherapy or hematopoietic stem cell transplantation for hematological malignancy at St. Jude Children's Research Hospital. We used patient-specific reference genomes to identify variants that arose over time in subsequent gastrointestinal and blood isolates from each patient and analyzed these variants for insight into how VREfm adapted during colonization and bloodstream infection within each patient. Variants were enriched in genes involved in carbohydrate metabolism, and phenotypic analysis identified associated differences in carbohydrate utilization among isolates. In particular, a Y585C mutation in the sorbitol operon transcriptional regulator was associated with increased bacterial growth in the presence of sorbitol. We also found differences in biofilm-formation capability between isolates and observed that increased biofilm formation correlated with mutations in the putative capsular polysaccharide () biosynthetic locus, with different mutations arising independently in distinct genetic backgrounds. Isolates with mutations showed improved survival following exposure to lysozyme, suggesting a possible reason for the selection of capsule-lacking bacteria. Finally, we observed mutations conferring increased tolerance of linezolid and daptomycin in patients who were treated with these antibiotics. Overall, this study documents known and previously undescribed ways that VREfm evolve during intestinal colonization and subsequent bloodstream infection in immunocompromised pediatric patients.
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.
Tao JP, Aakalu VK, Wladis EJ, Sobel RK, Freitag SK, Foster JA, Yen MT. Bioengineered Acellular Dermal Matrix Spacer Grafts for Lower Eyelid Retraction Repair: A Report by the American Academy of Ophthalmology. Ophthalmology 2020;127(5):689-695.Abstract
PURPOSE: To review the literature on the efficacy and safety of bioengineered acellular dermal matrix (BADM) grafts for lower eyelid retraction repair. METHODS: A literature search was conducted in the PubMed database initially in January 2018 and updated in July 2019 to identify all studies in the English language literature on the use of BADM grafts in eyelid reconstruction. The searches yielded 193 citations, and 15 of the 34 articles selected for full review met all inclusion criteria for this assessment. A panel methodologist then assigned a level of evidence rating for each study. Two of the 15 studies included were rated level II and 13 were rated level III. RESULTS: The definition of success varied, but lower eyelid position improvement using lower lid margin-to-pupillary reflex distance was the most common outcome measure. Other end points were the amount of lagophthalmos, cosmesis, exposure, reoperation, or complications, as well as prosthesis retention in anophthalmic socket cases. The surgeon-reported success rate of these outcomes ranged from 75% to 100%. Minor complications included cyst formation, infection, chemosis, pyogenic granuloma, and corneal abrasion. No serious complications such as blindness, anaphylactic reaction, or terminal disease transmission occurred. Of the 526 implants included for assessment in these disparate studies, 27 cases (5%) required reoperation. CONCLUSIONS: No level I evidence was available, and the existing level II and level III studies have variable primary end points, study design limitations, and only short-term follow-up data. The current literature suggests that BADM grafts represent an implantation option for lower eyelid retraction repair. Short-term results are favorable, and the materials used may fill an important gap in care for patients for whom no acceptable alternatives exist, but long-term safety and efficacy remain unknown.
Sohn EH, Strohbehn A, Stryjewski T, Brodowska K, Flamme-Wiese MJ, Mullins RF, Eliott D. POSTERIORLY INSERTED VITREOUS BASE: Preoperative Characteristics, Intraoperative Findings, and Outcomes After Vitrectomy. Retina 2020;40(5):943-950.Abstract
PURPOSE: To determine the preoperative characteristics, intraoperative and postoperative complications, and outcomes of eyes with posteriorly inserted vitreous base. METHODS: In this retrospective, observational, consecutive case series at 2 academic centers, 37 patients were studied who had posteriorly inserted vitreous base noted during vitrectomy. Posteriorly inserted vitreous base was defined as the insertion of the posterior hyaloid membrane being located posterior to the vortex veins. Fifteen eyes were analyzed in a histopathologic study of donor eyes to determine the average distance of the ora serrata from the vortex veins as this distance is uncertain. RESULTS: Posteriorly inserted vitreous base was identified during vitrectomy in 31 eyes with rhegmatogenous retinal detachment (84%), 4 with macular hole (11%), 1 with vitreous hemorrhage, and 1 with epiretinal membrane. Adjunctive buckle was used in 24%; 54% had 360° laser. Average number of tears seen preoperatively in those with rhegmatogenous retinal detachment was 3.1. Thirty percent had new breaks identified intraoperatively. Forty-one percent had lattice degeneration; new breaks were found in 40% of eyes with lattice. Thirteen percent of rhegmatogenous retinal detachments developed proliferative vitreoretinopathy. Average distance from the ora serrata to the vortex veins was 7.6 mm. CONCLUSION: Any eye undergoing vitrectomy may have posteriorly inserted vitreous base, but those with a high number of retinal breaks and lattice near the equator may be at highest risk. Redetachment and proliferative vitreoretinopathy still occur despite knowledge of the disorder and adjuvant treatments.
Fan N-W, Dohlman TH, Foulsham W, McSoley M, Singh RB, Chen Y, Dana R. The role of Th17 immunity in chronic ocular surface disorders. Ocul Surf 2020;Abstract
Th17 cells have been implicated in the pathogenesis of numerous inflammatory and autoimmune conditions. At the ocular surface, Th17 cells have been identified as key effector cells in chronic ocular surface disease. Evidence from murine studies indicates that following differentiation and expansion, Th17 cells migrate from the lymphoid tissues to the eye, where they release inflammatory cytokines including, but not limited to, their hallmark cytokine IL-17A. As the acute phase subsides, a population of long-lived memory Th17 cells persist, which predispose hosts both to chronic inflammation and severe exacerbations of disease; of great interest is the small subset of Th17/1 cells that secrete both IL-17A and IFN-γ in acute-on-chronic disease exacerbation. Over the past decade, substantial progress has been made in deciphering how Th17 cells interact with the immune and neuroimmune pathways that mediate chronic ocular surface disease. Here, we review (i) the evidence for Th17 immunity in chronic ocular surface disease, (ii) regulatory mechanisms that constrain the Th17 immune response, and (iii) novel therapeutic strategies targeting Th17 cells.
Dockery DM, Rowe SG, Murphy MA, Krzystolik MG. The Ocular Manifestations and Transmission of COVID-19: Recommendations for Prevention. J Emerg Med 2020;Abstract
BACKGROUND: Coronavirus disease-2019 (COVID-19), caused by a novel coronavirus termed severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has been linked to ocular signs and symptoms in several case reports. Research has demonstrated that SARS-CoV-2 is spread primarily through close contact via respiratory droplets, but there is the possibility for ocular transmission, with the conjunctiva as a conduit as well as a source of infection. DISCUSSION: Ocular manifestations of SARS-CoV-2 include follicular conjunctivitis, and have been repeatedly noted as an initial or subsequent symptom of COVID-19-positive patients. Particularly in patients with ocular manifestations, there is evidence that the virus may present in tears, based on the detection of SARS-CoV-2 in conjunctival swab samples via reverse transcription polymerase chain reaction. The virus may therefore be transmittable from the ocular surface to a new host via contact with the ocular mucosa, tears, or subsequent fomites. CONCLUSIONS: All health care professionals should ask patients about ocular symptoms consistent with SARS-CoV-2, and use eye protection such as goggles or face shields as part of the standard personal protective equipment for high-risk patients in addition to wearing of masks by both the patient and provider, and should consider tears to be potentially infectious.
Jakobiec FA, Eagle RC, Selig M, Ma L, Shields C. Clinical Implications of Goblet Cells in Dacryoadenosis and Normal Human Lacrimal Glands. Am J Ophthalmol 2020;213:267-282.Abstract
PURPOSE: The purpose of this study was to investigate an enlarged dacryoadenotic lacrimal gland and normal lacrimal glands for the presence of goblet cells (mucocytes). DESIGN: Retrospective clinicopathologic series. METHODS: An enlarged lacrimal gland (dacryoadenosis) without obvious histopathologic alterations was extensively evaluated histochemically, immunohistochemically, and ultrastructurally to detect the presence of goblet cells and to compare the findings with those in five normal lacrimal glands. RESULTS: Granular, zymogen-rich pyramidal acinar cells in normal glands predominated over a previously not reported subpopulation of nongranular, pale-staining cells in both dacryoadenotic and normal lacrimal glands. These cells histochemically stained positively with mucicarmine and Alcian blue. Immunohistochemical and electron microscopic evaluations established that there was a displacement or replacement of cytoplasmic gross cystic disease fluid protein-15 and CK 7-positive tonofilaments in the pale acinar cells by myriad mucus granules. The goblet cells constituted approximately 2% of the normal acinar cells and 5% of dacryoadenotic acinar cells. A depletion of myoepithelial cells and ectopic intra-acinar ductular cells were also observed in dacryoadenosis. CONCLUSION: Dacryoadenosis is caused by an increase in the number of acini without individual acinar cell hyperplasia. A normal cytologic feature of the lacrimal gland is the presence of acinar goblet cells that had been long overlooked; they are increased in number in dacryoadenosis. Intra-acinar ductular cells and the scattered loss of myoepithelial cells are other abnormalities in dacryoadenosis. The presence of lacrimal gland goblet cells may have physiologic implications for the precorneal tear film and its derangements as well as for the histogenesis of mucus-producing carcinomas.
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.
Farinha C, Cachulo ML, Coimbra R, Alves D, Nunes S, Pires I, Marques JP, Costa J, Martins A, Sobral I, Barreto P, Laíns I, Figueira J, Ribeiro L, Cunha-Vaz J, Silva R. Age-Related Macular Degeneration Staging by Color Fundus Photography vs. Multimodal Imaging-Epidemiological Implications (). J Clin Med 2020;9(5)Abstract
Epidemiology of age-related macular degeneration (AMD) is based on staging systems relying on color fundus photography (CFP). We aim to compare AMD staging using CFP to multimodal imaging with optical coherence tomography (OCT), infra-red (IR), and fundus autofluorescence (FAF), in a large cohort from the Epidemiologic AMD Coimbra Eye Study. All imaging exams from the participants of this population-based study were classified by a central reading center. CFP images were graded according to the International Classification and Grading System for AMD and staged with Rotterdam classification. Afterward, CFP images were reviewed with OCT, IR, and FAF and stage update was performed if necessary. Early and late AMD prevalence was compared in a total of 1616 included subjects. In CFP-based grading, the prevalence was 14.11% for early AMD ( = 228) and 1.05% ( = 17) for late AMD, nine cases (0.56%) had neovascular AMD (nAMD) and eight (0.50%) geographic atrophy (GA). Using multimodal grading, the prevalence increased to 14.60% for early AMD ( = 236) and 1.61% ( = 26) for late AMD, with 14 cases (0.87%) of nAMD and 12 (0.74%) of GA. AMD staging was more accurate with the multimodal approach and this was especially relevant for late AMD. We propose that multimodal imaging should be adopted in the future to better estimate and compare epidemiological data in different populations.
Hughes S, Gumas J, Lee R, Rumano M, Berger N, Gautam AK, Sfyroera G, Chan AL, Gnanaguru G, Connor KM, Kim BJ, Dunaief JL, Ricklin D, Hajishengallis G, Yancopoulou D, Reis ES, Mastellos DC, Lambris JD. Prolonged intraocular residence and retinal tissue distribution of a fourth-generation compstatin-based C3 inhibitor in non-human primates. Clin Immunol 2020;214:108391.Abstract
Age-related macular degeneration (AMD) is a leading cause of irreversible vision loss among the elderly population. Genetic studies in susceptible individuals have linked this ocular disease to deregulated complement activity that culminates in increased C3 turnover, retinal inflammation and photoreceptor loss. Therapeutic targeting of C3 has therefore emerged as a promising strategy for broadly intercepting the detrimental proinflammatory consequences of complement activation in the retinal tissue. In this regard, a PEGylated second-generation derivative of the compstatin family of C3-targeted inhibitors is currently in late-stage clinical development as a treatment option for geographic atrophy, an advanced form of AMD which lacks approved therapy. While efficacy has been strongly suggested in phase 2 clinical trials, crucial aspects still remain to be defined with regard to the ocular bioavailability, tissue distribution and residence, and dosing frequency of such inhibitors in AMD patients. Here we report the intraocular distribution and pharmacokinetic profile of the fourth-generation compstatin analog, Cp40-KKK in cynomolgus monkeys following a single intravitreal injection. Using a sensitive surface plasmon resonance (SPR)-based competition assay and ELISA, we have quantified both the amount of inhibitor and the concentration of C3 retained in the vitreous of Cp40-KKK-injected animals. Cp40-KKK displays prolonged intraocular residence, being detected at C3-saturating levels for over 3 months after a single intravitreal injection. Moreover, we have probed the distribution of Cp40-KKK within the ocular tissue by means of immunohistochemistry and highly specific anti-Cp40-KKK antibodies. Both C3 and Cp40-KKK were detected in the retinal tissue of inhibitor-injected animals, with prominent co-localization in the choroid one-month post intravitreal injection. These results attest to the high retinal tissue penetrance and target-driven distribution of Cp40-KKK. Given its subnanomolar binding affinity and prolonged ocular residence, Cp40-KKK constitutes a promising drug candidate for ocular pathologies underpinned by deregulated C3 activation.
Maleki A, Ueberroth JA, Walsh M, Foster F, Chang PY, Anesi SD, Foster CS. Combination of Intravenous Methotrexate and Methylprednisolone Therapy in the Treatment of Severe Ocular Inflammatory Diseases. Ocul Immunol Inflamm 2020;:1-5.Abstract
: To evaluate the efficacy of intravenous methotrexate and methylprednisolone in severe, sight-threatening ocular inflammatory conditions.: This was a retrospective observational case series. Patients who had received intravenous methotrexate for ocular inflammation with at least 24 months of follow-up were included in the study.: Ten patients (20 eyes) were included in this study. Mean age of the patients was 47.2 ± 17.7 (range:19-74). At 1-month follow-up visit, nine patients showed improvement and one patient failed treatment. At 12-month follow-up visit, all patients were in remission. Two patients were only on intravenous methotrexate infusions. At twenty-four-month follow-up visit, only one patient, in remission, was on intravenous methotrexate therapy. Leukopenia was the only adverse effect observed.: Intravenous methotrexate and methylprednisolone infusions can be an effective method of treatment in patients with severe, sight-threatening ocular inflammatory conditions.

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