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Moustafa GA, Topham AK, Aronow ME, Vavvas DG. Paediatric ocular adnexal lymphoma: a population-based analysis. BMJ Open Ophthalmol 2020;5(1):e000483.Abstract
Objective: To investigate the incidence, clinicopathological characteristics and survival of ocular adnexal lymphoma (OAL) in the paediatric population. Methods and analysis: In this retrospective case series, the Surveillance, Epidemiology and End Results database was accessed to identify individuals with OAL ≤18 years of age, diagnosed between 1973 and 2015. OAL located in the eyelid, conjunctiva, lacrimal apparatus and orbit were included. Main outcome measures were the age-adjusted incidence rates (IRs) per 1 000 000 population at risk (calculated for the period 2000-2015) and descriptive statistics of demographic and clinicopathological features. Results: The IR of paediatric OAL was 0.12 (95% CI 0.08 to 0.16) per 1 000 000. Males (0.15; 95% CI 0.10 to 0.22) and blacks (0.24; 95% CI 0.13 to 0.42) had a higher tendency for OAL development. A total of 55 tumours in 54 children were identified. The majority were localised (78.4%), conjunctival (49.1%) lymphomas. Extranodal marginal zone lymphoma (EMZL, 45.5%, n=25) was the most frequent subtype, followed by diffuse large B-cell lymphoma (DLBCL, 9.1%, n=5), B lymphoblastic lymphoma (7.3%, n=4), follicular lymphoma (5.5%, n=3), Burkitt lymphoma (5.5%, n=3), anaplastic large cell lymphoma (ALCL, 3.6%, n=2), small lymphocytic lymphoma (1.8%, n=1), diffuse large B-cell lymphoma, immunoblastic (1.8%, n=1) and panniculitis-like T-cell lymphoma (1.8%, n=1). Localised, low-grade, conjunctival lymphomas were frequently treated with complete excision with or without radiation, while high-grade and distant tumours usually received chemotherapy. Only 29.1% of paediatric OAL cases were treated with radiation. Three out of five (60%) patients with DLBCL died of lymphoma at a median follow-up of 21 (range 10-86) months, and 1 out of 2 (50%) patients with ALCL died of lymphoma at 23 months from diagnosis. Conclusion: OAL in the paediatric population is rare. The majority of OAL are EMZL and are characterised by excellent prognosis. The histological subtype was found to be the main predictor of outcome with cancer-specific deaths observed in patients with DLBCL and ALCL.
Xiao W, Kreiman G. XDream: Finding preferred stimuli for visual neurons using generative networks and gradient-free optimization. PLoS Comput Biol 2020;16(6):e1007973.Abstract
A longstanding question in sensory neuroscience is what types of stimuli drive neurons to fire. The characterization of effective stimuli has traditionally been based on a combination of intuition, insights from previous studies, and luck. A new method termed XDream (EXtending DeepDream with real-time evolution for activation maximization) combined a generative neural network and a genetic algorithm in a closed loop to create strong stimuli for neurons in the macaque visual cortex. Here we extensively and systematically evaluate the performance of XDream. We use ConvNet units as in silico models of neurons, enabling experiments that would be prohibitive with biological neurons. We evaluated how the method compares to brute-force search, and how well the method generalizes to different neurons and processing stages. We also explored design and parameter choices. XDream can efficiently find preferred features for visual units without any prior knowledge about them. XDream extrapolates to different layers, architectures, and developmental regimes, performing better than brute-force search, and often better than exhaustive sampling of >1 million images. Furthermore, XDream is robust to choices of multiple image generators, optimization algorithms, and hyperparameters, suggesting that its performance is locally near-optimal. Lastly, we found no significant advantage to problem-specific parameter tuning. These results establish expectations and provide practical recommendations for using XDream to investigate neural coding in biological preparations. Overall, XDream is an efficient, general, and robust algorithm for uncovering neuronal tuning preferences using a vast and diverse stimulus space. XDream is implemented in Python, released under the MIT License, and works on Linux, Windows, and MacOS.
Vu THK, Chen H, Pan L, Cho K-S, Doesburg D, Thee EF, Wu N, Arlotti E, Jager MJ, Chen DF. CD4 T-Cell Responses Mediate Progressive Neurodegeneration in Experimental Ischemic Retinopathy. Am J Pathol 2020;190(8):1723-1734.Abstract
Retinal ischemic events, which result from occlusion of the ocular vasculature share similar causes as those for central nervous system stroke and are among the most common cause of acute and irreversible vision loss in elderly patients. Currently, there is no established treatment, and the condition often leaves patients with seriously impaired vision or blindness. The immune system, particularly T-cell-mediated responses, is thought to be intricately involved, but the exact roles remain elusive. We found that acute ischemia-reperfusion injury to the retina induced a prolonged phase of retinal ganglion cell loss that continued to progress during 8 weeks after the procedure. This phase was accompanied by microglial activation and CD4 T-cell infiltration into the retina. Adoptive transfer of CD4 T cells isolated from diseased mice exacerbated retinal ganglion cell loss in mice with retinal reperfusion damage. On the other hand, T-cell deficiency or administration of T-cell or interferon-γ-neutralizing antibody attenuated retinal ganglion cell degeneration and retinal function loss after injury. These findings demonstrate a crucial role for T-cell-mediated responses in the pathogenesis of neural ischemia. These findings point to novel therapeutic targets of limiting or preventing neuron and function loss for currently untreatable conditions of optic neuropathy and/or central nervous system ischemic stroke.
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.
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.
Bowe T, Hunter DG, Mantagos IS, Kazlas M, Jastrzembski BG, Gaier ED, Massey G, Franz K, Schumann C, Brown C, Meyers H, Shah AS. Virtual Visits in Ophthalmology: Timely Advice for Implementation During the COVID-19 Public Health Crisis. Telemed J E Health 2020;26(9):1113-1117.Abstract
Virtual visits (VVs) are necessitated due to the public health crisis and social distancing mandates due to COVID-19. However, these have been rare in ophthalmology. Over 3.5 years of conducting >350 ophthalmological VVs, our group has gained numerous insights into best practices. This communication shares these experiences with the medical community to support patient care during this difficult time and beyond. We highlight that mastering the technological platform of choice, optimizing lighting, camera positioning, and "eye contact," being thoughtful and creative with the virtual eye examination, and ensuring good documenting and billing will make a successful and efficient VV. Moreover, we think these ideas will stimulate further VV creativity and expertise to be developed in ophthalmology and across medicine. This approach, holds promise for increasing its adoption after the crisis has passed.
Yu Z, Ma S, Wu M, Cui H, Wu R, Chen S, Xu C, Lu X, Feng S. Self-assembling hydrogel loaded with 5-FU PLGA microspheres as a novel vitreous substitute for proliferative vitreoretinopathy. J Biomed Mater Res A 2020;108(12):2435-2446.Abstract
The vitreous substitute for proliferative vitreoretinopathy (PVR) surgery remains an unmet clinical need in ophthalmology. In our study, we developed an in situ formed hydrogel by crosslinking polyvinyl alcohol (PVA) and chitosan as a potential vitreous substitute. 5-fluorouracil (5-FU) Poly (lactic-co-glycolic acid) (PLGA) microspheres were developed and loaded onto the PVA/chitosan hydrogels to treat PVR. In vitro, PVA/chitosan hydrogels at four concentrations were subjected to morphological, physical, rheological analyses, and cytotoxicity was evaluated together with the characterization of 5-FU PLGA microspheres. In vivo, pharmacologically induce PVR rabbits were performed a vitrectomy. In the PVA group, 3% PVA/chitosan hydrogel was injected into the vitreous cavity. In the PVA/MS group, 3% PVA/chitosan hydrogel and 5-FU PLGA microspheres were injected. In the Control group, phosphate-buffered saline was injected. Therapeutic efficacy was evaluated with postoperative examinations and histological analyses. This study demonstrated that the 3% PVA/chitosan hydrogel showed properties similar to those of the human vitreous and could be a novel in situ crosslinked vitreous substitute for PVR. Loading 5-FU PLGA microspheres onto this hydrogel may represent an effective strategy to improve the prognosis of PVR.
Ing EB, Xu QA, Salimi A, Torun N. Physician deaths from corona virus (COVID-19) disease. Occup Med (Lond) 2020;70(5):370-374.Abstract
BACKGROUND: The COVID-19 pandemic has caused much morbidity and mortality to patients but also health care providers. AIMS: We tabulated the cases of physician deaths from COVID-19 associated with front-line work in hopes of mitigating future events. METHODS: On 15 April 2020, a Google internet search was performed using the keywords 'doctor', 'physician', 'death', 'COVID' and 'coronavirus' in English and Farsi, and Chinese using the Baidu search engine. The age, sex and medical speciality of physicians who died from COVID-19 in the line of duty were recorded. Individuals greater than 90 years of age were excluded. RESULTS: We found 278 physicians who died with COVID-19 infection, but complete details were missing for 108 individuals. The average age of the physicians was 63.7 years with a median age of 66 years, and 90% were male (235/261). General practitioners and emergency room doctors (108/254), respirologists (5/254), internal medicine specialists (13/254) and anaesthesiologists (6/254) comprised 52% of those dying. Two per cent of the deceased were epidemiologists (5/254), 2% were infectious disease specialists (4/254), 6% were dentists (16/254), 4% were ENT (9/254) and 3% were ophthalmologists (8/254). The countries with the most reported physician deaths were Italy (121/278; 44%), Iran (43/278; 15%), Philippines (21/278; 8%), Indonesia (17/278; 6%), China (16/278; 6%), Spain (12/278; 4%), USA (12/278; 4%) and UK (11/278;4%). CONCLUSIONS: Physicians from all specialities may die from COVID. Lack of personal protective equipment was cited as a common cause of death. Consideration should be made to exclude older physicians from front-line work.
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.
Singh RB, Blanco T, Mittal SK, Taketani Y, Chauhan SK, Chen Y, Dana R. Pigment Epithelium-derived Factor secreted by corneal epithelial cells regulates dendritic cell maturation in dry eye disease. Ocul Surf 2020;18(3):460-469.Abstract
PURPOSE: In this study, we quantify Pigment Epithelium-derived Factor (PEDF) secreted by corneal epithelial cells and evaluate its immunomodulatory functions in a murine model of dry eye disease (DED). METHODS: We induced DED in female C57BL/6 mice using a controlled environment chamber for 14 days. We quantified mRNA expression of Serpinf1 gene and PEDF protein synthesis by corneal epithelial cells (CEpCs) using RT-PCR and ELISA. CEpCs from normal or DED mice were cultured with IFNγ-stimulated-dendritic cells (DCs) for 24 h, and expression of MHC-II and CD86 by DCs was determined using flow cytometry. Next, we either added recombinant PEDF (rPEDF) or anti-PEDF antibody to co-culture, and DC expression of the above maturation markers was quantified. Lastly, we treated DED mice with either topical rPEDF, anti-PEDF Ab or murine serum albumin (MSA), and DC maturation, expression of pro-inflammatory cytokines, and DED severity were investigated. RESULTS: Serpinf1 mRNA expression and PEDF protein production levels by CEpCs were upregulated in DED. CEpCs from DED mice exhibited an enhanced suppressive effect on the expression of MHC-II and CD86 by DCs, compared to normal mice. This effect was abolished by blocking endogenous PEDF with anti-PEDF Ab or enhanced by supplementing with rPEDF. Treatment with anti-PEDF antibody blocked the effect of endogenous-PEDF and increased DC maturation, expression of pro-inflammatory cytokines in conjunctivae, and exacerbated disease severity in DED mice. Conversely, topical rPEDF enhanced the suppressive effect of endogenous PEDF on DC maturation, decreased expression of pro-inflammatory cytokines in conjunctivae, and reduced disease severity. CONCLUSIONS: The results from our study elucidate the role of PEDF in impeding DC maturation, and suppression of ocular surface inflammation, explicating a promising therapeutic potential of PEDF in limiting the corneal epitheliopathy as a consequence of DED.
Chen D, Liu Y, Shu G, Chen C, Sullivan DA, Kam WR, Hann S, Fowler M, Warman ML. Ocular Manifestations of Chordin-like 1 Knockout Mice. Cornea 2020;39(9):1145-1150.Abstract
PURPOSE: In humans, loss-of-function mutations in the gene encoding Chordin-like 1 (CHRDL1) cause X-linked megalocornea (MGC1), characterized by bilateral corneal enlargement, decreased corneal thickness, and increased anterior chamber depth (ACD). We sought to determine whether Chrdl1 knockout (KO) mice would recapitulate the ocular findings found in patients with MGC1. METHODS: We generated mice with a Chrdl1 KO allele and confirmed that male Chrdl1 hemizygous KO mice do not express Chrdl1 mRNA. We examined the eyes of male mice that were hemizygous for either the wild-type (WT) or KO allele and measured corneal diameter, corneal area, corneal thickness, endothelial cell density, ACD, tear volume, and intraocular pressure. We also harvested retinas and counted retinal ganglion cell numbers. Eye segregation pattern in the dorsal lateral geniculate nucleus were also compared between male Chrdl1 KO and WT mice. RESULTS: Male Chrdl1 KO mice do not have larger cornea diameters than WT mice. KO mice have significantly thicker central corneas (116.5 ± 3.9 vs. 100.9 ± 4.2 μm, P = 0.013) and smaller ACD (325.7 ± 5.7 vs. 405.6 ± 6.3 μm, P < 0.001) than WT mice, which is the converse of what occurs in patients who lack CHRDL1. Retinal-thalamic projections and other ocular measurements did not significantly differ between KO and WT mice. CONCLUSIONS: Male Chrdl1 KO mice do not have the same anterior chamber abnormalities seen in humans with CHRDL1 mutations. Therefore, Chrdl1 KO mice do not recapitulate the human MGC1 phenotype. Nevertheless, Chrdl1 plays a role during mouse ocular development because corneas in KO mice differ from those in WT mice.
Wang J, Liu Y, Kam WR, Li Y, Sullivan DA. Toxicity of the cosmetic preservatives parabens, phenoxyethanol and chlorphenesin on human meibomian gland epithelial cells. Exp Eye Res 2020;196:108057.Abstract
Recently, we discovered that the cosmetic preservatives, benzalkonium chloride and formaldehyde, are especially toxic to human meibomian gland epithelial cells (HMGECs). Exposure to these agents, at concentrations approved for human use, leads within hours to cellular atrophy and death. We hypothesize that these effects are not unique, and that other cosmetic preservatives also exert adverse effects on HMGECs. Such compounds include parabens, phenoxyethanol and chlorphenesin, which have been reported to be toxic to corneal and conjunctival epithelial cells, the liver and kidney, as well as to irritate the eye. To test our hypothesis, we examined the influence of parabens, phenoxyethanol and chlorphenesin on the morphology, signaling, survival, proliferation and lipid expression of immortalized (I) HMGECs. These cells were cultured under proliferating or differentiating conditions with varying concentrations of methylparaben, ethylparaben, phenoxyethanol and chlorphenesin for up to 5 days. We monitored the signaling ability, appearance, number and neutral lipid content of the IHMGECs, as well as their lysosome accumulation. Our findings show that a 30-min exposure of IHMGECs to these preservatives results in a significant reduction in the activity of the Akt pathway. This effect is dose-dependent and occurs at concentrations equal to (chlorphenesin) and less than (all others) those dosages approved for human use. Further, a 24-h treatment of the IHMGECs with concentrations of methylparaben, ethylparaben, phenoxyethanol and chlorphenesin close to, or at, the approved human dose induces cellular atrophy and death. At all concentrations tested, no preservative stimulated IHMGEC proliferation. Of particular interest, it was not possible to evaluate the influence of these preservatives, at close to human approved dosages, on IHMGEC differentiation, because the cells did not survive the treatment. In summary, our results support our hypothesis and show that methylparaben, ethylparaben, phenoxyethanol and chlorphenesin are toxic to IHMGECs.
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.

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