Infectious Disease

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Lebreton F, Manson AL, Saavedra JT, Straub TJ, Earl AM, Gilmore MS. Tracing the Enterococci from Paleozoic Origins to the Hospital. Cell 2017;169(5):849-861.e13.Abstract
We examined the evolutionary history of leading multidrug resistant hospital pathogens, the enterococci, to their origin hundreds of millions of years ago. Our goal was to understand why, among the vast diversity of gut flora, enterococci are so well adapted to the modern hospital environment. Molecular clock estimation, together with analysis of their environmental distribution, phenotypic diversity, and concordance with host fossil records, place the origins of the enterococci around the time of animal terrestrialization, 425-500 mya. Speciation appears to parallel the diversification of hosts, including the rapid emergence of new enterococcal species following the End Permian Extinction. Major drivers of speciation include changing carbohydrate availability in the host gut. Life on land would have selected for the precise traits that now allow pathogenic enterococci to survive desiccation, starvation, and disinfection in the modern hospital, foreordaining their emergence as leading hospital pathogens.
Lebreton F, Valentino MD, Schaufler K, Earl AM, Cattoir V, Gilmore MS. Transferable vancomycin resistance in clade B commensal-type Enterococcus faecium. J Antimicrob Chemother 2018;73(6):1479-1486.Abstract
Objectives: Vancomycin-resistant Enterococcus faecium is a leading cause of MDR hospital infection. Two genetically definable populations of E. faecium have been identified: hospital-adapted MDR isolates (clade A) and vancomycin-susceptible commensal strains (clade B). VanN-type vancomycin resistance was identified in two isolates of E. faecium recovered from blood and faeces of an immunocompromised patient. To understand the genomic context in which VanN occurred in the hospitalized patient, the risk it posed for transmission in the hospital and its origins, it was of interest to determine where these strains placed within the E. faecium population structure. Methods: We obtained the genome sequence of the VanN isolates and performed comparative and functional genomics of the chromosome and plasmid content. Results: We show that, in these strains, VanN occurs in a genetic background that clusters with clade B E. faecium, which is highly unusual. We characterized the chromosome and the conjugative plasmid that carries VanN resistance in these strains, pUV24. This plasmid exhibits signatures of in-host selection on the vanN operon regulatory system, which are associated with a constitutive expression of vancomycin resistance. VanN resistance in clade B strains may go undetected by current methods. Conclusions: We report a case of vancomycin resistance in a commensal lineage of E. faecium responsible for an atypical bacteraemia in an immunocompromised patient. A reservoir of transferable glycopeptide resistance in the community could pose a concern for public health.
Lee JS, Ismail AM, Lee JY, Zhou X, Materne EC, Chodosh J, Rajaiya J. Impact of dynamin 2 on adenovirus nuclear entry. Virology 2019;529:43-56.Abstract
The large GTPase dynamin 2 controls both endosomal fission and microtubule acetylation. Here we report that dynamin 2 alters microtubules and regulates the trafficking of human adenovirus type 37. Dynamin 2 knockdown by siRNA in infected cells resulted in accumulation of acetylated tubulin, repositioning of microtubule organizing centers (MTOCs) closer to cell nuclei, increased virus in the cytosol (with a compensatory decrease in endosomal virus), reduced proinflammatory cytokine induction, and increased binding of virus to the nucleoporin, Nup358. These events led to increased viral DNA nuclear entry and viral replication. Overexpression of dynamin 2 generated opposite effects. Therefore, dynamin 2 inhibits adenovirus replication and promotes innate immune responses by the infected cell. MTOC transposition in dynamin 2 knockdown promotes a closer association with nuclear pore complexes to facilitate viral DNA delivery. Dynamin 2 plays a key role in adenoviral trafficking and influences host responses to infection.
Lee JY, Lee JS, Materne EC, Rajala R, Ismail AM, Seto D, Dyer DW, Rajaiya J, Chodosh J. Bacterial RecA Protein Promotes Adenoviral Recombination during Infection. mSphere 2018;3(3)Abstract
Adenovirus infections in humans are common and sometimes lethal. Adenovirus-derived vectors are also commonly chosen for gene therapy in human clinical trials. We have shown in previous work that homologous recombination between adenoviral genomes of human adenovirus species D (HAdV-D), the largest and fastest growing HAdV species, is responsible for the rapid evolution of this species. Because adenovirus infection initiates in mucosal epithelia, particularly at the gastrointestinal, respiratory, genitourinary, and ocular surfaces, we sought to determine a possible role for mucosal microbiota in adenovirus genome diversity. By analysis of known recombination hot spots across 38 human adenovirus genomes in species D (HAdV-D), we identified nucleotide sequence motifs similar to bacterial Chi sequences, which facilitate homologous recombination in the presence of bacterial Rec enzymes. These motifs, referred to here as Chi, were identified immediately 5' to the sequence encoding penton base hypervariable loop 2, which expresses the arginine-glycine-aspartate moiety critical to adenoviral cellular entry. Coinfection with two HAdV-Ds in the presence of an lysate increased recombination; this was blocked in a RecA mutant strain, DH5α, or upon RecA depletion. Recombination increased in the presence of lysate despite a general reduction in viral replication. RecA colocalized with viral DNA in HAdV-D-infected cell nuclei and was shown to bind specifically to Chi sequences. These results indicate that adenoviruses may repurpose bacterial recombination machinery, a sharing of evolutionary mechanisms across a diverse microbiota, and unique example of viral commensalism. Adenoviruses are common human mucosal pathogens of the gastrointestinal, respiratory, and genitourinary tracts and ocular surface. Here, we report finding Chi-like sequences in adenovirus recombination hot spots. Adenovirus coinfection in the presence of bacterial RecA protein facilitated homologous recombination between viruses. Genetic recombination led to evolution of an important external feature on the adenoviral capsid, namely, the penton base protein hypervariable loop 2, which contains the arginine-glycine-aspartic acid motif critical to viral internalization. We speculate that free Rec proteins present in gastrointestinal secretions upon bacterial cell death facilitate the evolution of human adenoviruses through homologous recombination, an example of viral commensalism and the complexity of virus-host interactions, including regional microbiota.
Lee CS, Lee AY, Akileswaran L, Stroman D, Najafi-Tagol K, Kleiboeker S, Chodosh J, Magaret A, Wald A, Van Gelder RN, Van Gelder RN. Determinants of Outcomes of Adenoviral Keratoconjunctivitis. Ophthalmology 2018;125(9):1344-1353.Abstract
PURPOSE: To determine host and pathogen factors predictive of outcomes in a large clinical cohort with keratoconjunctivitis. DESIGN: Retrospective analyses of the clinical and molecular data from a randomized, controlled, masked trial for auricloscene for keratoconjunctivitis (NVC-422 phase IIB, NovaBay; clinicaltrials.gov identifier, NCT01877694). PARTICIPANTS: Five hundred participants from United States, India, Brazil, and Sri Lanka with clinical diagnosis of keratoconjunctivitis and positive rapid test results for adenovirus. METHODS: Clinical signs and symptoms and bilateral conjunctival swabs were obtained on days 1, 3, 6, 11, and 18. Polymerase chain reaction (PCR) analysis was performed to detect and quantify adenovirus in all samples. Regression models were used to evaluate the association of various variables with keratoconjunctivitis outcomes. Time to resolution of each symptom or sign was assessed by adenoviral species with Cox regression. MAIN OUTCOME MEASURES: The difference in composite scores of clinical signs between days 1 and 18, mean visual acuity change between days 1 and 18, and time to resolution of each symptom or sign. RESULTS: Of 500 participants, 390 (78%) showed evidence of adenovirus by PCR. Among adenovirus-positive participants, adenovirus D species was most common (63% of total cases), but a total of 4 species and 21 different types of adenovirus were detected. Adenovirus D was associated with more severe signs and symptoms, a higher rate of subepithelial infiltrate development, and a slower decline in viral load compared with all other adenovirus species. The clinical courses of all patients with non-adenovirus D species infection and adenovirus-negative keratoconjunctivitis were similar. Mean change in visual acuity between days 1 and 18 was a gain of 1.9 letters; worse visual outcome was associated with older age. CONCLUSIONS: A substantial proportion of keratoconjunctivitis is not associated with a detectable adenovirus. The clinical course of those with adenovirus D keratoconjunctivitis is significantly more severe than those with non-adenovirus D species infections or adenovirus-negative keratoconjunctivitis; high viral load at presentation and non-United States origin of participants is associated with poorer clinical outcome.
Lee DH, Cohen LM, Yoon MK, Tao JP. Punctal stenosis associated with dupilumab therapy for atopic dermatitis. J Dermatolog Treat 2021;32(7):737-740.Abstract
In this case series, the authors report three patients with severe atopic dermatitis who presented with epiphora and conjunctivitis while undergoing dupilumab therapy. On clinical examination, all patients were found to have punctal stenosis, with one case having progressed to punctal obstruction. An assortment of strategies was elected, including discontinuation of dupilumab, treatment of conjunctivitis, and surgical intervention with probing, punctoplasty, and silicone intubation. This report spotlights punctal stenosis as an important new side effect of dupilumab and suggests that additional cases of dupilumab-associated lacrimal drainage impairment will continue to emerge.
Leme RCP, Martins Bispo PJ, Salles MJ. Community-genotype methicillin-resistant Staphylococcus aureus skin and soft tissue infections in Latin America: a systematic review. Braz J Infect Dis 2021;:101539.Abstract
BACKGROUND: Community-genotype methicillin-resistant Staphylococcus aureus (CG-MRSA) emerged in the 1990s as a global community pathogen primarily involved in skin and soft tissue infections (SSTIs) and pneumonia. To date, the CG-MRSA SSTI burden in Latin America (LA) has not been assessed. OBJECTIVE: The main objective of this study was to report the rate and genotypes of community-genotype methicillin-resistant Staphylococcus aureus (CG-MRSA) causing community-onset skin and soft tissue infections (CO-SSTIs) in LA over the last two decades. In addition, this research determined relevant data related to SSTIs due to CG-MRSA, including risk factors, other invasive diseases, and mortality. DATA SOURCES: Relevant literature was searched and extracted from five major databases: Embase, PubMed, LILACS, SciELO, and Web of Science. METHODS: A systematic review was performed, and a narrative review was constructed. RESULTS: An analysis of 11 studies identified epidemiological data across LA, with Argentina presenting the highest percentage of SSTIs caused by CG-MRSA (88%). Other countries had rates of CG-MRSA infection ranging from 0 to 51%. Brazil had one of the lowest rates of CG-MRSA SSTI (4.5-25%). In Argentina, being younger than 50 years of age and having purulent lesions were predictive factors for CG-MRSA CO-SSTIs. In addition, the predominant genetic lineages in LA belonged to sequence types 8, 30, and 5 (ST8, ST30, and ST5). CONCLUSION: There are significant regional differences in the rates of CG-MRSA causing CO-SSTIs. It is not possible to conclude whether or not CG-MRSA CO-SSTIs resulted in more severe SSTI presentations or in a higher mortality rate.
Letko E, Yeh S, Foster SC, Pleyer U, Brigell M, Grosskreutz CL, Grosskreutz CL. Efficacy and safety of intravenous secukinumab in noninfectious uveitis requiring steroid-sparing immunosuppressive therapy. Ophthalmology 2015;122(5):939-48.Abstract
PURPOSE: Secukinumab, a fully human anti-interleukin-17A monoclonal antibody, exhibited promising activity in a proof-of-concept study when administered in intravenous (IV) doses to patients with active, chronic, noninfectious uveitis. This study compared the efficacy and safety of different IV and subcutaneous (SC) doses of secukinumab in patients with noninfectious uveitis. DESIGN: Multicenter, randomized, double-masked, dose-ranging, phase 2 clinical trial. PARTICIPANTS: Thirty-seven patients with active noninfectious intermediate uveitis, posterior uveitis, or panuveitis who required corticosteroid-sparing immunosuppressive therapy. METHODS: Patients were randomized to secukinumab 300 mg SC every 2 weeks for 4 doses, secukinumab 10 mg/kg IV every 2 weeks for 4 doses, or secukinumab 30 mg/kg IV every 4 weeks for 2 doses. Intravenous or SC saline was administered to maintain masking. Efficacy was assessed on day 57 (2-4 weeks after last dose). MAIN OUTCOME MEASURES: Percentage of patients with treatment response, defined as (1) at least a 2-grade reduction in vitreous haze score or trace or absent vitreous haze in the study eye without an increase in corticosteroid dose and without uveitis worsening or (2) reduction in corticosteroid dosages to prespecified levels without uveitis worsening. Percentage of patients with remission, defined as anterior chamber cell and vitreous haze scores of 0 or 0.5+ in both eyes without corticosteroid therapy or uveitis worsening. RESULTS: Secukinumab 30 mg/kg IV and 10 mg/kg IV, compared with the 300 mg SC dose, produced higher responder rates (72.7% and 61.5% vs. 33.3%, respectively) and remission rates (27.3% and 38.5% vs. 16.7%, respectively). Statistical and clinical superiority for the 30 mg/kg IV dose compared with the 300 mg SC dose was established in a Bayesian probability model. Other measures, including time to response onset, change in visual acuity, and change in vitreous haze score, showed numeric trends favoring IV dosing. Secukinumab, administered in IV or SC formulations, appeared safe and was well tolerated. CONCLUSIONS: Intravenous secukinumab was effective and well tolerated in noninfectious uveitis requiring systemic corticosteroid-sparing immunosuppressive therapy. Greater activity with IV dosing suggests that patients may not receive sufficient drug with SC administration. High-dose IV secukinumab may be necessary to deliver secukinumab in therapeutic concentrations.
Li H, Reksten TR, Ice JA, Kelly JA, Adrianto I, Rasmussen A, Wang S, He B, Grundahl KM, Glenn SB, Miceli-Richard C, Bowman S, Lester S, Eriksson P, Eloranta M-L, Brun JG, Gøransson LG, Harboe E, Guthridge JM, Kaufman KM, Kvarnström M, Cunninghame Graham DS, Patel K, Adler AJ, Farris DA, Brennan MT, Chodosh J, Gopalakrishnan R, Weisman MH, Venuturupalli S, Wallace DJ, Hefner KS, Houston GD, Huang AJW, Hughes PJ, Lewis DM, Radfar L, Vista ES, Edgar CE, Rohrer MD, Stone DU, Vyse TJ, Harley JB, Gaffney PM, James JA, Turner S, Alevizos I, Anaya J-M, Rhodus NL, Segal BM, Montgomery CG, Scofield HR, Kovats S, Mariette X, Rönnblom L, Witte T, Rischmueller M, Wahren-Herlenius M, Omdal R, Jonsson R, Ng W-F, for Registry UKPS's S, Nordmark G, Lessard CJ, Sivils KL. Identification of a Sjögren's syndrome susceptibility locus at OAS1 that influences isoform switching, protein expression, and responsiveness to type I interferons. PLoS Genet 2017;13(6):e1006820.Abstract
Sjögren's syndrome (SS) is a common, autoimmune exocrinopathy distinguished by keratoconjunctivitis sicca and xerostomia. Patients frequently develop serious complications including lymphoma, pulmonary dysfunction, neuropathy, vasculitis, and debilitating fatigue. Dysregulation of type I interferon (IFN) pathway is a prominent feature of SS and is correlated with increased autoantibody titers and disease severity. To identify genetic determinants of IFN pathway dysregulation in SS, we performed cis-expression quantitative trait locus (eQTL) analyses focusing on differentially expressed type I IFN-inducible transcripts identified through a transcriptome profiling study. Multiple cis-eQTLs were associated with transcript levels of 2'-5'-oligoadenylate synthetase 1 (OAS1) peaking at rs10774671 (PeQTL = 6.05 × 10-14). Association of rs10774671 with SS susceptibility was identified and confirmed through meta-analysis of two independent cohorts (Pmeta = 2.59 × 10-9; odds ratio = 0.75; 95% confidence interval = 0.66-0.86). The risk allele of rs10774671 shifts splicing of OAS1 from production of the p46 isoform to multiple alternative transcripts, including p42, p48, and p44. We found that the isoforms were differentially expressed within each genotype in controls and patients with and without autoantibodies. Furthermore, our results showed that the three alternatively spliced isoforms lacked translational response to type I IFN stimulation. The p48 and p44 isoforms also had impaired protein expression governed by the 3' end of the transcripts. The SS risk allele of rs10774671 has been shown by others to be associated with reduced OAS1 enzymatic activity and ability to clear viral infections, as well as reduced responsiveness to IFN treatment. Our results establish OAS1 as a risk locus for SS and support a potential role for defective viral clearance due to altered IFN response as a genetic pathophysiological basis of this complex autoimmune disease.
Lieberman MT, Van Tyne D, Dzink-Fox JA, Ma EJ, Gilmore MS, Fox JG. Long-Term Colonization Dynamics of Enterococcus faecalis in Implanted Devices in Research Macaques. Appl Environ Microbiol 2018;84(18)Abstract
is a common opportunistic pathogen that colonizes cephalic recording chambers (CRCs) of macaques used in cognitive neuroscience research. We previously characterized 15 strains isolated from macaques at the Massachusetts Institute of Technology (MIT) in 2011. The goal of this study was to examine how a 2014 protocol change prohibiting the use of antimicrobials within CRCs affected colonizing strains. We collected 20 isolates from 10 macaques between 2013 and 2017 for comparison to 4 isolates previously characterized in 2011 with respect to the sequence type (ST) distribution, antimicrobial resistance, biofilm formation, and changes in genes that might confer a survival advantage. ST4 and ST55 were predominant among the isolates characterized in 2011, whereas the less antimicrobial-resistant lineage ST48 emerged to dominance after 2013. Two macaques remained colonized by ST4 and ST55 strains for 5 and 4 years, respectively. While the antimicrobial resistance and virulence factors identified in these ST4 and ST55 strains remained relatively stable, we detected an increase in biofilm formation ability over time in both isolates. We also found that ST48 strains were typically robust biofilm formers, which could explain why this ST increased in prevalence. Finally, we identified mutations in the DNA mismatch repair genes and in separate ST55 and ST4 strains and confirmed that strains bearing these mutations displayed a hypermutator phenotype. The presence of a hypermutator phenotype may complicate future antimicrobial treatment for clinically relevant infections in macaques. is a common cause of health care-associated infections in humans, largely due to its ability to persist in the hospital environment, colonize patients, acquire antimicrobial resistance, and form biofilms. Understanding how enterococci evolve in health care settings provides insight into factors affecting enterococcal survival and persistence. Macaques used in neuroscience research have long-term cranial implants that, despite best practices, often become colonized by This provides a unique opportunity to noninvasively examine the evolution of enterococci on a long-term indwelling device. We collected strains from cephalic implants over a 7-year period and characterized the sequence type, antimicrobial resistance, virulence factors, biofilm production, and hypermutator phenotypes. Improved antimicrobial stewardship allowed a less-antimicrobial-resistant strain to predominate at the implant interface, potentially improving antimicrobial treatment outcomes if future clinical infections occur. Biofilm formation appears to play an important role in the persistence of the strains associated with these implants.
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Ma KK, Kinde B, Doan T, Jacobs DS, Ong Tone S. Dual Molecular Diagnosis of Microsporidia (Encephalitozoon hellem) Keratoconjunctivitis in an Immunocompetent Adult. Cornea 2021;40(2):242-244.Abstract
PURPOSE: To report a case of microsporidia (Encephalitozoon hellem) keratoconjunctivitis acquired through avian transmission in an immunocompetent adult, diagnosed by metagenomic deep sequencing (MDS), and confirmed by polymerase chain reaction. METHODS: A case report. RESULTS: An 18-year-old woman was referred with unilateral keratoconjunctivitis unresponsive to topical and systemic therapy after exposure to birdcage debris. Slit-lamp examination of the left eye revealed a follicular papillary reaction of the palpebral conjunctiva and multiple corneal punctate epithelial opacities that stained minimally with fluorescein. In vivo confocal microscopy revealed bright double-walled structures and smaller bright round structures in the superficial epithelial debris and epithelium. Molecular diagnosis with MDS of E. hellem was confirmed by polymerase chain reaction. Clinical resolution and normalization of in vivo confocal microscopy was observed after a 6-week course of topical azithromycin. The patient elected a 3-week course of topical voriconazole 1% for definitive antimicrosporidial treatment, with no evidence of persistent infection 1 month later. CONCLUSIONS: Microsporidial (E. hellem) keratoconjunctivitis can occur through avian transmission in immunocompetent hosts. Topical azithromycin may be effective against this pathogen. MDS has utility in the diagnosis of atypical keratoconjunctivitis.
Manson AL, Van Tyne D, Straub TJ, Clock S, Crupain M, Rangan U, Gilmore MS, Earl AM. Chicken Meat-Associated Enterococci: Influence of Agricultural Antibiotic Use and Connection to the Clinic. Appl Environ Microbiol 2019;85(22)Abstract
Industrial farms are unique, human-created ecosystems that provide the perfect setting for the development and dissemination of antibiotic resistance. Agricultural antibiotic use amplifies naturally occurring resistance mechanisms from soil ecologies, promoting their spread and sharing with other bacteria, including those poised to become endemic within hospital environments. To better understand the role of enterococci in the movement of antibiotic resistance from farm to table to clinic, we characterized over 300 isolates of cultured from raw chicken meat purchased at U.S. supermarkets by the Consumers Union in 2013. and were the predominant species found, and antimicrobial susceptibility testing uncovered striking levels of resistance to medically important antibiotic classes, particularly from classes approved by the FDA for use in animal production. While nearly all isolates were resistant to at least one drug, bacteria from meat labeled as raised without antibiotics had fewer resistances, particularly for Whole-genome sequencing of 92 isolates revealed that both commensal- and clinical-isolate-like enterococcal strains were associated with chicken meat, including isolates bearing important resistance-conferring elements and virulence factors. The ability of enterococci to persist in the food system positions them as vehicles to move resistance genes from the industrial farm ecosystem into more human-proximal ecologies. Bacteria that contaminate food can serve as a conduit for moving drug resistance genes from farm to table to clinic. Our results show that chicken meat-associated isolates of are often multidrug resistant, closely related to pathogenic lineages, and harbor worrisome virulence factors. These drug-resistant agricultural isolates could thus represent important stepping stones in the evolution of enterococci into drug-resistant human pathogens. Although significant efforts have been made over the past few years to reduce the agricultural use of antibiotics, continued assessment of agricultural practices, including the roles of processing plants, shared breeding flocks, and probiotics as sources for resistance spread, is needed in order to slow the evolution of antibiotic resistance. Because antibiotic resistance is a global problem, global policies are needed to address this threat. Additional measures must be taken to mitigate the development and spread of antibiotic resistance elements from farms to clinics throughout the world.
Marmalidou A, Kheirkhah A, Dana R. Conjunctivochalasis: A Systematic Review. Surv Ophthalmol 2017;Abstract
Conjunctivochalasis (CCH) is a conjunctival condition characterized by loose, redundant conjunctival folds, most typically in the inferior bulbar conjunctiva of both eyes. Although CCH is a common cause of ocular irritation and discomfort, especially in the elderly, it is often overlooked in clinical practice. Conjunctivochalasis may be associated with various ocular and non-ocular conditions; however, the most important risk factor is aging. Although often asymptomatic, CCH may cause symptoms related to tear film instability and/or delayed tear clearance. Pathogenesis of CCH remains largely unknown, but may involve different elements such as aged conjunctiva, unstable tear film, mechanical friction, ocular surface inflammation, and delayed tear clearance. Contradictory results have been reported on histopathologic changes in CCH, with some studies showing a normal microscopic structure. For symptomatic CCH, medical treatment may include lubrication and anti-inflammatory medications. For symptomatic patients who fail to respond to medical treatment, a surgical procedure may be considered. Although various surgical procedures have been used for CCH, more often it consists of conjunctival cauterization or excision of the redundant conjunctiva, with or without amniotic membrane transplantation.
Marsiglia M, Chwalisz BK, Maher M. Neuroradiologic Imaging of Neurologic and Neuro-Ophthalmic Complications of Coronavirus-19 Infection. J Neuroophthalmol 2021;41(4):452-460.Abstract
BACKGROUND: To review the literature and provide a summary of COVID-19-related neurologic and neuro-ophthalmic complications. METHODS: The currently available literature was reviewed on PubMed and Google Scholar using the following keywords for searches: CNS, Neuro-Ophthalmology, COVID-19, SARS-CoV-2, coronavirus, optic neuritis, pseudotumor cerebri, Acute Disseminated Encephalomyelitis, posterior reversible encephalopathy syndrome (PRES), meningitis, encephalitis, acute necrotizing hemorrhagic encephalopathy, and Guillain-Barré and Miller Fisher syndromes. RESULTS: Neuroradiologic findings of neurologic and neuro-ophthalmologic complications in relationship to COVID-19 infection were reviewed. Afferent visual pathway-related disorders with relevant imaging manifestations included fundus nodules on MRI, papilledema and pseudotumor cerebri syndrome, optic neuritis, Acute Disseminated Encephalomyelitis, vascular injury with thromboembolism and infarct, leukoencephalopathy, gray matter hypoxic injury, hemorrhage, infectious meningitis/encephalitis, acute necrotizing hemorrhagic encephalopathy, and PRES. Efferent visual pathway-related complications with relevant imaging manifestations were also reviewed, including orbital abnormalities, cranial neuropathy, Guillain-Barré and Miller Fisher syndromes, and nystagmus and other eye movement abnormalities related to rhombencephalitis. CONCLUSION: COVID-19 can cause central and peripheral nervous system disease, including along both the afferent and efferent components of visual axis. Manifestations of disease and long-term sequela continue to be studied and described. Familiarity with the wide variety of neurologic, ophthalmic, and neuroradiologic presentations can promote prompt and appropriate treatment and continue building a framework to understand the underlying mechanism of disease.
McAlinden C, González-Andrades M, Kiadaresi E. Hordeolum: Acute abscess within an eyelid sebaceous gland. Cleve Clin J Med 2016;83(5):332-4.
McGilligan VE, Gregory-Ksander MS, Li D, Moore JE, Hodges RR, Gilmore MS, Moore TCB, Dartt DA. Staphylococcus aureus activates the NLRP3 inflammasome in human and rat conjunctival goblet cells. PLoS One 2013;8(9):e74010.Abstract
The conjunctiva is a moist mucosal membrane that is constantly exposed to an array of potential pathogens and triggers of inflammation. The NACHT, leucine rich repeat (LRR), and pyrin domain-containing protein 3 (NLRP3) is a Nod-like receptor that can sense pathogens or other triggers, and is highly expressed in wet mucosal membranes. NLRP3 is a member of the multi-protein complex termed the NLRP3 inflammasome that activates the caspase 1 pathway, inducing the secretion of biologically active IL-1β, a major initiator and promoter of inflammation. The purpose of this study was to: (1) determine whether NLRP3 is expressed in the conjunctiva and (2) determine whether goblet cells specifically contribute to innate mediated inflammation via secretion of IL-1β. We report that the receptors known to be involved in the priming and activation of the NLRP3 inflammasome, the purinergic receptors P2X4 and P2X7 and the bacterial Toll-like receptor 2 are present and functional in conjunctival goblet cells. Toxin-containing Staphylococcus aureus (S. aureus), which activates the NLRP3 inflammasome, increased the expression of the inflammasome proteins NLRP3, ASC and pro- and mature caspase 1 in conjunctival goblet cells. The biologically active form of IL-1β was detected in goblet cell culture supernatants in response to S. aureus, which was reduced when the cells were treated with the caspase 1 inhibitor Z-YVAD. We conclude that the NLRP3 inflammasome components are present in conjunctival goblet cells. The NRLP3 inflammasome appears to be activated in conjunctival goblet cells by toxin-containing S. aureus via the caspase 1 pathway to secrete mature IL1-β. Thus goblet cells contribute to the innate immune response in the conjunctiva by activation of the NLRP3 inflammasome.
de Mello SS, Van Tyne D, Dabul ANG, Gilmore MS, Camargo ILBC. High-Quality Draft Genome Sequence of the Multidrug-Resistant Clinical Isolate Enterococcus faecium VRE16. Genome Announc 2016;4(5)Abstract

Specific lineages of the commensal bacterium Enterococcus faecium belonging to CC17, especially ST412, have been isolated from patients in several hospitals worldwide and harbor antibiotic resistance genes and virulence factors. Here, we report a high-quality draft genome sequence and highlight features of E. faecium VRE16, a representative of this ST.

Menon BB, Govindarajan B. Identification of an atypical zinc metalloproteinase, ZmpC, from an epidemic conjunctivitis-causing strain of Streptococcus pneumoniae. Microb Pathog 2013;56:40-6.Abstract
Streptococcus pneumoniae is a pathogen associated with a range of invasive and noninvasive infections. Despite the identification of the majority of virulence factors expressed by S. pneumoniae, knowledge of the strategies used by this bacterium to trigger infections, especially those originating at wet-surfaced epithelia, remains limited. In this regard, we recently reported a mechanism used by a nonencapsulated, epidemic conjunctivitis-causing strain of S. pneumoniae (strain SP168) to gain access into ocular surface epithelial cells. Mechanistically, strain SP168 secretes a zinc metalloproteinase, encoded by a truncated zmpC gene, to cleave off the ectodomain of a vital defense component - the membrane mucin MUC16 - from the apical glycocalyx barrier of ocular surface epithelial cells and, thereby invades underlying epithelial cells. Here, we compare the truncated SP168 ZmpC to its highly conserved archetype from S. pneumoniae serotype 4 (TIGR4), which has been linked to pneumococcal virulence in previous studies. Comparative nucleotide sequence analyses revealed that the zmpC gene corresponding to strain SP168 has two stretches of DNA deleted near its 5' end. A third 3 bp in-frame deletion, resulting in the elimination of an alanine residue, was found towards the middle segment of the SP168 zmpC. Closer examination of the primary structure revealed that the SP168 ZmpC lacks the canonical LPXTG motif - a signature typical of several surface proteins of gram-positive bacteria and of other pneumococcal zinc metalloproteinases. Surprisingly, in vitro assays performed using recombinant forms of ZmpC indicated that the truncated SP168 ZmpC induces more cleavage of the MUC16 ectodomain than its TIGR4 counterpart. This feature may help explain, in part, why S. pneumoniae strain SP168 is better equipped at abrogating the MUC16 glycocalyx barrier en route to causing epidemic conjunctivitis.
Modjtahedi BS, Finn AP, Eliott D. Association of Endogenous Endophthalmitis With Intravenous Drug Use: An Emerging Public Health Challenge. JAMA Ophthalmol 2017;
Moon JY, Miller JB, Katz R, Ta T, Szypko C, Garg I, Lorch AC, Gardiner MF, Armstrong GW. The Impact of the COVID-19 Pandemic on Ophthalmic Care at an Eye-Specific Emergency Department in an Outbreak Hotspot. Clin Ophthalmol 2020;14:4155-4163.Abstract
Purpose: During the COVID-19 pandemic, there is growing concern that patients are forgoing necessary care. Emergency departments (ED) represent an important site of eye care. We analyzed patterns of ED visits at an eye-specific ED since the declaration of the public health crisis. Materials and Methods: In this retrospective, cross-sectional single center study, medical records of 6744 patients who presented to the Massachusetts Eye and Ear ED between March 1st and April 30th in 2018, 2019, and 2020 were studied. The primary outcome measures were total volume of ED visits, proportion of urgent ED visits, and proportion of surgical visits. Results: Overall, the median number of daily visits to the ED decreased by 18 visits per day since the declaration of public health guidelines (interquartile range, 9-24, p < 0.001). This accounted for a 32% decrease in the total volume of ED visits in 2020 compared to prior years during the study period (p < 0.001). There was a 9% increase in the proportion of primary diagnoses considered urgent (p = 0.002). The proportion of visits requiring urgent surgery increased by 39% (p = 0.004). Conclusion: The total number of eye-specific ED visits dropped compared to prior years while the proportion of urgent visits increased. Patients were likely more reluctant to seek eye care, deferring less urgent evaluation.

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