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Inomata T, Kitazawa K, Kuno T, Sung J, Nakamura M, Iwagami M, Takagi H, Midorikawa-Inomata A, Zhu J, Fujimoto K, Okumura Y, Miura M, Fujio K, Hirosawa K, Akasaki Y, Kuwahara M, Dana R, Murakami A.
Clinical and Prodromal Ocular Symptoms in Coronavirus Disease: A Systematic Review and Meta-Analysis. Invest Ophthalmol Vis Sci 2020;61(10):29.
AbstractPurpose: This systematic review aimed to determine currently reported clinical and prodromal ocular symptoms in patients with coronavirus disease 2019 (COVID-19). Methods: An online article search was performed in PubMed and EMBASE. Altogether 15 studies (retrospective, prospective, or case studies) involving 1533 patients with COVID-19, reporting on ocular symptoms, and with outcome data available were identified. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses reporting guidelines were followed. Study-specific estimates (incidence rates of ocular symptoms in patients with COVID-19) of cases were combined using one-group meta-analysis in a random-effects model. Results: Of all included studies, 11.2% (95% confidence interval, 5.5-16.9; 78/1526 cases) reported ocular symptoms. The most common ocular finding was conjunctivitis. Prodromal ocular symptoms occurred in 12.5% (13/104 cases) of patients with COVID-19. Positive real-time polymerase chain reaction results were obtained for 16.7% (10/60 cases) of conjunctival samples and 0% (0/17 cases) of tear samples. Twelve ocular conjunctival swab samples tested positive for SARS-CoV-2. Ten cases were from subjects showing ocular symptoms (16.7%, 10/60 cases), and the remaining two cases were from subjects without ocular manifestation (1.8%, 2/113 cases). Limitations included the short study period, small sample size, findings were limited to the Asian population, only seven articles included ophthalmologic examination details, and there is currently no consensus on COVID-19 management. Conclusions: Ocular symptoms may occur in the presymptomatic phase as a prodromal symptom (12.5%, 13/104 cases), suggesting the possibility of viral transmission from the conjunctiva.
Inomata T, Ono K, Matsuba T, Shiang T, Di Zazzo A, Nakatani S, Yamaguchi M, Ebihara N, Murakami A.
Pre-banking microbial contamination of donor conjunctiva and storage medium for penetrating keratoplasty. Jpn J Ophthalmol 2017;
AbstractPURPOSE: The aims of this study were to investigate the incidence of positive donor tissue cultures before transfer to preservation medium (Optisol™-GS) for penetrating keratoplasty, to verify the efficacy of antibiotics contained in Optisol™-GS by examining the drug susceptibility and to assess the relationship between the results of our microbial assessments as well as donor factors and the incidence of contamination. METHODS: We conducted a retrospective, cross-sectional study using Juntendo Eye Bank records for all corneal transplantations. Two hundred donor conjunctiva harvestings and storage medium (EP-II(®)) cultures were performed between July 2008 and June 2011. We analyzed the associations between donor factors (age, gender, history of cataract surgery, death-to-preservation interval, cause of death) and contamination rates using multivariate analysis by the generalized estimating equation model. RESULTS: We obtained positive bacterial cultures from 154 of the 200 eyes (77.0%). The isolated bacteria were indigenous, such as coagulase-negative Staphylococci, Corynebacterium sp., and methicillin-resistant Staphylococcus aureus (MRSA). There was significant resistance to levofloxacin (18 eyes, 9.0%) and gentamicin (12 eyes, 6.0%), and no vancomycin-resistant bacteria were detected. The donor factors did not correlate with the prevalence of bacterial contamination in our criteria. CONCLUSIONS: Pre-banking microbial assessment allows for microbial detection, bacterial susceptibility and resistance testing. This is useful for developing preservation mediums containing effective spectrum antibiotic agents for high quality control of corneal banking.
Ismail AM, Lee JS, Dyer DW, Seto D, Rajaiya J, Chodosh J.
Selection Pressure in the Human Adenovirus Fiber Knob Drives Cell Specificity in Epidemic Keratoconjunctivitis. J Virol 2016;90(21):9598-9607.
AbstractHuman adenoviruses (HAdVs) contain seven species (HAdV-A to -G), each associated with specific disease conditions. Among these, HAdV-D includes those viruses associated with epidemic keratoconjunctivitis (EKC), a severe ocular surface infection. The reasons for corneal tropism for some but not all HAdV-Ds are not known. The fiber protein is a major capsid protein; its C-terminal "knob" mediates binding with host cell receptors to facilitate subsequent viral entry. In a comprehensive phylogenetic analysis of HAdV-D capsid genes, fiber knob gene sequences of HAdV-D types associated with EKC formed a unique clade. By proteotyping analysis, EKC virus-associated fiber knobs were uniquely shared. Comparative structural modeling showed no distinct variations in fiber knobs of EKC types but did show variation among HAdV-Ds in a region overlapping with the known CD46 binding site in HAdV-B. We also found signature amino acid positions that distinguish EKC from non-EKC types, and by in vitro studies we showed that corneal epithelial cell tropism can be predicted by the presence of a lysine or alanine at residue 240. This same amino acid residue in EKC viruses shows evidence for positive selection, suggesting that evolutionary pressure enhances fitness in corneal infection, and may be a molecular determinant in EKC pathogenesis. IMPORTANCE: Viruses adapt various survival strategies to gain entry into target host cells. Human adenovirus (HAdV) types are associated with distinct disease conditions, yet evidence for connections between genotype and cellular tropism is generally lacking. Here, we provide a structural and evolutionary basis for the association between specific genotypes within HAdV species D and epidemic keratoconjunctivitis, a severe ocular surface infection. We find that HAdV-D fiber genes of major EKC pathogens, specifically the fiber knob gene region, share a distinct phylogenetic clade. Deeper analysis of the fiber gene revealed that evolutionary pressure at crucial amino acid sites has a significant impact on its structural conformation, which is likely important in host cell binding and entry. Specific amino acids in hot spot residues provide a link to ocular cell tropism and possibly to corneal pathogenesis.
Ismail AM, Saha A, Lee JS, Painter DF, Chen Y, Singh G, Condezo GN, Chodosh J, San Martín C, Rajaiya J.
RANBP2 and USP9x regulate nuclear import of adenovirus minor coat protein IIIa. PLoS Pathog 2022;18(6):e1010588.
AbstractAs intracellular parasites, viruses exploit cellular proteins at every stage of infection. Adenovirus outbreaks are associated with severe acute respiratory illnesses and conjunctivitis, with no specific antiviral therapy available. An adenoviral vaccine based on human adenovirus species D (HAdV-D) is currently in use for COVID-19. Herein, we investigate host interactions of HAdV-D type 37 (HAdV-D37) protein IIIa (pIIIa), identified by affinity purification and mass spectrometry (AP-MS) screens. We demonstrate that viral pIIIa interacts with ubiquitin-specific protease 9x (USP9x) and Ran-binding protein 2 (RANBP2). USP9x binding did not invoke its signature deubiquitination function but rather deregulated pIIIa-RANBP2 interactions. In USP9x-knockout cells, viral genome replication and viral protein expression increased compared to wild type cells, supporting a host-favored mechanism for USP9x. Conversely, RANBP2-knock down reduced pIIIa transport to the nucleus, viral genome replication, and viral protein expression. Also, RANBP2-siRNA pretreated cells appeared to contain fewer mature viral particles. Transmission electron microscopy of USP9x-siRNA pretreated, virus-infected cells revealed larger than typical paracrystalline viral arrays. RANBP2-siRNA pretreatment led to the accumulation of defective assembly products at an early maturation stage. CRM1 nuclear export blockade by leptomycin B led to the retention of pIIIa within cell nuclei and hindered pIIIa-RANBP2 interactions. In-vitro binding analyses indicated that USP9x and RANBP2 bind to C-terminus of pIIIa amino acids 386-563 and 386-510, respectively. Surface plasmon resonance testing showed direct pIIIa interaction with recombinant USP9x and RANBP2 proteins, without competition. Using an alternative and genetically disparate adenovirus type (HAdV-C5), we show that the demonstrated pIIIa interaction is also important for a severe respiratory pathogen. Together, our results suggest that pIIIa hijacks RANBP2 for nuclear import and subsequent virion assembly. USP9x counteracts this interaction and negatively regulates virion synthesis. This analysis extends the scope of known adenovirus-host interactions and has potential implications in designing new antiviral therapeutics.
Ismail AM, Cui T, Dommaraju K, Singh G, Dehghan S, Seto J, Shrivastava S, Fedorova NB, Gupta N, Stockwell TB, Halpin R, Madupu R, Heim A, Kajon AE, Romanowski EG, Kowalski RP, Malathi J, Therese KL, Madhavan HN, Zhang Q, Ferreyra LJ, Jones MS, Rajaiya J, Dyer DW, Chodosh J, Seto D.
Author Correction: Genomic analysis of a large set of currently-and historically-important human adenovirus pathogens. Emerg Microbes Infect 2018;7(1):208.
AbstractThe original publication of this article [1] was missing the below author that made contributions to the research and the published article.
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Jager MJ, Seddon JM.
Eye Diseases Direct Interest to Complement Pathway and Macrophages as Regulators of Inflammation in COVID-19. Asia Pac J Ophthalmol (Phila) 2020;
AbstractMany of the risk factors for developing severe coronavirus disease 2019 (COVID-19) are also risk factors for eye diseases such as age-related macular degeneration (AMD). During the past decades, macrophages and the complement pathway (as a part of the innate immune system) have been identified as important contributors to the development of AMD, and we suggest that these mechanisms are of similar importance for the clinical course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. Based on the experience with AMD, we discuss how behavioral factors such as diet, smoking and higher body mass index, as well as genetic determinants such as the complement and immune pathway genes may lead to the overactive inflammatory phenotypes seen in some patients with COVID-19, and may in part explain the heterogeneity of disease manifestations and outcomes. Based on this experience, we discuss potential genetic research projects and elaborate on preventive and treatment approaches related to COVID-19.
Jain R, Sharma N, Basu S, Iyer G, Ueta M, Sotozono C, Kannabiran C, Rathi VM, Gupta N, Kinoshita S, Gomes JAP, Chodosh J, Sangwan VS.
Stevens-Johnson syndrome: The role of an ophthalmologist. Surv Ophthalmol 2016;61(4):369-99.
AbstractStevens-Johnson syndrome (SJS) is an acute blistering disease of the skin and mucous membranes. Acute SJS leads to the acute inflammation of the ocular surface and chronic conjunctivitis. If not properly treated, it causes chronic cicatricial conjunctivitis and cicatricial lid margin abnormalities. Persistent inflammation and ulceration of the ocular surface with cicatricial complications of the lids leads to chronic ocular sequelae, ocular surface damage, and corneal scarring. The destruction of the glands that secrete the tear film leads to a severe form of dry eye that makes the management of chronic SJS difficult. The option that is routinely used for corneal visual rehabilitation, keratoplasty, is best avoided in such cases. We describe the management strategies that are most effective during the acute and chronic stages of SJS. Although treatments for acute SJS involve immunosuppressive and immunomodulatory therapies, amniotic membrane transplantation is also useful. The options for visual rehabilitation in patients with chronic SJS are undergoing radical change. We describe the existing literature regarding the management of SJS and highlight recent advances in the management of this disorder.
Johnston T, Van Tyne D, Chen RF, Fawzi NL, Kwon B, Kelso MJ, Gilmore MS, Mylonakis E.
Propyl-5-hydroxy-3-methyl-1-phenyl-1H-pyrazole-4-carbodithioate (HMPC): a new bacteriostatic agent against methicillin-resistant Staphylococcus aureus. Sci Rep 2018;8(1):7062.
AbstractThe emergence of Staphylococcus aureus strains resistant to 'last resort' antibiotics compels the development of new antimicrobials against this important human pathogen. We found that propyl 5-hydroxy-3-methyl-1-phenyl-1H-pyrazole-4-carbodithioate (HMPC) shows bacteriostatic activity against S. aureus (MIC = 4 μg/ml) and rescues Caenorhabditis elegans from S. aureus infection. Whole-genome sequencing of S. aureus mutants resistant to the compound, along with screening of a S. aureus promoter-lux reporter array, were used to explore possible mechanisms of action. All mutants resistant to HMPC acquired missense mutations at distinct codon positions in the global transcriptional regulator mgrA, followed by secondary mutations in the phosphatidylglycerol lysyltransferase fmtC/mprF. The S. aureus promoter-lux array treated with HMPC displayed a luminescence profile that was unique but showed similarity to DNA-damaging agents and/or DNA replication inhibitors. Overall, HMPC is a new anti-staphylococcal compound that appears to act via an unknown mechanism linked to the global transcriptional regulator MgrA.
Jonas RA, Ung L, Rajaiya J, Chodosh J.
Mystery Eye: Human Adenovirus and the Enigma of Epidemic Keratoconjunctivitis. Prog Retin Eye Res 2019;:100826.
AbstractKnown to occur in widespread outbreaks, epidemic keratoconjunctivitis (EKC) is a severe ocular surface infection with a strong historical association with human adenovirus (HAdV). While the conjunctival manifestations can vary from mild follicular conjunctivitis to hyper-acute, exudative conjunctivitis with formation of conjunctival membranes, EKC is distinct as the only form of adenovirus conjunctivitis in which the cornea is also involved, likely due to specific corneal epithelial tropism of its causative viral agents. The initial development of a punctate or geographic epithelial keratitis may herald the later formation of stromal keratitis, and manifest as subepithelial infiltrates which often persist or recur for months to years after the acute infection has resolved. The chronic keratitis in EKC is associated with foreign body sensation, photophobia, glare, and reduced vision. However, over a century since the first clinical descriptions of EKC, and over 60 years since the first causative agent, human adenovirus type 8, was identified, our understanding of this disorder remains limited. This is underscored by a current lack of effective diagnostic tools and treatments. In part, stasis in our knowledge base has been encouraged by the continued acceptance, and indeed propagation of, inaccurate paradigms pertaining to disease etiology and pathogenesis, particularly with regard to mechanisms of innate and adaptive immunity within the cornea. Owing to its often persistent and medically refractory visual sequelae, reconsideration of key aspects of EKC disease biology is warranted to identify new treatment targets to curb its worldwide socioeconomic burden.
Junk AK, Chen PP, Lin SC, Nouri-Mahdavi K, Radhakrishnan S, Singh K, Chen TC.
Disinfection of Tonometers: A Report by the American Academy of Ophthalmology. Ophthalmology 2017;124(12):1867-1875.
AbstractOBJECTIVE: To examine the efficacy of various disinfection methods for reusable tonometer prisms in eye care and to highlight how disinfectants can damage tonometer tips and cause subsequent patient harm. METHODS: Literature searches were conducted last in October 2016 in the PubMed and the Cochrane Library databases for original research investigations. Reviews, non-English language articles, nonophthalmology articles, surveys, and case reports were excluded. RESULTS: The searches initially yielded 64 unique citations. After exclusion criteria were applied, 10 laboratory studies remained for this review. Nine of the 10 studies used tonometer prisms and 1 used steel discs. The infectious agents covered in this assessment include adenovirus 8 and 19, herpes simplex virus (HSV) 1 and 2, human immunodeficiency virus 1, hepatitis C virus, enterovirus 70, and variant Creutzfeldt-Jakob disease. All 4 studies of adenovirus 8 concluded that after sodium hypochlorite (dilute bleach) disinfection, the virus was undetectable, but only 2 of the 4 studies found that 70% isopropyl alcohol (e.g., alcohol wipes or soaks) eradicated all viable virus. All 3 HSV studies concluded that both sodium hypochlorite and 70% isopropyl alcohol eliminated HSV. Ethanol, 70% isopropyl alcohol, dilute bleach, and mechanical cleaning all lack the ability to remove cellular debris completely, which is necessary to prevent prion transmission. Therefore, single-use tonometer tips or disposable tonometer covers should be considered when treating patients with suspected prion disease. Damage to tonometer prisms can be caused by sodium hypochlorite, 70% isopropyl alcohol, 3% hydrogen peroxide, ethyl alcohol, water immersion, ultraviolet light, and heat exposure. Disinfectants can cause tonometer tips to swell and crack by dissolving the glue that holds the hollow tip together. The tonometer tip cracks can irritate the cornea, harbor microbes, or allow disinfectants to enter the interior of the tonometer tip. CONCLUSIONS: Sodium hypochlorite (dilute bleach) offers effective disinfection against adenovirus and HSV, the viruses commonly associated with nosocomial outbreaks in eye care. Tonometer prisms should be examined regularly for signs of damage.
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Kaseke C, Park RJ, Singh NK, Koundakjian D, Bashirova A, Garcia Beltran WF, Takou Mbah OC, Ma J, Senjobe F, Urbach JM, Nathan A, Rossin EJ, Tano-Menka R, Khatri A, Piechocka-Trocha A, Waring MT, Birnbaum ME, Baker BM, Carrington M, Walker BD, Gaiha GD.
HLA class-I-peptide stability mediates CD8+ T cell immunodominance hierarchies and facilitates HLA-associated immune control of HIV. Cell Rep 2021;36(2):109378.
AbstractDefining factors that govern CD8+ T cell immunodominance is critical for the rational design of vaccines for viral pathogens. Here, we assess the contribution of human leukocyte antigen (HLA) class-I-peptide stability for 186 optimal HIV epitopes across 18 HLA alleles using transporter associated with antigen processing (TAP)-deficient mono-allelic HLA-expressing cell lines. We find that immunodominant HIV epitopes increase surface stabilization of HLA class-I molecules in comparison to subdominant epitopes. HLA class-I-peptide stability is also strongly correlated with overall immunodominance hierarchies, particularly for epitopes from high-abundance proteins (e.g., Gag). Moreover, HLA alleles associated with HIV protection are preferentially stabilized by epitopes derived from topologically important viral regions at a greater frequency than neutral and risk alleles. These findings indicate that relative stabilization of HLA class-I is a key factor for CD8+ T cell epitope immunodominance hierarchies, with implications for HIV control and the design of T-cell-based vaccines.
Kaufman AR, Chodosh J, Pineda R.
Monkeypox Virus and Ophthalmology-A Primer on the 2022 Monkeypox Outbreak and Monkeypox-Related Ophthalmic Disease. JAMA Ophthalmol 2023;141(1):78-83.
AbstractIMPORTANCE: An ongoing global monkeypox virus outbreak in 2022 includes the US and other nonendemic countries. Monkeypox ophthalmic manifestations may present to the ophthalmologist, or the ophthalmologist may be involved in comanagement. This narrative review creates a primer for the ophthalmologist of clinically relevant information regarding monkeypox, its ophthalmic manifestations, and the 2022 outbreak. OBSERVATIONS: Monkeypox virus is an Orthopoxvirus (genus includes variola [smallpox] and vaccinia [smallpox vaccine]). The 2022 outbreak is of clade II (historically named West African clade), specifically subclade IIb. In addition to historic transmission patterns (skin lesions, bodily fluids, respiratory droplets), sexual transmission has also been theorized in the current outbreak due to disproportionate occurrence in men who have sex with men. Monkeypox causes a characteristic skin eruption and mucosal lesions and may cause ophthalmic disease. Monkeypox-related ophthalmic disease (MPXROD) includes a spectrum of ocular pathologies including eyelid/periorbital skin lesions, blepharoconjunctivitis, and keratitis). Smallpox vaccination may reduce MPXROD occurrence. MPXROD seems to be rarer in the 2022 outbreaks than in historical outbreaks. MPXROD may result in corneal scarring and blindness. Historical management strategies for MPXROD include lubrication and prevention/management of bacterial superinfection in monkeypox keratitis. Case reports and in vitro data for trifluridine suggest a possible role in MPXROD. Tecovirimat, cidofovoir, brincidofovir and vaccinia immune globulin intravenous may be used for systemic infection. There is a theoretical risk for monkeypox transmission by corneal transplantation, and the Eye Bank Association of America has provided guidance. Smallpox vaccines (JYNNEOS [Bavarian Nordic] and ACAM2000 [Emergent Product Development Gaithersburg Inc]) provide immunity against monkeypox. CONCLUSIONS AND RELEVANCE: The ophthalmologist may play an important role in the diagnosis and management of monkeypox. MPXROD may be associated with severe ocular and visual morbidity. As the current outbreak evolves, up-to-date guidance from public health organizations and professional societies are critical.
Keffeler EC, Iyer VS, Parthasarathy S, Ramsey MM, Gorman MJ, Barke TL, Varahan S, Olson S, Gilmore MS, Abdullahi ZH, Hancock EN, Hancock LE.
Influence of the Alternative Sigma Factor RpoN on Global Gene Expression and Carbon Catabolism in Enterococcus faecalis V583. mBio 2021;12(3)
AbstractThe alternative sigma factor σ54 has been shown to regulate the expression of a wide array of virulence-associated genes, as well as central metabolism, in bacterial pathogens. In Gram-positive organisms, the σ54 is commonly associated with carbon metabolism. In this study, we show that the Enterococcus faecalis alternative sigma factor σ54 (RpoN) and its cognate enhancer binding protein MptR are essential for mannose utilization and are primary contributors to glucose uptake through the Mpt phosphotransferase system. To gain further insight into how RpoN contributes to global transcriptional changes, we performed microarray transcriptional analysis of strain V583 and an isogenic rpoN mutant grown in a chemically defined medium with glucose as the sole carbon source. Transcripts of 340 genes were differentially affected in the rpoN mutant; the predicted functions of these genes mainly related to nutrient acquisition. These differentially expressed genes included those with predicted catabolite-responsive element (cre) sites, consistent with loss of repression by the major carbon catabolite repressor CcpA. To determine if the inability to efficiently metabolize glucose/mannose affected infection outcome, we utilized two distinct infection models. We found that the rpoN mutant is significantly attenuated in both rabbit endocarditis and murine catheter-associated urinary tract infection (CAUTI). Here, we examined a ccpA mutant in the CAUTI model and showed that the absence of carbon catabolite control also significantly attenuates bacterial tissue burden in this model. Our data highlight the contribution of central carbon metabolism to growth of E. faecalis at various sites of infection.IMPORTANCE Hospital-acquired infections account for 2 billion dollars annually in increased health care expenses and cause more than 100,000 deaths in the United States alone. Enterococci are the second leading cause of hospital-acquired infections. They form biofilms at surgical sites and are often associated with infections of the urinary tract following catheterization. Nutrient uptake and growth are key factors that influence their ability to cause disease. Our research identified a large set of genes that illuminate nutrient uptake pathways in enterococci. Perturbation of the metabolic circuit reduces virulence in a rabbit endocarditis model, as well as in catheter-associated urinary tract infection in mice. Targeting metabolic pathways that are important in infection may lead to new treatments against multidrug-resistant enterococcal infections.
Keilty M, Houston KE, Collins C, Trehan R, Chen Y-T, Merabet L, Watts A, Pundlik S, Luo G.
Inpatient Virtual Vision Clinic Improves Access to Vision Rehabilitation Before and During the COVID-19 Pandemic. Arch Rehabil Res Clin Transl 2021;3(1):100100.
AbstractObjective: To describe and evaluate a secure video call system combined with a suite of iPad vision testing apps to improve access to vision rehabilitation assessment for inpatients. Design: Retrospective. Setting: Two acute care inpatient rehabilitation hospitals and 1 long-term acute care (LTAC) hospital. Participants: Records of inpatients seen by the vision service. Interventions: Records from a 1-year telemedicine pilot performed at acute rehabilitation (AR) hospital 1 and then expanded to AR hospital 2 and LTAC hospital during coronavirus disease 2019 (COVID-19) were reviewed. In the virtual visits, an occupational therapist measured the patients' vision with the iPad applications and forwarded results to the off-site Doctor of Optometry (OD) for review prior to a video visit. The OD provided diagnosis and education, press-on prism application supervision, strategies and modifications, and follow-up recommendations. Providers completed the telehealth usability questionnaire (10-point scale). Main Outcome Measures: Vision examinations per month at AR hospital 1 before and with telemedicine. Results: With telemedicine at AR hospital 1, mean visits per month significantly increased from 10.7±5 to 14.9±5 (=.002). Prism was trialed in 40% of cases of which 83% were successful, similar to previously reported in-person success rates. COVID-19 caused only a marginal decrease in visits per month (=.08) at AR1, whereas the site without an established program (AR hospital 2) had a 3-4 week gap in care while the program was initiated. Cases at the LTAC hospital tended to be more complex and difficult to manage virtually. The telehealth usability questionnaire median category scores were 7 for , 8 for , 6 for , and 9 for . Conclusions: The virtual vision clinic process improved inpatient access to eye and visual neurorehabilitation assessment before and during the COVID-19 quarantine and was well accepted by providers and patients.
Kempen JH, Tekle-Haimanot R, Hunduma L, Alemayehu M, Pistilli M, Abashawl A, Lawrence SD, Alemayehu W.
Fluorometholone 0.1% as Ancillary Therapy for Trachomatous Trichiasis Surgery: Randomized Clinical Trial. Am J Ophthalmol 2019;197:145-155.
AbstractPURPOSE: To assess the hypothesis that fluorometholone 0.1% eye drops are safe and effective as adjunctive therapy for trachomatous trichiasis (TT) surgery; determining the most promising dose. DESIGN: Randomized, placebo-controlled, double-masked parallel dose-ranging clinical trial. METHODS: Patients undergoing upper lid TT surgery at a rural Ethiopian hospital were randomized to fluorometholone 0.1% twice daily for 4 weeks, 4 times daily for 4 weeks, 4 times daily for 8 weeks, or matching frequency placebo in a 3:1:3:1:3:1 ratio for 1 eye. Randomization was stratified by TT severity (1-4 vs ≥5 lashes touching the globe). Safety outcomes (intraocular pressure [IOP] elevation, cataract, and other dose-limiting toxicities) and postoperative TT incidence were assessed over 1 year. RESULTS: Subjects randomized were 39:13:39:13:38:13 in the respective groups, and 1 subject in the 8-weeks fluorometholone group was withdrawn. Of 154 subjects, 148 (96.1%) completed 1 year's follow-up. Among 76 eyes receiving fluorometholone 4 times daily, 1 developed IOP elevation ≥ 30 mm Hg (to 37 mm Hg) and 1 had an allergic reaction attributed to the study drug; each resolved upon drug cessation without sequelae. No cataract or other dose-limiting toxicity events occurred. Postoperative TT within 1 year occurred in 29.3% of placebo eyes vs 17.7%, 19.6%, and 23.2% among the respective fluorometholone groups (P = .29 comparing placebo vs all active treatments combined). CONCLUSIONS: The results suggest fluorometholone 0.1% is likely to be safe and efficacious to reduce postoperative TT following TT surgery, and 1 drop twice daily for 4 weeks is the most promising dose. Confirmation in a full-scale clinical trial is needed before programmatic implementation.
Kempen JH, Abashawl A, Suga HK, Nigussie Difabachew M, Kempen CJ, Tesfaye Debele M, Menkir AA, Assefa MT, Asfaw EH, Habtegabriel LB, Sitotaw Addisie Y, Nilles EJ, Longenecker JC.
SARS-CoV-2 Serosurvey in Addis Ababa, Ethiopia. Am J Trop Med Hyg 2020;103(5):2022-2023.
AbstractIn a serosurvey of asymptomatic people from the general population recruited from a clinical laboratory in May 2020 in Addis Ababa, Ethiopia, three of 99 persons tested positive for SARS-CoV-2 IgG (3.0%, 95% binomial exact confidence interval: 0.6-8.6%). Taking into account pretest probability and the sampling scheme, the range of plausible population prevalence values was approximately 1.0-8.4%. These results suggest that a larger number of people have been infected than the counts detected by surveillance to date; nevertheless, the results suggest the large majority of the general population in Addis Ababa currently is susceptible to COVID-19.
Kim W, Zhu W, Hendricks GL, Van Tyne D, Steele AD, Keohane CE, Fricke N, Conery AL, Shen S, Pan W, Lee K, Rajamuthiah R, Fuchs BB, Vlahovska PM, Wuest WM, Gilmore MS, Gao H, Ausubel FM, Mylonakis E.
A new class of synthetic retinoid antibiotics effective against bacterial persisters. Nature 2018;556(7699):103-107.
AbstractA challenge in the treatment of Staphylococcus aureus infections is the high prevalence of methicillin-resistant S. aureus (MRSA) strains and the formation of non-growing, dormant 'persister' subpopulations that exhibit high levels of tolerance to antibiotics and have a role in chronic or recurrent infections. As conventional antibiotics are not effective in the treatment of infections caused by such bacteria, novel antibacterial therapeutics are urgently required. Here we used a Caenorhabditis elegans-MRSA infection screen to identify two synthetic retinoids, CD437 and CD1530, which kill both growing and persister MRSA cells by disrupting lipid bilayers. CD437 and CD1530 exhibit high killing rates, synergism with gentamicin, and a low probability of resistance selection. All-atom molecular dynamics simulations demonstrated that the ability of retinoids to penetrate and embed in lipid bilayers correlates with their bactericidal ability. An analogue of CD437 was found to retain anti-persister activity and show an improved cytotoxicity profile. Both CD437 and this analogue, alone or in combination with gentamicin, exhibit considerable efficacy in a mouse model of chronic MRSA infection. With further development and optimization, synthetic retinoids have the potential to become a new class of antimicrobials for the treatment of Gram-positive bacterial infections that are currently difficult to cure.
KL P, van W S, RJL W, MS G.
Enterococcal Genomics. In: Enterococci: From Commensals to Leading Causes of Drug Resistant Infection [Internet]. Boston: Massachusetts Eye and Ear Infirmary; 2014-. . 2014
Abstract Kohanim S, Daniels AB, Huynh N, Eliott D, Chodosh J.
Utility of ocular ultrasonography in diagnosing infectious endophthalmitis in patients with media opacities. Semin Ophthalmol 2012;27(5-6):242-5.
AbstractAssessment of patients with infectious endophthalmitis is frequently limited by media opacities, and ocular ultrasonography is routinely performed in this setting. We examined the literature to assess the level of evidence for the utility of ocular ultrasonography in these patients. Common ultrasonographic findings reported include low amplitude mobile echoes, vitreous membranes, and thickening of the retina and choroid. Based on the available evidence, we conclude that ocular ultrasound may be a useful adjunct in guiding treatment and minimizing complications. While positive findings may be confirmatory in cases in which the clinical suspicion is high, ocular ultrasound alone cannot be used to prove or to exclude the diagnosis of infectious endophthalmitis.
Kos VN, Desjardins CA, Griggs A, Cerqueira G, Van Tonder A, Holden MTG, Godfrey P, Palmer KL, Bodi K, Mongodin EF, Wortman J, Feldgarden M, Lawley T, Gill SR, Haas BJ, Birren B, Gilmore MS.
Comparative genomics of vancomycin-resistant Staphylococcus aureus strains and their positions within the clade most commonly associated with Methicillin-resistant S. aureus hospital-acquired infection in the United States. MBio 2012;3(3)
AbstractUNLABELLED: Methicillin-resistant Staphylococcus aureus (MRSA) strains are leading causes of hospital-acquired infections in the United States, and clonal cluster 5 (CC5) is the predominant lineage responsible for these infections. Since 2002, there have been 12 cases of vancomycin-resistant S. aureus (VRSA) infection in the United States-all CC5 strains. To understand this genetic background and what distinguishes it from other lineages, we generated and analyzed high-quality draft genome sequences for all available VRSA strains. Sequence comparisons show unambiguously that each strain independently acquired Tn1546 and that all VRSA strains last shared a common ancestor over 50 years ago, well before the occurrence of vancomycin resistance in this species. In contrast to existing hypotheses on what predisposes this lineage to acquire Tn1546, the barrier posed by restriction systems appears to be intact in most VRSA strains. However, VRSA (and other CC5) strains were found to possess a constellation of traits that appears to be optimized for proliferation in precisely the types of polymicrobic infection where transfer could occur. They lack a bacteriocin operon that would be predicted to limit the occurrence of non-CC5 strains in mixed infection and harbor a cluster of unique superantigens and lipoproteins to confound host immunity. A frameshift in dprA, which in other microbes influences uptake of foreign DNA, may also make this lineage conducive to foreign DNA acquisition. IMPORTANCE: Invasive methicillin-resistant Staphylococcus aureus (MRSA) infection now ranks among the leading causes of death in the United States. Vancomycin is a key last-line bactericidal drug for treating these infections. However, since 2002, vancomycin resistance has entered this species. Of the now 12 cases of vancomycin-resistant S. aureus (VRSA), each was believed to represent a new acquisition of the vancomycin-resistant transposon Tn1546 from enterococcal donors. All acquisitions of Tn1546 so far have occurred in MRSA strains of the clonal cluster 5 genetic background, the most common hospital lineage causing hospital-acquired MRSA infection. To understand the nature of these strains, we determined and examined the nucleotide sequences of the genomes of all available VRSA. Genome comparison identified candidate features that position strains of this lineage well for acquiring resistance to antibiotics in mixed infection.
