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  • Articles  (2,896)
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  • Articles  (2,896)
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  • 1
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    Antimicrobial Peptide Resistance Mechanism Contributes to Staphylococcus aureus Infection (2018)
    Oxford University Press
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    Publication Date: 2018-03-14
    Description: Antimicrobial peptides (AMPs) constitute an important part of innate host defense. Possibly limiting the therapeutic potential of AMPs is the fact that bacteria have developed AMP resistance mechanisms during their co-evolution with humans. However, there is no direct evidence that AMP resistance per se is important during an infection. Here we show that the Staphylococcus aureus Pmt ABC transporter defends the bacteria from killing by important human AMPs and elimination by human neutrophils. By showing that Pmt contributes to virulence during skin infection in an AMP-dependent manner, we provide evidence that AMP resistance plays a key role in bacterial infection.
    Print ISSN: 0022-1899
    Electronic ISSN: 1537-6613
    Topics: Medicine
    Published by Oxford University Press on behalf of The Infectious Diseases Society of America (IDSA).
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  • 2
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    Emergence of Nonfalciparum Plasmodium Infection Despite Regular Artemisinin Combination Therapy in an 18-Month Longitudinal Study of Ugandan Children and Their Mothers (2018)
    Oxford University Press
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    Publication Date: 2018-03-14
    Description: As part of a longitudinal cohort investigation of intestinal schistosomiasis and malaria in Ugandan children and their mothers on the shorelines of Lakes Victoria and Albert, we documented risk factors and morbidity associated with nonfalciparum Plasmodium infections and the longitudinal dynamics of Plasmodium species in children. Host age, household location, and Plasmodium falciparum infection were strongly associated with nonfalciparum Plasmodium infections, and Plasmodium malariae infection was associated with splenomegaly. Despite regular artemisinin combination therapy treatment, there was a 3-fold rise in P. malariae prevalence, which was not accountable for by increasing age of the child. Worryingly, our findings reveal the consistent emergence of nonfalciparum infections in children, highlighting the complex dynamics underlying multispecies infections here. Given the growing body of evidence that nonfalciparum malaria infections cause significant morbidity, we encourage better surveillance for nonfalciparum Plasmodium infections, particularly in children, with more sensitive DNA detection methods and improved field-based diagnostics.
    Print ISSN: 0022-1899
    Electronic ISSN: 1537-6613
    Topics: Medicine
    Published by Oxford University Press on behalf of The Infectious Diseases Society of America (IDSA).
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  • 3
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    Diminished Capsule Exacerbates Virulence, Blood–Brain Barrier Penetration, Intracellular Persistence, and Antibiotic Evasion of Hyperhemolytic Group B Streptococci (2018)
    Oxford University Press
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    Publication Date: 2018-03-14
    Description: Group B streptococci (GBS) are encapsulated, β-hemolytic bacteria that are a common cause of infections in human newborns and certain adults. Two factors important for GBS virulence are the sialic acid capsular polysaccharide that promotes immune evasion and the hemolytic pigment that induces host cell cytotoxcity. These virulence factors are often oppositely regulated by the CovR/CovS two-component system. Clinical GBS strains exhibiting hyperhemolysis and low capsule due to pathoadaptive covR/S mutations have been isolated from patients. Given the importance of capsule to GBS virulence, we predicted that a decrease or loss of capsule would attenuate the virulence of covR/S mutants. Surprisingly, hyperhemolytic GBS with low or no capsule exhibit increased virulence, intracellular persistence, and blood–brain barrier penetration, which was independent of a Trojan horse mechanism of barrier penetration. Additionally, intracellular persistence enabled both hemolytic and hyperhemolytic GBS to evade antibiotics routinely used to treat these infections. The finding that diminished capsule expression promotes GBS virulence, intracellular persistence, and antibiotic evasion has important implications for sustained antibiotic therapy and efficacy of capsule-based vaccines.
    Print ISSN: 0022-1899
    Electronic ISSN: 1537-6613
    Topics: Medicine
    Published by Oxford University Press on behalf of The Infectious Diseases Society of America (IDSA).
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  • 4
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    Improvements in Quality of Life: A New Indication for Treating Hepatitis C Virus Infection in Persons With Substance Use Disorders (2018)
    Oxford University Press
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    Publication Date: 2018-03-14
    Description: ( See the Major Article by Stepanova et al, on pages 1033–43 .)
    Print ISSN: 0022-1899
    Electronic ISSN: 1537-6613
    Topics: Medicine
    Published by Oxford University Press on behalf of The Infectious Diseases Society of America (IDSA).
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  • 5
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    Respiratory Syncytial Virus and Rhinovirus Bronchiolitis Are Associated With Distinct Metabolic Pathways (2018)
    Oxford University Press
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    Publication Date: 2018-03-14
    Description: Background Bronchiolitis, the leading cause of hospitalization among infants in the United States, is most commonly caused by respiratory syncytial virus (RSV), followed by rhinovirus (RV). Conventional perception is that bronchiolitis is a single entity, albeit with different viral etiologies and degrees of severity. Methods We conducted a cross-sectional study of nasopharyngeal aspirates from 106 infants hospitalized with bronchiolitis due to either RSV only (80 patients) or RV only (26 patients). We performed metabolomics analysis and 16S ribosomal RNA gene sequencing on all samples and metagenomic sequencing on 58 of 106 samples. Results Infants with RSV-only and RV-only infections had significantly different nasopharyngeal metabolome profiles ( P 〈 .001) and bacterial metagenome profiles ( P 〈 .05). RSV-only infection was associated with metabolites from a range of pathways and with a microbiome dominated by Streptococcus pneumoniae . By contrast, RV-only infection was associated with increased levels of essential and nonessential N-acetyl amino acids and with a high relative abundance of Haemophilus influenzae . These co-occurring species were associated with driving the bacterially derived metabolic pathways. Multi-omic analysis showed that both the virus and the microbiome were significantly associated with metabolic function in infants hospitalized with bronchiolitis. Conclusion Although replication of these findings is necessary, they highlight that bronchiolitis is not a uniform disease between RSV and RV infections, a result with future implications for prevention and treatment.
    Print ISSN: 0022-1899
    Electronic ISSN: 1537-6613
    Topics: Medicine
    Published by Oxford University Press on behalf of The Infectious Diseases Society of America (IDSA).
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  • 6
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    Pharmacodynamics of the Novel Antifungal Agent F901318 for Acute Sinopulmonary Aspergillosis Caused by Aspergillus flavus (2018)
    Oxford University Press
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    Publication Date: 2018-03-14
    Description: Background Aspergillus flavus is one of the most common agents of invasive aspergillosis and is associated with high mortality. The orotomides are a new class of antifungal agents with a novel mechanism of action. An understanding of the pharmacodynamics (PD) of the lead compound F901318 is required to plan safe and effective regimens for clinical use. Methods The pharmacokinetics (PK) and PD of F901318 were evaluated by developing new in vitro and in vivo models of invasive fungal sinusitis. Galactomannan was used as a pharmacodynamic endpoint in all models. Mathematical PK-PD models were used to describe dose-exposure-response relationships. Results F901318 minimum inhibitory concentrations (MICs) ranged from 0.015 to 0.06 mg/L. F901318 induced a concentration-dependent decline in galactomannan. In the in vitro model, a minimum concentration:MIC of 10 resulted in suppression of galactomannan; however, values of approximately 10 and 9–19 when assessed by survival of mice or the decline in galactomannan, respectively, were equivalent or exceeded the effect induced by posaconazole. There was histological clearance of lung tissue that was consistent with the effects of F901318 on galactomannan. Conclusions F901318 is a potential new agent for the treatment of invasive infections caused by A flavus with PDs that are comparable with other first-line triazole agents.
    Print ISSN: 0022-1899
    Electronic ISSN: 1537-6613
    Topics: Medicine
    Published by Oxford University Press on behalf of The Infectious Diseases Society of America (IDSA).
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  • 7
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    Varicella-Zoster Virus DNA in Blood After Administration of Herpes Zoster Vaccine (2018)
    Oxford University Press
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    Publication Date: 2018-03-14
    Description: We studied the relationship between varicella-zoster virus (VZV) DNAemia and development of VZV-specific immunity after administration of live-attenuated zoster vaccine. VZV-DNAemia, detected by polymerase chain reaction (PCR), and VZV-specific effector (Teff) and memory (Tmem) T cells, was measured in 67 vaccinees. PCR was positive in 56% (9 direct, 28 nested) on day 1 and in 16% (1 direct, 10 nested) on day 14. Teff progressively increased in direct-PCR-positive vaccinees up to day 30, but Tmem did not. Conversely, Tmem, but not Teff, increased in direct-PCR-negative vaccinees on day 7. The kinetics of these immune responses and VZV DNAemia suggested that direct-PCR sample positive represented viremia.
    Print ISSN: 0022-1899
    Electronic ISSN: 1537-6613
    Topics: Medicine
    Published by Oxford University Press on behalf of The Infectious Diseases Society of America (IDSA).
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  • 8
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    The Existing Drug Vorinostat as a New Lead Against Cryptosporidiosis by Targeting the Parasite Histone Deacetylases (2018)
    Oxford University Press
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    Publication Date: 2018-03-14
    Description: Background Cryptosporidiosis affects all human populations, but can be much more severe or life-threatening in children and individuals with weak or weakened immune systems. However, current options to treat cryptosporidiosis are limited. Methods An in vitro phenotypic screening assay was employed to screen 1200 existing drugs for their anticryptosporidial activity and to determine the inhibitory kinetics of top hits. Selected top hits were further evaluated in mice. The action of the lead compound vorinostat on the parasite histone deacetylase (HDAC) was biochemically validated. Results Fifteen compounds exhibited anticryptosporidial activity at nanomolar level in vitro. Among them, the histone deacetylase (HDAC) inhibitor vorinostat retained outstanding efficacy in vitro (half maximal effective concentration, EC 50 = 203 nM) and in an interleukin 12 knockout mouse model (50% inhibition dose = 7.5 mg/kg). Vorinostat was effective on various parasite developmental stages and could irreversibly kill the parasite. Vorinostat was highly effective against the parasite native HDAC enzymes (half maximal inhibitory concentration, IC 50 = 90.0 nM) and a recombinant Cryptosporidium parvum HDAC (the inhibitor constant, K i = 123.0 nM). Conclusions These findings suggest the potential for repurposing of vorinostat to treat cryptosporidiosis, and imply that the parasite HDAC can be explored for developing more selective anticryptosporidial therapeutics.
    Print ISSN: 0022-1899
    Electronic ISSN: 1537-6613
    Topics: Medicine
    Published by Oxford University Press on behalf of The Infectious Diseases Society of America (IDSA).
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  • 9
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    Innovative and New Approaches to Laboratory Diagnosis of Zika and Dengue: A Meeting Report (2018)
    Oxford University Press
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    Publication Date: 2018-03-14
    Description: Epidemics of dengue, Zika, and other arboviral diseases are increasing in frequency and severity. Current efforts to rapidly identify and manage these epidemics are limited by the short diagnostic window in acute infection, the extensive serologic cross-reactivity among flaviviruses, and the lack of point-of-care diagnostic tools to detect these viral species in primary care settings. The Partnership for Dengue Control organized a workshop to review the current landscape of Flavivirus diagnostic tools, identified current gaps, and developed strategies to accelerate the adoption of promising novel technologies into national programs. The rate-limiting step to bringing new diagnostic tools to the market is access to reference materials and well-characterized clinical samples to facilitate performance evaluation. We suggest the creation of an international laboratory-response consortium for flaviviruses with a decentralized biobank of well-characterized samples to facilitate assay validation. Access to proficiency panels are needed to ensure quality control, in additional to in-country capacity building.
    Print ISSN: 0022-1899
    Electronic ISSN: 1537-6613
    Topics: Medicine
    Published by Oxford University Press on behalf of The Infectious Diseases Society of America (IDSA).
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  • 10
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    Antigenic Characterization of a Novel Recombinant GII.P16-GII.4 Sydney Norovirus Strain With Minor Sequence Variation Leading to Antibody Escape (2018)
    Oxford University Press
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    Publication Date: 2018-03-14
    Description: Background Human noroviruses are the leading cause of acute gastroenteritis. Strains of the GII.4 genotype cause pandemic waves associated with viral evolution and subsequent antigenic drift and ligand-binding modulation. In November 2015, a novel GII.4 Sydney recombinant variant (GII.P16-GII.4 Sydney) emerged and replaced GII.Pe-GII.4 Sydney as the predominant cause of acute gastroenteritis in the 2016–2017 season in the United States. Methods Virus-like particles of GII.4 2012 and GII.4 2015 were compared for ligand binding and antibody reactivity, using a surrogate neutralization assay. Results Residue changes in the capsid between GII.4 2012 and GII.4 2015 decreased the potency of human polyclonal sera and monoclonal antibodies. A change in epitope A resulted in the complete loss of reactivity of a class of blockade antibodies and reduced levels of a second antibody class. Epitope D changes modulated monoclonal antibody potency and ligand-binding patterns. Conclusions Substitutions in blockade antibody epitopes between GII.4 2012 and GII.4 2015 influenced antigenicity and ligand-binding properties. Although the impact of polymerases on fitness remains uncertain, antigenic variation resulting in decreased potency of antibodies to epitope A, coupled with altered ligand binding, likely contributed significantly to the spread of GII.4 2015 and its replacement of GII.4 2012 as the predominant norovirus outbreak strain.
    Print ISSN: 0022-1899
    Electronic ISSN: 1537-6613
    Topics: Medicine
    Published by Oxford University Press on behalf of The Infectious Diseases Society of America (IDSA).
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