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  • 1
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    Oxford University Press
    Publication Date: 2018-03-14
    Description: “Safety of single dose primaquine in G6PD-deficient and G6PD-normal males in Mali without malaria: an open- label, phase 1, dose-adjustment trial” by Chen et al. [J Infect Dis 2018; doi: 10.1093/infdis/jiy014 ]. This is an Open Access article and should have contained the following copyright line: © The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America. This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0/ ), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
    Print ISSN: 0022-1899
    Electronic ISSN: 1537-6613
    Topics: Medicine
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  • 2
    Publication Date: 2018-03-14
    Description: Background Respiratory syncytial virus (RSV) is a leading cause of respiratory infections. An RSV-A genotype (ON1) that contains a 72-nt duplication was reported in 2012 and has since extended worldwide. Methods We analyzed 345 respiratory samples obtained between 2003 and 2014 to assess the relevance of ON1 infections. Nucleotidic and deduced amino acid sequences from viruses detected in San Luis Potosí and sequences previously reported were analyzed. Results RSV ON1 was detected in 105 samples. The earliest case of ON1 infection was detected in November 2009, almost 1 year prior to detection of this virus in Canada. Amino acid sequence analysis of the duplication region showed the presence of Y273N and L274P substitutions in RSV GA2 viruses that, when combined, resulted in 4 different GXXSPSQ sequence motifs at positions 272–278. Three of these motifs were present in both the original and duplicated regions of ON1 strains. Additional signature amino acid substitutions were observed in ON1 strains that have the different sequence motifs. Conclusions ON1 strains include viruses that appear to be the result of at least 3 independent duplication events. Molecular data of strains from diverse geographical regions should help define the frequency and implications of this evolution mechanism.
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  • 3
    Publication Date: 2018-03-14
    Description: Background The kinetics of the antibody response during severe influenza are not well documented. Methods Critically ill patients infected with 2009 pandemic influenza A(H1N1) virus (A[H1N1]pdm09), confirmed by reverse-transcription polymerase chain reaction analysis or seroconversion (defined as a ≥4-fold rise in titers), during 2009–2011 in Canada were prospectively studied. Antibody titers in serially collected sera were determined using hemagglutinin inhibition (HAI) and microneutralization assays. Average antibody curves were estimated using linear mixed-effects models and compared by patient outcome, age, and corticosteroid treatment. Results Of 47 patients with A(H1N1)pdm09 virus infection (median age, 47 years), 59% had baseline HAI titers of 〈40, and 68% had baseline neutralizing titers of 〈40. Antibody titers rose quickly after symptom onset, and, by day 14, 83% of patients had HAI titers of ≥40, and 80% had neutralizing titers ≥40. Baseline HAI titers were significantly higher in patients who died compared with patients who survived; however, the antibody kinetics were similar by patient outcome and corticosteroid treatment. Geometric mean titers over time in older patients were lower than those in younger patients. Conclusions Critically ill patients with influenza A(H1N1)pdm09 virus infection had strong HAI and neutralizing antibody responses during their illness. Antibody kinetics differed by age but were not associated with patient outcome.
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  • 4
    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.
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  • 5
    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.
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  • 6
    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.
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  • 7
    Publication Date: 2018-03-14
    Description: HIV associated neurocognitive disorderHANDHIV antibodiesCSFHIV cure
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  • 8
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    Oxford University Press
    Publication Date: 2018-03-14
    Description: To the Editor —With great interest, I read the article by McLaren et al that described the impact of functional genetic variation on the control of human immunodeficiency virus type 1 (HIV-1) replication. Although this investigation used large data sets and sophisticated analytical tools, it might be premature to conclude that non-HLA “exonic variants with large effect sizes are unlikely to have a major contribution to host control of HIV infection” [ 1 ]. In fact, a comprehensive analysis of the role of humoral immunity in HIV-1 control by Lai et al concluded that the “presence or absence of protective HLA alleles is not associated with strikingly divergent antibody responses” [ 2 ] among HIV-1 controllers.
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  • 9
    Publication Date: 2018-03-14
    Description: Background Despite effective antiretroviral therapy (ART), human immunodeficiency virus (HIV) likely persists in the central nervous system (CNS) in treated individuals. We examined anti-HIV antibodies in cerebrospinal fluid (CSF) and blood as markers of persistence. Methods Human immunodeficiency virus antibodies were measured in paired CSF and serum before and after long-term treatment of chronic (n = 10) and early infection (n = 12), along with untreated early infection (n = 10). Results Treatment of chronic infection resulted in small reductions of anti-HIV antibodies in CSF and serum despite 〉10 years of suppressive ART. In untreated early infection, anti-HIV antibodies emerged in blood by day 30, whereas CSF antibodies reached similar levels 2 weeks later. Compared with long-term treatment of chronic infection, early ART initiation reduced CSF antibodies by 43-fold ( P 〉 .0001) and blood antibodies by 7-fold ( P = .0003). Two individuals receiving pre-exposure prophylaxis and then ART early after infection failed to develop antibodies in CSF or blood, whereas CSF antibodies were markedly reduced in the Berlin patient. Conclusions To the extent that differential CSF and blood antibodies indicate HIV persistence, these data suggest a relative delay in establishment of the CNS compared with the systemic HIV reservoir that provides an opportunity for early treatment to have a greater impact on the magnitude of long-term CNS infection.
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  • 10
    Publication Date: 2018-03-14
    Description: To determine rates of both symptomatic and asymptomatic infection among ambulatory adults, we collected nasopharyngeal swab specimens, demographic characteristics, and survey information from 1477 adult visitors to a New York City tourist attraction during April–July 2016. Multiplex polymerase chain reaction analysis was used to identify specimens positive for common respiratory viruses. A total of 7.2% of samples tested positive for respiratory viruses; among positive samples, 71.0% contained rhinovirus, and 21.5% contained coronavirus. Influenza virus, respiratory syncytial virus, and parainfluenza virus were also detected. Depending on symptomatologic definition, 57.7%–93.3% of positive samples were asymptomatic. These findings indicate that significant levels of asymptomatic respiratory viral shedding exist during summer among the ambulatory adult population.
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