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  • Articles  (2,896)
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  • Medicine  (2,896)
  • 1
    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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    Electronic ISSN: 1537-6613
    Topics: Medicine
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  • 2
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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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  • 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: 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.
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  • 5
    Publication Date: 2018-03-14
    Description: Background The natural history of chronic hepatitis B virus (HBV) infection was divided into 4 phases. Patients in the inactive carrier (IC) status and immune tolerant (IT) phase had normal alanine aminotransferase levels but huge different viral loads. The mechanism underlying low viral replication status in IC phase is unknown. Methods We determined the intrahepatic transcriptomes of 83 chronic hepatitis B patients by microarray analysis of liver biopsies, and screened the effect of differentially regulated genes on HBV replication using specific small interfering RNAs in vitro. Results The gene profile distinguishing active chronic hepatitis from IT and IC was predominantly composed of immune-related genes. The liver transcriptomes between the IT and IC phase were largely similar, and 109 expressed genes were significantly different. By performing systematic screening, 5 candidate genes including EVA1A , which were expressed at a relative higher level in IC phase than IT, were identified to regulate HBV replication and gene expression in cellular models. Conclusions The immune-related pathways were up-regulated in the active chronic hepatitis phase but not in the IT and IC phase. A number of intrahepatic genes highly expressed in the IC phase may participate in the control of HBV replication and determine the inactive status of HBV infection.
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  • 6
    Publication Date: 2018-03-14
    Description: ( See the Major Article by Stepanova et al, on pages 1033–43 .)
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  • 7
    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.
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  • 8
    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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  • 9
    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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  • 10
    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.
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