Prevalent Multidrug-resistant Nonvaccine Serotypes in Pneumococcal Carriage of Healthy Korean Children Associated with the Low Coverage of the Seven-valent Pneumococcal Conjugate Vaccine

AbstractObjectivesOur previous longitudinal multicenter-based carriage study showed that the average carriage rate of Streptococcus pneumoniae was 16.8% in 582 healthy children attending kindergarten or elementary school in Seoul, Korea. We assessed serotype-specific prevalence and antimicrobial resistance among colonizing pneumococcal isolates from young children in the era of low use of the seven-valent pneumococcal conjugate vaccine (PCV7).MethodsSerotypes were determined by an agglutination test with specific antisera or by a multiplex polymerase chain reaction (PCR) assay. An antimicrobial susceptibility test was performed with broth microdilution in Korean 96-well panels from Dade-MicroScan (Sacramento, CA, USA).ResultsPneumococcal colonization patterns were dynamic and longterm persistent carriage was rare, which indicated a sequential turnover of pneumococcal strains. Of the 369 pneumococci (except for 23 killed isolates), 129 (34.9%) isolates were PCV7 vaccine serotypes (VTs); 213 (57.8%) isolates were nonvaccine serotypes (NVTs); and the remaining 27 (7.2%) isolates were nontypable (NT). The highest rates of multidrug resistance (MDR) were observed in VTs (86.0%; 111/129 isolates) and NVTs (70.0%; 149/213 isolates).ConclusionThis study overall showed the frequent carriage of VTs and NVTs with MDR in healthy children attending kindergarten or elementary school. Efforts should be directed toward reducing the extensive prescription of antibiotics and using new broader vaccines to reduce the expansion of MDR strains of NVTs in our community

An informed approach to the development of primary care pediatric firearm safety messages

BACKGROUND: Firearm ownership is prevalent in the US and many children spend time in areas where firearms are not stored safely. The AAP recommends firearm safety counseling at pediatric well-visits. METHODS: We developed and tested six contextual messages to promote safe firearm storage based on: absence of harm, collective appeal to understanding child behavior, pediatrician\u27s authority, evidence-based, fear appeal, and general safety considerations. One hundred four parents who keep firearms at home were recruited from Amazon Mechanical Turk Prime and viewed video messages and reported behavioral intentions and emotional reactions following each message. RESULTS: All six contextual messages were perceived as important and believable and increased parents\u27 intentions to follow safety advice provided, but also elicited negative emotions. The authority message elicited more negative emotions and resulted in lower intentions to follow safe storage advice. CONCLUSIONS: Including firearm messages with other child safety advice merits further evaluation. Authority messages should be avoided

WISARD: workbench for integrated superfast association studies for related datasets

Background: A Mendelian transmission produces phenotypic and genetic relatedness between family members, giving family-based analytical methods an important role in genetic epidemiological studies—from heritability estimations to genetic association analyses. With the advance in genotyping technologies, whole-genome sequence data can be utilized for genetic epidemiological studies, and family-based samples may become more useful for detecting de novo mutations. However, genetic analyses employing family-based samples usually suffer from the complexity of the computational/statistical algorithms, and certain types of family designs, such as incorporating data from extended families, have rarely been used. Results: We present a Workbench for Integrated Superfast Association studies for Related Data (WISARD) programmed in C/C++. WISARD enables the fast and a comprehensive analysis of SNP-chip and next-generation sequencing data on extended families, with applications from designing genetic studies to summarizing analysis results. In addition, WISARD can automatically be run in a fully multithreaded manner, and the integration of R software for visualization makes it more accessible to non-experts. Conclusions: Comparison with existing toolsets showed that WISARD is computationally suitable for integrated analysis of related subjects, and demonstrated that WISARD outperforms existing toolsets. WISARD has also been successfully utilized to analyze the large-scale massive sequencing dataset of chronic obstructive pulmonary disease data (COPD), and we identified multiple genes associated with COPD, which demonstrates its practical value. Electronic supplementary material The online version of this article (10.1186/s12920-018-0345-y) contains supplementary material, which is available to authorized users

Evaluating the contribution of rare variants to type 2 diabetes and related traits using pedigrees

Significance Contributions of rare variants to common and complex traits such as type 2 diabetes (T2D) are difficult to measure. This paper describes our results from deep whole-genome analysis of large Mexican-American pedigrees to understand the role of rare-sequence variations in T2D and related traits through enriched allele counts in pedigrees. Our study design was well-powered to detect association of rare variants if rare variants with large effects collectively accounted for large portions of risk variability, but our results did not identify such variants in this sample. We further quantified the contributions of common and rare variants in gene expression profiles and concluded that rare expression quantitative trait loci explain a substantive, but minor, portion of expression heritability.</jats:p

A new strategy for enhancing imputation quality of rare variants from next-generation sequencing data via combining SNP and exome chip data

Background: Rare variants have gathered increasing attention as a possible alternative source of missing heritability. Since next generation sequencing technology is not yet cost-effective for large-scale genomic studies, a widely used alternative approach is imputation. However, the imputation approach may be limited by the low accuracy of the imputed rare variants. To improve imputation accuracy of rare variants, various approaches have been suggested, including increasing the sample size of the reference panel, using sequencing data from study-specific samples (i.e., specific populations), and using local reference panels by genotyping or sequencing a subset of study samples. While these approaches mainly utilize reference panels, imputation accuracy of rare variants can also be increased by using exome chips containing rare variants. The exome chip contains 250 K rare variants selected from the discovered variants of about 12,000 sequenced samples. If exome chip data are available for previously genotyped samples, the combined approach using a genotype panel of merged data, including exome chips and SNP chips, should increase the imputation accuracy of rare variants. Results: In this study, we describe a combined imputation which uses both exome chip and SNP chip data simultaneously as a genotype panel. The effectiveness and performance of the combined approach was demonstrated using a reference panel of 848 samples constructed using exome sequencing data from the T2D-GENES consortium and 5,349 sample genotype panels consisting of an exome chip and SNP chip. As a result, the combined approach increased imputation quality up to 11 %, and genomic coverage for rare variants up to 117.7 % (MAF < 1 %), compared to imputation using the SNP chip alone. Also, we investigated the systematic effect of reference panels on imputation quality using five reference panels and three genotype panels. The best performing approach was the combination of the study specific reference panel and the genotype panel of combined data. Conclusions: Our study demonstrates that combined datasets, including SNP chips and exome chips, enhances both the imputation quality and genomic coverage of rare variants

The Impact of Emotional Words on Listeners’ Emotional and Cognitive Responses in the Context of Advertisements

The study examined how individual words occurring in mediated messages affect listeners’ emotional and cognitive responses. Scripts from actual radio advertisements were altered by replacing original words with target words that varied in valence—either positive, negative, or neutral. The scripts were then reproduced by nonprofessional speakers. Real-time processing of the target words was examined through the use of psychophysiological measures of dynamic emotional and cognitive responses collected from subjects (n = 55) and time-locked to the stimuli. Recognition memory provided a measure of encoding efficiency. As predicted, listeners had greater frown muscle responses following the onset of negatively valenced words compared with positively valenced words. Results also showed that positively valenced words elicited orienting responses in listeners but negatively valenced words did not. Recognition data show that positively valenced words were encoded better than neutrally valenced words, followed by negatively valenced words, which was consistent with the finding for the impact of emotional words on orienting responses

Levels of Fgfrs are altered in the lenses of <i>Dlg10CRE</i> mice.

<p>(A) RIPA, triton soluble (cytosolic) and triton insoluble (cytoskeletal-associated) extracts from P2 control and <i>Dlg10CRE</i> lenses were subjected to western blot analysis for Fgfr1, Fgfr2, and Fgfr3 and the blots reprobed for Gapdh as a loading control. Representative blots are shown. (B) Quantification of protein levels. Shown are the levels of each Fgfr in extracts from <i>Dlg10CRE</i> lenses relative to levels in the control (control levels set at 1.0). Signal intensities were quantified by phosphorimager analysis, as described in Materials and Methods, and the data subjected to statistical analysis using the two-sided One Sample t-test. At least 3 protein pools were analyzed in triplicate over 1–3 blots. The relative levels of Fgfr2 were reduced in the whole cell extract and cytoskeletal associated fraction compared to controls whereas the levels of Fgfr1 were increased as compared to controls. Error bars = standard deviations. * = FDR<0.05, ** = FDR<0.01.</p

Loss of <i>Dlg-1</i> in the Mouse Lens Impairs Fibroblast Growth Factor Receptor Signaling

<div><p>Coordination of cell proliferation, differentiation and survival is essential for normal development and maintenance of tissues in the adult organism. Growth factor receptor tyrosine kinase signaling pathways and planar cell polarity pathways are two regulators of many developmental processes. We have previously shown through analysis of mice conditionally null in the lens for the planar cell polarity gene (PCP), <i>Dlg-1,</i> that <i>Dlg-1</i> is required for fiber differentiation. Herein, we asked if <i>Dlg-1</i> is a regulator of the Fibroblast growth factor receptor (Fgfr) signaling pathway, which is known to be required for fiber cell differentiation. Western blot analysis of whole fiber cell extracts from control and <i>Dlg-1</i> deficient lenses showed that levels of the Fgfr signaling intermediates pErk, pAkt, and pFrs2α, the Fgfr target, Erm, and the fiber cell specific protein, Mip26, were reduced in the <i>Dlg-1</i> deficient fiber cells. The levels of Fgfr2 were decreased in <i>Dlg-1</i> deficient lenses compared to controls. Conversely, levels of Fgfr1 in <i>Dlg-1</i> deficient lenses were increased compared to controls. The changes in Fgfr levels were found to be specifically in the triton insoluble, cytoskeletal associated fraction of <i>Dlg-1</i> deficient lenses. Immunofluorescent staining of lenses from E13.5 embryos showed that expression levels of pErk were reduced in the transition zone, a region of the lens that exhibits PCP, in the <i>Dlg-1</i> deficient lenses as compared to controls. In control lenses, immunofluorescent staining for Fgfr2 was observed in the epithelium, transition zone and fibers. By E13.5, the intensity of staining for Fgfr2 was reduced in these regions of the <i>Dlg-1</i> deficient lenses. Thus, loss of <i>Dlg-1</i> in the lens impairs Fgfr signaling and leads to altered levels of Fgfrs, suggesting that <i>Dlg-1</i> is a modulator of Fgfr signaling pathway at the level of the receptors and that <i>Dlg-1</i> regulates fiber cell differentiation through its role in PCP.</p></div

Levels of Fgfr signaling intermediates are reduced in both <i>Dlg10CRE</i> and <i>Dlg39CRE</i> fiber cells.

<p>(A) RIPA lysates from P2 control, <i>Dlg10CRE</i>, and <i>Dlg39CRE</i> fiber cells were immunoblotted for the pErk and pFrs2α and the blots reprobed for Gapdh as a loading control. Representative blots are shown. (B) Quantification of protein levels. Shown are the levels of the indicated proteins in extracts from <i>Dlg10CRE</i> fiber cells relative to levels in the controls (control levels set at 1.0). Signal intensities were quantified by phosphorimager analysis, as described in Materials and Methods, and the data subjected to statistical analysis using the two-sided One Sample t-test. At least 3 protein pools were blotted in triplicate over 1–3 blots. The relative levels of Fgfr signaling intermediates were reduced in the fiber cells of <i>Dlg39CRE</i> mice as well as <i>Dlg10CRE</i> mice compared to controls, indicating that the effect was fiber cell autonomous. Error bars = standard deviations. ** = FDR<0.01.</p