Person: Skurnik, David
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Skurnik
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Skurnik, David
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Publication Covariate selection for association screening in multiphenotype genetic studies(Springer Science and Business Media LLC, 2017-10-16) Aschard, Hugues; Guillemot, Vincent; Vilhjalmsson, Bjarni; Patel, Chirag; Skurnik, David; Ye, Chun J; Wolpin, Brian; Kraft, Phillip; Zaitlen, NoahPublication Randomized Controlled Trial of Parent Therapeutic Education on Antibiotics to Improve Parent Satisfaction and Attitudes in a Pediatric Emergency Department(Public Library of Science, 2013) Angoulvant, François; Rouault, Anne; Prot-Labarthe, Sonia; Boizeau, Priscilla; Skurnik, David; Morin, Laurence; Mercier, Jean-Christophe; Alberti, Corinne; Bourdon, OlivierObjective: To evaluate therapeutic education delivered in a pediatric emergency department to improve parents’ satisfaction and attitudes about judicious antibiotic use. Methods: In an emergency department of a tertiary pediatric hospital, children aged 1 month to 6 years and discharged with an oral antibiotic prescription for an acute respiratory or urinary tract infection were randomized to a patient therapeutic education on antibiotic use (intervention group) or fever control (control group) delivered to the parents (in the presence of the children) by a pharmacist trained in therapeutic education. Education consisted in a 30-minute face-to-face session with four components: educational diagnosis, educational contract, education, and evaluation. The main outcome measure was parent satisfaction about information on antibiotics received at the hospital, as assessed by a telephone interview on day 14. The secondary outcome was attitudes about antibiotic use evaluated on day 14 and at month 6. Results: Of the 300 randomized children, 150 per arm, 259 were evaluated on day 14. Parent satisfaction with information on antibiotics was higher in the intervention group (125/129, 96.9%, versus 108/130, 83.0%; P=0.002, exact Fisher test). Intervention Group parents had higher proportions of correct answers on day 14 to questions on attitudes about judicious antibiotic use than did control-group parents (P=0.017, Mann-Whitney U test). Conclusion: Therapeutic education delivered by a clinical pharmacist in the pediatric emergency department holds promise for improving the use of antibiotics prescribed to pediatric outpatients. Trial Registration ClinicalTrials.gov NCT00948779 http://clinicaltrials.gov/show/NCT00948779Publication A Comprehensive Analysis of In Vitro and In Vivo Genetic Fitness of Pseudomonas aeruginosa Using High-Throughput Sequencing of Transposon Libraries(Public Library of Science, 2013) Skurnik, David; Roux, Damien; Aschard, Hugues; Cattoir, Vincent; Yoder-Himes, Deborah; Lory, Stephen; Pier, GeraldHigh-throughput sequencing of transposon (Tn) libraries created within entire genomes identifies and quantifies the contribution of individual genes and operons to the fitness of organisms in different environments. We used insertion-sequencing (INSeq) to analyze the contribution to fitness of all non-essential genes in the chromosome of Pseudomonas aeruginosa strain PA14 based on a library of ∼300,000 individual Tn insertions. In vitro growth in LB provided a baseline for comparison with the survival of the Tn insertion strains following 6 days of colonization of the murine gastrointestinal tract as well as a comparison with Tn-inserts subsequently able to systemically disseminate to the spleen following induction of neutropenia. Sequencing was performed following DNA extraction from the recovered bacteria, digestion with the MmeI restriction enzyme that hydrolyzes DNA 16 bp away from the end of the Tn insert, and fractionation into oligonucleotides of 1,200–1,500 bp that were prepared for high-throughput sequencing. Changes in frequency of Tn inserts into the P. aeruginosa genome were used to quantify in vivo fitness resulting from loss of a gene. 636 genes had <10 sequencing reads in LB, thus defined as unable to grow in this medium. During in vivo infection there were major losses of strains with Tn inserts in almost all known virulence factors, as well as respiration, energy utilization, ion pumps, nutritional genes and prophages. Many new candidates for virulence factors were also identified. There were consistent changes in the recovery of Tn inserts in genes within most operons and Tn insertions into some genes enhanced in vivo fitness. Strikingly, 90% of the non-essential genes were required for in vivo survival following systemic dissemination during neutropenia. These experiments resulted in the identification of the P. aeruginosa strain PA14 genes necessary for optimal survival in the mucosal and systemic environments of a mammalian host.Publication A Poly-N-Acetylglucosamine−Shiga Toxin Broad-Spectrum Conjugate Vaccine for Shiga Toxin-Producing Escherichia coli(American Society of Microbiology, 2014) Lu, Xi; Skurnik, David; Pozzi, Clarissa; Roux, Damien; Cywes-Bentley, Colette; Ritchie, Jennifer M.; Munera, Diana; Gening, Marina L.; Tsvetkov, Yury E.; Nifantiev, Nikolay E.; Waldor, Matthew K.; Pier, Gerald B.ABSTRACT Many pathogens produce the β-(1−6)-linked poly-N-acetylglucosamine (PNAG) surface polysaccharide that is being developed as a broadly protective antimicrobial vaccine. However, it is unknown whether systemically injected PNAG vaccines or antibodies would provide protective immunity against pathogens confined to the gastrointestinal tract such as Shiga toxin (Stx)-producing Escherichia coli (STEC), an important group of gastrointestinal (GI) pathogens for which effective immunotherapeutics are lacking. To ascertain whether systemic IgG antibody to PNAG impacts this infectious situation, a vaccine consisting of a synthetic nonamer of nonacetylated PNAG, 9GlcNH2, conjugated to the Shiga toxin 1b subunit (9GlcNH2-Stx1b) was produced. Rabbit antibodies raised to the conjugate vaccine were tested for bacterial killing and toxin neutralization in vitro and protection against infection in infant mice. Cell surface PNAG was detected on all 9 STEC isolates tested, representing 6 STEC serogroups, including E. coli O157:H7. Antibody to the 9GlcNH2-Stx1b conjugate neutralized Stx1 potently and Stx2 modestly. For O157:H7 and O104:H4 STEC strains, antibodies elicited by the 9GlcNH2-Stx1b conjugate possessed opsonic killing and bactericidal activity. Following intraperitoneal injection, antibodies to both PNAG and Stx were needed for infant mouse protection against O157 STEC. These antibodies also mediated protection against the Stx2-producing O104:H4 strain that was the cause of a recent outbreak in Germany, although sufficient doses of antibody to PNAG alone were protective against this strain in infant mice. Our observations suggest that vaccination against both PNAG and Stx, using a construct such as the 9GlcNH2-Stx1b conjugate vaccine, would be protective against a broad range of STEC serogroups.Publication Transcriptional Response of Mucoid Pseudomonas aeruginosa to Human Respiratory Mucus(American Society of Microbiology, 2012) Cattoir, V.; Narasimhan, G.; Skurnik, David; Aschard, Hugues; Roux, Damien; Ramphal, R.; Jyot, J.; Lory, StephenAdaptation of bacterial pathogens to a host can lead to the selection and accumulation of specific mutations in their genomes with profound effects on the overall physiology and virulence of the organisms. The opportunistic pathogen Pseudomonas aeruginosa is capable of colonizing the respiratory tract of individuals with cystic fibrosis (CF), where it undergoes evolution to optimize survival as a persistent chronic human colonizer. The transcriptome of a host-adapted, alginate-overproducing isolate from a CF patient was determined following growth of the bacteria in the presence of human respiratory mucus. This stable mucoid strain responded to a number of regulatory inputs from the mucus, resulting in an unexpected repression of alginate production. Mucus in the medium also induced the production of catalases and additional peroxide-detoxifying enzymes and caused reorganization of pathways of energy generation. A specific antibacterial type VI secretion system was also induced in mucus-grown cells. Finally, a group of small regulatory RNAs was identified and a fraction of these were mucus regulated. This report provides a snapshot of responses in a pathogen adapted to a human host through assimilation of regulatory signals from tissues, optimizing its long-term survival potential.Publication Evidence for large-scale gene-by-smoking interaction effects on pulmonary function(Oxford University Press, 2017) Aschard, Hugues; Tobin, Martin D; Hancock, Dana B; Skurnik, David; Sood, Akshay; James, Alan; Vernon Smith, Albert; Manichaikul, Ani W; Campbell, Archie; Prins, Bram P; Hayward, Caroline; Loth, Daan W; Porteous, David J; Strachan, David P; Zeggini, Eleftheria; O’Connor, George T; Brusselle, Guy G; Boezen, H Marike; Schulz, Holger; Deary, Ian J; Hall, Ian P; Rudan, Igor; Kaprio, Jaakko; Wilson, James F; Wilk, Jemma B; Huffman, Jennifer E; Hua Zhao, Jing; de Jong, Kim; Lyytikäinen, Leo-Pekka; Wain, Louise V; Jarvelin, Marjo-Riitta; Kähönen, Mika; Fornage, Myriam; Polasek, Ozren; Cassano, Patricia A; Barr, R Graham; Rawal, Rajesh; Harris, Sarah E; Gharib, Sina A; Enroth, Stefan; Heckbert, Susan R; Lehtimäki, Terho; Gyllensten, Ulf; Jackson, Victoria E; Gudnason, Vilmundur; Tang, Wenbo; Dupuis, Josée; Soler Artigas, María; Joshi, Amit; London, Stephanie J; Kraft, PhillipAbstract Background: Smoking is the strongest environmental risk factor for reduced pulmonary function. The genetic component of various pulmonary traits has also been demonstrated, and at least 26 loci have been reproducibly associated with either FEV1 (forced expiratory volume in 1 second) or FEV1/FVC (FEV1/forced vital capacity). Although the main effects of smoking and genetic loci are well established, the question of potential gene-by-smoking interaction effect remains unanswered. The aim of the present study was to assess, using a genetic risk score approach, whether the effect of these 26 loci on pulmonary function is influenced by smoking. Methods: We evaluated the interaction between smoking exposure, considered as either ever vs never or pack-years, and a 26-single nucleotide polymorphisms (SNPs) genetic risk score in relation to FEV1 or FEV1/FVC in 50 047 participants of European ancestry from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) and SpiroMeta consortia. Results: We identified an interaction (βint = –0.036, 95% confidence interval, –0.040 to –0.032, P = 0.00057) between an unweighted 26 SNP genetic risk score and smoking status (ever/never) on the FEV1/FVC ratio. In interpreting this interaction, we showed that the genetic risk of falling below the FEV1/FVC threshold used to diagnose chronic obstructive pulmonary disease is higher among ever smokers than among never smokers. A replication analysis in two independent datasets, although not statistically significant, showed a similar trend in the interaction effect. Conclusions: This study highlights the benefit of using genetic risk scores for identifying interactions missed when studying individual SNPs and shows, for the first time, that persons with the highest genetic risk for low FEV1/FVC may be more susceptible to the deleterious effects of smoking.