Effectiveness of measures to eradicate Staphylococcus aureus carriage in patients with community-associated skin and soft-tissue infections: A randomized trial

BACKGROUND: Despite a paucity of evidence, decolonization measures are prescribed for outpatients with recurrent Staphylococcus aureus skin and soft tissue infections (SSTI). OBJECTIVE: Compare the effectiveness of four regimens for eradicating S. aureus carriage. DESIGN: Open-label, randomized controlled trial. Colonization status and recurrent SSTI were ascertained at one and four months. SETTING: Barnes-Jewish and St. Louis Children’s Hospitals, St. Louis, Missouri, 2007–2009. PARTICIPANTS: Three hundred patients with community-onset SSTI and S. aureus colonization in the nares, axilla, or inguinal folds. INTERVENTIONS: Participants were randomized to receive no therapeutic intervention (controls) or perform one of three 5-day regimens: 2% mupirocin ointment applied to the nares twice daily, intranasal mupirocin plus daily 4% chlorhexidine body washes, or intranasal mupirocin plus daily dilute bleach water baths. RESULTS: Among 244 participants with one-month colonization data, modified intention-to-treat analysis revealed S. aureus eradication in 38% of participants in the education only (control) group; 56% in the mupirocin group (p=0.03 vs. controls); 55% in the mupirocin/chlorhexidine group (p=0.05); and 63% in the mupirocin/bleach group (p=0.006). Of 229 participants with four-month colonization data, eradication rates were 48% in controls; 56% for mupirocin only (p=0.40 vs. controls); 54% for mupirocin/chlorhexidine (p=0.51); and 71% for mupirocin/bleach (p=0.02). At one and four months, respectively, recurrent SSTI was reported by 20% and 36% of participants. CONCLUSIONS: An inexpensive regimen of dilute bleach baths, intranasal mupirocin, and hygiene education effectively eradicated S. aureus over four months. High rates of recurrent SSTI suggest factors other than endogenous colonization as important determinants of infection

Gene Expression Profiling of Gliadin Effects on Intestinal Epithelial Cells Suggests Novel Non-Enzymatic Functions of Pepsin and Trypsin

Peer reviewe

IL23R in the Swedish, Finnish, Hungarian and Italian populations: association with IBD and psoriasis, and linkage to celiac disease

Background Association of the interleukin-23 receptor (IL23R) with inflammatory bowel disease (IBD) has been confirmed in several populations. IL23R also associates with psoriasis, suggesting that the gene may be an important candidate for many chronic inflammatory diseases. Methods We studied association of single-nucleotide variants in IL23R with IBD in Swedish patients, in both Crohn's disease (CD) and ulcerative colitis (UC) subsets. The same genetic variants were also studied in Finnish patients with psoriasis or celiac disease, and in Hungarian and Italian patients with celiac disease. Results Association of IL23R with IBD was replicated in our Swedish patients, and linkage and association of the IL23R region with psoriasis was found in the Finnish population. The IL23R region was also linked to celiac disease in Finnish families, but no association of IL23R variants with celiac disease was found in the Finnish, Hungarian or Italian samples. Conclusion Our study is the first to demonstrate association of IL23R with CD and UC in Swedish patients with IBD. It is also the first study to report linkage and association of the IL23R region with psoriasis in the Finnish population. Importantly, this is the first report of linkage of the IL23R region to celiac disease, a chronic inflammatory condition in which IL23R has not been previously implicated.BioMed Central Open acces

Evaluating the causal impact of individual alcohol licensing decisions on local health and crime using natural experiments with synthetic controls.

BACKGROUND AND AIMS: Given the costs of alcohol to society, it is important to evaluate whether local alcohol licensing decisions can mitigate the effects of alcohol misuse. Robust natural experiment evaluations of the impact of individual licensing decisions could potentially inform and improve local decision-making. We aimed to assess whether alcohol licensing decisions could be evaluated at small spatial scale by using a causal inference framework. DESIGN: Three natural experiments. SETTING AND PARTICIPANTS: Three English local areas of 1000-15 000 people each. INTERVENTION AND COMPARATOR: The case study interventions were (i) the closure of a nightclub following reviews; (ii) closure of a restaurant/nightclub following reviews and (iii) implementation of new local licensing guidance (LLG). Trends in outcomes were compared with synthetic counterfactuals created using Bayesian structural time-series. MEASUREMENTS: Time-series data were obtained on emergency department admissions, ambulance call-outs and alcohol-related crime at the Lower or Middle Super Output geographical aggregation level. FINDINGS: Closure of the nightclub led to temporary 4-month reductions in antisocial behaviour (-18%; 95% credible interval - 37%, -4%), with no change in other outcomes. Closure of the restaurant/nightclub did not lead to measurable changes in outcomes. The new licensing guidance led to small reductions in drunk and disorderly behaviour (nine of a predicted 21 events averted), and the unplanned end of the LLG coincided with an increase in domestic violence of two incidents per month. CONCLUSIONS: The impact of local alcohol policy, even at the level of individual premises, can be evaluated using a causal inference framework. Local government actions such as closure or restriction of alcohol venues and alcohol licensing may have a positive impact on health and crime in the immediate surrounding area

Direct molecular mimicry enables off-target cardiovascular toxicity by an enhanced affinity TCR designed for cancer immunotherapy

Natural T-cell responses generally lack the potency to eradicate cancer. Enhanced affinity T-cell receptors (TCRs) provide an ideal approach to target cancer cells, with emerging clinical data showing significant promise. Nevertheless, the risk of off target reactivity remains a key concern, as exemplified in a recent clinical report describing fatal cardiac toxicity, following administration of MAGE-A3 specific TCR-engineered T-cells, mediated through cross-reactivity with an unrelated epitope from the Titin protein presented on cardiac tissue. Here, we investigated the structural mechanism enabling TCR cross-recognition of MAGE-A3 and Titin, and applied the resulting data to rationally design mutants with improved antigen discrimination, providing a proof-of-concept strategy for altering the fine specificity of a TCR towards an intended target antigen. This study represents the first example of direct molecular mimicry leading to clinically relevant fatal toxicity, mediated by a modified enhanced affinity TCR designed for cancer immunotherapy. Furthermore, these data demonstrate that self-antigens that are expressed at high levels on healthy tissue should be treated with extreme caution when designing immuno-therapeutics

Defining the relative performance of isothermal assays that can be used for rapid and sensitive detection of foot-and-mouth disease virus

This study describes the first multiway comparison of portable isothermal assays for the detection of foot-and-mouth disease virus (FMDV), benchmarked against real-time reverse transcription RT-PCR (rRT-PCR). The selected isothermal chemistries included reverse transcription loop-mediated isothermal amplification (RT-LAMP) and reverse transcription recombinase polymerase amplification (RT-RPA). The analytical sensitivity of RT-LAMP was comparable to rRT-PCR (101 RNA copies), while RT-RPA was one log10 less sensitive (102 RNA copies). Diagnostic performance was evaluated using a panel of 35 samples from FMDV-positive cattle and eight samples from cattle infected with other vesicular viruses. Assay concordance for RT-LAMP and RT-RPA was 86?98% and 67?77%, respectively, when compared to rRT-PCR, with discordant samples consistently having high rRT-PCR cycle threshold values (no false-positives were detected for any assay). In addition, a hierarchy of sample preparation methods, from robotic extraction to simple dilution of samples, for epithelial suspensions, serum and oesophageal-pharyngeal (OP) fluid were evaluated. Results obtained for RT-LAMP confirmed that FMDV RNA can be detected in the absence of RNA extraction. However, simple sample preparation methods were less encouraging for RT-RPA, with accurate results only obtained when using RNA extraction. Although the evaluation of assay performance is specific to the conditions tested in this study, the compatibility of RT-LAMP chemistry with multiple sample types, both in the presence and absence of nucleic acid extraction, provides advantages over alternative isothermal chemistries and alternative pen-side diagnostics such as antigen-detection lateral-flow devices. These characteristics of RT-LAMP enable the assay to be performed over a large diagnostic detection window, providing a realistic means to rapidly confirm positive FMD cases close to the point of sampling

Primers used for qRT-PCR.

<p>Primers used for qRT-PCR.</p

Venn diagrams showing the number of probes differentially expressed in response to pepsin- and trypsin-digested gliadin (PT-G) (Figure 1a) compared to medium control (MED-CTL) and the blank pepsin- and trypsin (PT) control.

<p>The probes that were affected by PT treatment compared to MED-CTL are also displayed. <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0066307#pone-0066307-g001" target="_blank">Figure 1b</a> shows the probes affected by PT, PT-G and p31-43 peptide compared to MED-CTL. The numbers in parenthesis represent the number of probes obtained after multiple testing correction as described in materials and methods.</p

Comparison of microarray data with previous studies.

<p>Comparison of microarray data with previous studies.</p