Optimised chronic infection models demonstrate that siderophore ‘cheating’ in Pseudomonas aeruginosa is context specific

The potential for siderophore mutants of Pseudomonas aeruginosa to attenuate virulence during infection, and the possibility of exploiting this for clinical ends, have attracted much discussion. This has largely been based on the results of in vitro experiments conducted in iron-limited growth medium, in which siderophore mutants act as social ‘cheats:’ increasing in frequency at the expense of the wild type to result in low-productivity, low-virulence populations dominated by mutants. We show that insights from in vitro experiments cannot necessarily be transferred to infection contexts. First, most published experiments use an undefined siderophore mutant. Whole-genome sequencing of this strain revealed a range of mutations affecting phenotypes other than siderophore production. Second, iron-limited medium provides a very different environment from that encountered in chronic infections. We conducted cheating assays using defined siderophore deletion mutants, in conditions designed to model infected fluids and tissue in cystic fibrosis lung infection and non-healing wounds. Depending on the environment, siderophore loss led to cheating, simple fitness defects, or no fitness effect at all. Our results show that it is crucial to develop defined in vitro models in order to predict whether siderophores are social, cheatable and suitable for clinical exploitation in specific infection contexts

Building capacity for evidence informed decision making in public health: a case study of organizational change

<p>Abstract</p> <p>Background</p> <p>Core competencies for public health in Canada require proficiency in evidence informed decision making (EIDM). However, decision makers often lack access to information, many workers lack knowledge and skills to conduct systematic literature reviews, and public health settings typically lack infrastructure to support EIDM activities. This research was conducted to explore and describe critical factors and dynamics in the early implementation of one public health unit's strategic initiative to develop capacity to make EIDM standard practice.</p> <p>Methods</p> <p>This qualitative case study was conducted in one public health unit in Ontario, Canada between 2008 and 2010. In-depth information was gathered from two sets of semi-structured interviews and focus groups (n = 27) with 70 members of the health unit, and through a review of 137 documents. Thematic analysis was used to code the key informant and document data.</p> <p>Results</p> <p>The critical factors and dynamics for building EIDM capacity at an organizational level included: clear vision and strong leadership, workforce and skills development, ability to access research (library services), fiscal investments, acquisition and development of technological resources, a knowledge management strategy, effective communication, a receptive organizational culture, and a focus on change management.</p> <p>Conclusion</p> <p>With leadership, planning, commitment and substantial investments, a public health department has made significant progress, within the first two years of a 10-year initiative, towards achieving its goal of becoming an evidence informed decision making organization.</p

Diagnostic accuracy for the extent and activity of newly diagnosed and relapsed Crohn’s disease: a multicentre prospective comparison of magnetic resonance enterography and small bowel ultrasound –The METRIC Trial

Background Magnetic resonance enterography (MRE) and ultrasound (US) are used to image Crohn’s disease, but comparative accuracy for disease extent and activity is not known with certainty. We undertook a prospective multicentre cohort trial to address this Methods We recruited from 8 UK hospitals. Eligible patients were 16 years or older, newly diagnosed with Crohn’s disease, or had established disease with suspected relapse. Consecutive patients underwent MRE and US in addition to standard investigations. Discrepancy between MRE and US for small bowel (SB) disease presence triggered an additional investigation, if not already available. The primary outcome was difference in per patient sensitivity for SB disease extent (correct identification and segmental localisation) against a construct reference standard (panel diagnosis). Accuracy for SB and colonic disease presence and activity were secondary outcomes. The trial is completed (ISRCTN03982913). Findings 284 patients completed the trial (133 new diagnosis, 151 relapse). MRE sensitivity (n=233) for SB disease extent (80% [95%CI 72 to 86]) and presence (97% [91 to 99]) were significantly greater than US (70% [62 to 78], 92% [84 to 96]); a 10% (1 to 18; p=0.027), and 5% (1 to 9), difference respectively. MRE specificity for SB disease extent (95% [85 to 98]) was significantly greater than US (81% [64 to 91]). Sensitivity for active SB disease was significantly greater for MRE than US (96% [92 to 99] vs. 90% [82 to 95]), difference 6% (2 to 11). Overall, there were no significant accuracy differences for colonic disease presence. Accuracy in newly diagnosed and relapse patients was similar, although US had significantly greater sensitivity for colonic disease than MRE in newly diagnosed patients (67% [49 to 81) vs. 47% [31 to 64]), difference 20% (1 to 39). There were no serious adverse events. Interpretation MRE has higher diagnostic accuracy for the extent and activity of SB Crohn’s disease than US when tested in a prospective multi centre cohort trial setting

Diagnostic accuracy of magnetic resonance enterography and small bowel ultrasound for the extent and activity of newly diagnosed and relapsed Crohn's disease (METRIC): a multicentre trial

Magnetic resonance enterography (MRE) and ultrasound are used to image Crohn's disease, but their comparative accuracy for assessing disease extent and activity is not known with certainty. Therefore, we did a multicentre trial to address this issue. We recruited patients from eight UK hospitals. Eligible patients were 16 years or older, with newly diagnosed Crohn's disease or with established disease and suspected relapse. Consecutive patients had MRE and ultrasound in addition to standard investigations. Discrepancy between MRE and ultrasound for the presence of small bowel disease triggered an additional investigation, if not already available. The primary outcome was difference in per-patient sensitivity for small bowel disease extent (correct identification and segmental localisation) against a construct reference standard (panel diagnosis). This trial is registered with the International Standard Randomised Controlled Trial, number ISRCTN03982913, and has been completed. 284 patients completed the trial (133 in the newly diagnosed group, 151 in the relapse group). Based on the reference standard, 233 (82%) patients had small bowel Crohn's disease. The sensitivity of MRE for small bowel disease extent (80% [95% CI 72-86]) and presence (97% [91-99]) were significantly greater than that of ultrasound (70% [62-78] for disease extent, 92% [84-96] for disease presence); a 10% (95% CI 1-18; p=0·027) difference for extent, and 5% (1-9; p=0·025) difference for presence. The specificity of MRE for small bowel disease extent (95% [85-98]) was significantly greater than that of ultrasound (81% [64-91]); a difference of 14% (1-27; p=0·039). The specificity for small bowel disease presence was 96% (95% CI 86-99) with MRE and 84% (65-94) with ultrasound (difference 12% [0-25]; p=0·054). There were no serious adverse events. Both MRE and ultrasound have high sensitivity for detecting small bowel disease presence and both are valid first-line investigations, and viable alternatives to ileocolonoscopy. However, in a national health service setting, MRE is generally the preferred radiological investigation when available because its sensitivity and specificity exceed ultrasound significantly. National Institute of Health and Research Health Technology Assessment. [Abstract copyright: Copyright © 2018 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.

Caregiving process and caregiver burden: Conceptual models to guide research and practice

BACKGROUND: Parental care for a child with a developmental disability is an enormous responsibility, one that can far exceed that of typical parental care. While most parents adapt well to the situation of caring for a child with a disability, some do not. To understand parents' adaptations to their children's disabilities, the complex nature of stress processes must be accounted for and the constructs and factors that play a role in the caregiving must be considered. DISCUSSION: Evidence suggests that there is considerable variation in how caregivers adapt to their caregiving demands. Many studies have sought to qualify the association between caregiving and health outcomes of the caregivers. Contextual factors such as SES, child factors such as child behaviour problems and severity of disability, intra-psychic factors such as mastery and self-esteem, coping strategies and social supports have all been associated with psychological and/or physical outcome or parents or primary caregivers. In reviewing these issues, the literature appears to be limited by the use of traditional analytic approaches which examine the relationship between a factor and an outcome. It is clear, however, that changes to single factors, as represented in these studies, occur very rarely even in the experimental context. The literature has also been limited by lack of reliance on specific theoretical frameworks. SUMMARY: This conceptual paper documents the state of current knowledge and explores the current theoretical frameworks that have been used to describe the caregiving process from two diverse fields, pediatrics and geriatrics. Integration of these models into one comprehensive model suitable for this population of children with disabilities and their caregivers is proposed. This model may guide future research in this area

The cystic fibrosis microbiome in an ecological perspective and its impact in antibiotic therapy

The recent focus on the cystic fibrosis (CF) complex microbiome has led to the recognition that the microbes can interact between them and with the host immune system, affecting the disease progression and treatment routes. Although the main focus remains on the interactions between traditional pathogens, growing evidence supports the contribution and the role of emergent species. Understanding the mechanisms and the biological effects involved in polymicrobial interactions may be the key to improve effective therapies and also to define new strategies for disease control. This review focuses on the interactions between microbe-microbe and host-microbe, from an ecological point of view, discussing their impact on CF disease progression. There are increasing indications that these interactions impact the success of antimicrobial therapy. Consequently, a new approach where therapy is personalized to patients by taking into account their individual CF microbiome is suggested.Portuguese Foundation for Science and Technology (FCT), the strategic funding of UID/BIO/04469/2013-CEB and UID/EQU/00511/2013-LEPABE units. This study was also supported by FCT and the European Community fund FEDER, through Program COMPETE, under the scope of the Projects “DNA mimics” PIC/IC/82815/2007, RECI/BBB-EBI/0179/2012 (FCOMP-01-0124-FEDER-027462), “BioHealth—Biotechnology and Bioengineering approaches to improve health quality”, Ref. NORTE-07-0124-FEDER-000027 and NORTE-07-0124-FEDER-000025—RL2_ Environment and Health, co-funded by the Programa Operacional Regional do Norte (ON.2 – O Novo Norte), QREN, FEDER. The authors also acknowledge the grant of Susana P. Lopes (SFRH/BPD/95616/2013) and of the COST-Action TD1004: Theragnostics for imaging and therapy

The Airway Microbiota in Cystic Fibrosis: A Complex Fungal and Bacterial Community—Implications for Therapeutic Management

International audienceBackground Given the polymicrobial nature of pulmonary infections in patients with cystic fibrosis (CF), it is essential to enhance our knowledge on the composition of the microbial community to improve patient management. In this study, we developed a pyrosequencing approach to extensively explore the diversity and dynamics of fungal and prokaryotic populations in CF lower airways. Methodology and Principal Findings Fungi and bacteria diversity in eight sputum samples collected from four adult CF patients was investigated using conventional microbiological culturing and high-throughput pyrosequencing approach targeting the ITS2 locus and the 16S rDNA gene. The unveiled microbial community structure was compared to the clinical profile of the CF patients. Pyrosequencing confirmed recently reported bacterial diversity and observed complex fungal communities, in which more than 60% of the species or genera were not detected by cultures. Strikingly, the diversity and species richness of fungal and bacterial communities was significantly lower in patients with decreased lung function and poor clinical status. Values of Chao1 richness estimator were statistically correlated with values of the Shwachman-Kulczycki score, body mass index, forced vital capacity, and forced expiratory volume in 1 s (p = 0.046, 0.047, 0.004, and 0.001, respectively for fungal Chao1 indices, and p = 0.010, 0.047, 0.002, and 0.0003, respectively for bacterial Chao1 values). Phylogenetic analysis showed high molecular diversities at the sub-species level for the main fungal and bacterial taxa identified in the present study. Anaerobes were isolated with Pseudomonas aeruginosa, which was more likely to be observed in association with Candida albicans than with Aspergillus fumigatus

Interleukin-15 promotes intestinal dysbiosis with butyrate deficiency associated with increased susceptibility to colitis

Dysbiosis resulting in gut-microbiome alterations with reduced butyrate production are thought to disrupt intestinal immune homeostasis and promote complex immune disorders. However, whether and how dysbiosis develops before the onset of overt pathology remains poorly defined. Interleukin-15 (IL-15) is upregulated in distressed tissue and its overexpression is thought to predispose susceptible individuals to and have a role in the pathogenesis of celiac disease and inflammatory bowel disease (IBD). Although the immunological roles of IL-15 have been largely studied, its potential impact on the microbiota remains unexplored. Analysis of 16S ribosomal RNA-based inventories of bacterial communities in mice overexpressing IL-15 in the intestinal epithelium (villin-IL-15 transgenic (v-IL-15tg) mice) shows distinct changes in the composition of the intestinal bacteria. Although some alterations are specific to individual intestinal compartments, others are found across the ileum, cecum and feces. In particular, IL-15 overexpression restructures the composition of the microbiota with a decrease in butyrate-producing bacteria that is associated with a reduction in luminal butyrate levels across all intestinal compartments. Fecal microbiota transplant experiments of wild-type and v-IL-15tg microbiota into germ-free mice further indicate that diminishing butyrate concentration observed in the intestinal lumen of v-IL-15tg mice is the result of intrinsic alterations in the microbiota induced by IL-15. This reconfiguration of the microbiota is associated with increased susceptibility to dextran sodium sulfate-induced colitis. Altogether, this study reveals that IL-15 impacts butyrate-producing bacteria and lowers butyrate levels in the absence of overt pathology, which represent events that precede and promote intestinal inflammatory diseases

Uneven Power and the Pursuit of Peace: How Regional Power Transitions Motivate Integration. CES Working Paper, no. 150, 2007

This paper addresses two related puzzles confronting students of regional and international integration: Why do states willingly pool and delegate sovereignty within international institutions? What accounts for the timing and content of regional integration agreements? Most theories of integration suggest that states integrate in order to solve problems of incomplete information and reduce transaction costs and other barriers to economic growth. In contrast I argue that integration can serve to establish a credible commitment that rules out the risk of future conflict among states of unequal power. Specifically, I suggest that integration presents an alternative to preventive war as a means to preclude a rising revisionist power from establishing a regional hegemony. The implication is that it is not countries enjoying stable and peaceful relations that are most likely to pursue integration, but rather countries that find themselves caught in a regional security dilemma, which they hope to break out of by means of institutionalized cooperation. I evaluate this proposition against evidence from two historical cases of regional integration: the German Zollverein and the European Communities