Envelope Determinants of Equine Lentiviral Vaccine Protection

Lentiviral envelope (Env) antigenic variation and associated immune evasion present major obstacles to vaccine development. The concept that Env is a critical determinant for vaccine efficacy is well accepted, however defined correlates of protection associated with Env variation have yet to be determined. We reported an attenuated equine infectious anemia virus (EIAV) vaccine study that directly examined the effect of lentiviral Env sequence variation on vaccine efficacy. The study identified a significant, inverse, linear correlation between vaccine efficacy and increasing divergence of the challenge virus Env gp90 protein compared to the vaccine virus gp90. The report demonstrated approximately 100% protection of immunized ponies from disease after challenge by virus with a homologous gp90 (EV0), and roughly 40% protection against challenge by virus (EV13) with a gp90 13% divergent from the vaccine strain. In the current study we examine whether the protection observed when challenging with the EV0 strain could be conferred to animals via chimeric challenge viruses between the EV0 and EV13 strains, allowing for mapping of protection to specific Env sequences. Viruses containing the EV13 proviral backbone and selected domains of the EV0 gp90 were constructed and in vitro and in vivo infectivity examined. Vaccine efficacy studies indicated that homology between the vaccine strain gp90 and the N-terminus of the challenge strain gp90 was capable of inducing immunity that resulted in significantly lower levels of post-challenge virus and significantly delayed the onset of disease. However, a homologous N-terminal region alone inserted in the EV13 backbone could not impart the 100% protection observed with the EV0 strain. Data presented here denote the complicated and potentially contradictory relationship between in vitro virulence and in vivo pathogenicity. The study highlights the importance of structural conformation for immunogens and emphasizes the need for antibody binding, not neutralizing, assays that correlate with vaccine protection. © 2013 Craigo et al

Arduous implementation: Does the Normalisation Process Model explain why it's so difficult to embed decision support technologies for patients in routine clinical practice

Background: decision support technologies (DSTs, also known as decision aids) help patients and professionals take part in collaborative decision-making processes. Trials have shown favorable impacts on patient knowledge, satisfaction, decisional conflict and confidence. However, they have not become routinely embedded in health care settings. Few studies have approached this issue using a theoretical framework. We explained problems of implementing DSTs using the Normalization Process Model, a conceptual model that focuses attention on how complex interventions become routinely embedded in practice.Methods: the Normalization Process Model was used as the basis of conceptual analysis of the outcomes of previous primary research and reviews. Using a virtual working environment we applied the model and its main concepts to examine: the 'workability' of DSTs in professional-patient interactions; how DSTs affect knowledge relations between their users; how DSTs impact on users' skills and performance; and the impact of DSTs on the allocation of organizational resources.Results: conceptual analysis using the Normalization Process Model provided insight on implementation problems for DSTs in routine settings. Current research focuses mainly on the interactional workability of these technologies, but factors related to divisions of labor and health care, and the organizational contexts in which DSTs are used, are poorly described and understood.Conclusion: the model successfully provided a framework for helping to identify factors that promote and inhibit the implementation of DSTs in healthcare and gave us insights into factors influencing the introduction of new technologies into contexts where negotiations are characterized by asymmetries of power and knowledge. Future research and development on the deployment of DSTs needs to take a more holistic approach and give emphasis to the structural conditions and social norms in which these technologies are enacte

DUF2285 is a novel helix-turn-helix domain variant that orchestrates both activation and antiactivation of conjugative element transfer in proteobacteria.

Horizontal gene transfer is tightly regulated in bacteria. Often only a fraction of cells become donors even when regulation of horizontal transfer is coordinated at the cell population level by quorum sensing. Here, we reveal the widespread 'domain of unknown function' DUF2285 represents an 'extended-turn' variant of the helix-turn-helix domain that participates in both transcriptional activation and antiactivation to initiate or inhibit horizontal gene transfer. Transfer of the integrative and conjugative element ICEMlSymR7A is controlled by the DUF2285-containing transcriptional activator FseA. One side of the DUF2285 domain of FseA has a positively charged surface which is required for DNA binding, while the opposite side makes critical interdomain contacts with the N-terminal FseA DUF6499 domain. The QseM protein is an antiactivator of FseA and is composed of a DUF2285 domain with a negative surface charge. While QseM lacks the DUF6499 domain, it can bind the FseA DUF6499 domain and prevent transcriptional activation by FseA. DUF2285-domain proteins are encoded on mobile elements throughout the proteobacteria, suggesting regulation of gene transfer by DUF2285 domains is a widespread phenomenon. These findings provide a striking example of how antagonistic domain paralogues have evolved to provide robust molecular control over the initiation of horizontal gene transfer

Simultaneous endovascular repair of an iatrogenic carotid-jugular fistula and a large iliocaval fistula presenting with multiorgan failure: a case report

<p>Abstract</p> <p>Introduction</p> <p>Iliocaval fistulas can complicate an iliac artery aneurysm. The clinical presentation is classically a triad of hypotension, a pulsatile mass and heart failure. In this instance, following presentation with multiorgan failure, management included the immediate use of an endovascular stent graft on discovery of the fistula.</p> <p>Case presentation</p> <p>A 62-year-old Caucasian man presented to our tertiary hospital for management of iatrogenic trauma due to the insertion of a central venous line into his right common carotid artery, causing transient ischemic attack. Our patient presented to a peripheral hospital with fever, nausea, vomiting, acute renal failure, acute hepatic dysfunction and congestive heart failure. A provisional diagnosis of sepsis of unknown origin was made. There was a 6.5 cm×6.5 cm right iliac artery aneurysm present on a non-contrast computed tomography scan. An unexpected intra-operative diagnosis of an iliocaval fistula was made following the successful angiographic removal of the central line to his right common carotid artery. Closure of the iliocaval fistula and repair of the iliac aneurysm using a three-piece endovascular aortic stent graft was then undertaken as part of the same procedure. This was an unexpected presentation of an iliocaval fistula.</p> <p>Conclusion</p> <p>Our case demonstrates that endovascular repair of a large iliac artery aneurysm associated with a caval fistula is safe and effective and can be performed at the time of the diagnostic angiography. The presentation of an iliocaval fistula in this case was unusual which made the diagnosis difficult and unexpected at the time of surgery. The benefit of immediate repair, despite hemodynamic instability during anesthesia, is clear. Our patient had two coronary angiograms through his right femoral artery decades ago. Unusual iatrogenic causes of iliocaval fistulas secondary to previous coronary angiograms with wire and/or catheter manipulation should be considered in patients such as ours.</p

Psychometric test of the Team Climate Inventory-short version investigated in Dutch quality improvement teams

Abstract BACKGROUND: Although some studies have used the Team Climate Inventory within teams working in health care settings, none of these included quality improvement teams. The aim of our study is to investigate the psychometric properties of the 14-item version of the Team Climate Inventory in healthcare quality improvement teams participating in a Dutch quality collaborative. METHODS: This study included quality improvement teams participating in the Care for Better improvement program for home care, care for the handicapped and the elderly in the Netherlands between 2006 and 2008. As part of a larger evaluation study 270 written questionnaires from team members were collected at baseline and 139 questionnaires at end measurement. Confirmatory factor analyses, reliability, Pearson correlations and paired samples t-tests were conducted to investigate construct validity, reliability, predictive validity and temporal stability. RESULTS: Confirmatory factor analyses revealed the expected four-factor structure and good fit indices. For the four subscales--vision, participative safety, task orientation and support for innovation--acceptable Cronbach's alpha coefficients and high inter-item correlations were found. The four subscales all proved significant predictors of perceived team effectiveness, with participatory safety being the best predictor. As expected the four subscales were found to be stable over time; i.e. without significant changes between baseline and end measurement. CONCLUSION: The psychometric properties of the Dutch version of the TCI-14 are satisfactory. Together these results show that the TCI-14 is a useful instrument to assess to what extent aspects of team climate influence perceived team effectiveness of quality improvement teams

High Level of Pyrethroid Resistance in an Anopheles funestus Population of the Chokwe District in Mozambique

Background Although Anopheles funestus is difficult to rear, it is crucial to analyse field populations of this malaria vector in order to successfully characterise mechanisms of insecticide resistance observed in this species in Africa. In this study we carried out a large-scale field collection and rearing of An. funestus from Mozambique in order to analyse its susceptibility status to insecticides and to broadly characterise the main resistance mechanisms involved in natural populations. Methodology/Principal Findings 3,000 F1 adults were obtained through larval rearing. WHO susceptibility assays indicated a very high resistance to pyrethroids with no mortality recorded after 1h30min exposure and less than 50% mortality at 3h30min. Resistance to the carbamate, bendiocarb was also noted, with 70% mortality after 1h exposure. In contrast, no DDT resistance was observed, indicating that no kdr-type resistance was involved. The sequencing of the acetylcholinesterase gene indicated the absence of the G119S and F455W mutations associated with carbamate and organophosphate resistance. This could explain the absence of malathion resistance in this population. Both biochemical assays and quantitative PCR implicated up-regulated P450 genes in pyrethroid resistance, with GSTs playing a secondary role. The carbamate resistance observed in this population is probably conferred by the observed altered AChE with esterases also involved. Conclusion/Significance The high level of pyrethroid resistance in this population despite the cessation of pyrethroid use for IRS in 1999 is a serious concern for resistance management strategies such as rotational use of insecticides. As DDT has now been re-introduced for IRS, susceptibility to DDT needs to be closely monitored to prevent the appearance and spread of resistance to this insecticide

Windblown Lead Carbonate as the Main Source of Lead in Blood of Children from a Seaside Community: An Example of Local Birds as “Canaries in the Mine”

Background: In late 2006, the seaside community in Esperance, Western Australia, was alerted to thousands of native bird species dying. The source of the lead was thought to derive from the handling of Pb carbonate concentrate from the Magellan mine through the port of Esperance, begun in July 2005. Concern was expressed for the impact of this process on the community. Objective: This study was designed to evaluate the source of Pb in blood of a random sample of the community using Pb isotope ratios. Methods: The cohort comprised 49 children (48 20 years of age) with a bias toward higher blood lead (PbB) values to facilitate source identification. Results: Mean PbB level of the children was 7.5 μg/dL (range, 1.5-25.7 μg/dL; n = 49; geometric mean, 6.6 μg/dL), with four children whose PbB was > 12 μg/dL. The isotopic data for blood samples lay around two distinct arrays. The blood of all children analyzed for Pb isotopes contained a contribution of Pb from the Magellan mine, which for young children ranged from 27% up to 93% (mean, 64%; median, 71%). Subtraction of the ore component gave a mean background PbB of 2.3 μg/dL. Several children whose PbB was > 9 μg/dL and most of the older subjects have complex sources of Pb. Conclusions: The death of the birds acted as a sentinel event; otherwise, the exposure of the community, arising from such a toxic form of Pb, could have been tragic. Isotopic data and mineralogic and particle size analyses indicate that, apart from the recognized pathway of Pb exposure by hand-to-mouth activity in children, the inhalation pathway could have been a significant contributor to PbB for some of the very young children and in some parents.7 page(s

Assessment of the general public's knowledge about rheumatic diseases: evidence from a Portuguese population-based survey

Background. To identify incorrect beliefs and common knowledge about rheumatic diseases in the general population. Methods. Participants were selected during the follow-up of a representative cohort of adult population of Porto, Portugal; 1626 participants completed a questionnaire that included general knowledge items about rheumatic diseases. Discrete and continuous latent variable models were used to identify knowledge flaws and the target groups. Odds ratios (OR) estimated by multinomial logistic regression, and 95% confidence intervals (95%CI) were computed to evaluate magnitude of associations. Results. A continuous latent variable model identified two dimensions: one related to general beliefs (latent 1) and another concerning characteristics, treatment and impact of rheumatic diseases (latent 2). A 3-class latent variable model refined these results: the first class presented the lowest probabilities of correct answer for items associated with the first latent (mean of 39%), and the second class presented the lowest probabilities of correct answer for items with the second latent (mean of 62%). The third class showed the highest probability of a correct answer for almost all the items (mean of 79%). The age and sex standardized prevalence of the classes was 25.7%, 30.8% and 43.5%. Taking class 2 as reference, class 1 was positively associated with the presence of rheumatic diseases (OR = 2.79; CI95% = (2.10-3.70)), with females (OR = 1.28 CI95% = (0.99-1.67)) and older individuals (OR = 1.04; CI95% = (1.03-1.05)), and was negatively associated with education (OR = 0.84; CI95% = (0.81-0.86)); class 3 was positively associated with education (OR = 1.03; CI95% = (1.00-1.05)) and the presence of rheumatic diseases (OR = 1.29; CI95% = (0.97-1.70)). Conclusions. There are several knowledge flaws about rheumatic diseases in the general public. One out of four participants considered false general beliefs as true and approximately 30% did not have detailed knowledge on rheumatic disease. Higher education and the presence of disease contributed positively to the overall knowledge. These results suggest some degree of effectiveness of patient education, either conducted by health professionals or self-driven. © 2010 Severo et al; licensee BioMed Central Ltd

Detection of Gamma-Ray Emission from the Starburst Galaxies M82 and NGC 253 with the Large Area Telescope on Fermi

We report the detection of high-energy gamma-ray emission from two starburst galaxies using data obtained with the Large Area Telescope on board the Fermi Gamma-ray Space Telescope. Steady point-like emission above 200 MeV has been detected at significance levels of 6.8 sigma and 4.8 sigma respectively, from sources positionally coincident with locations of the starburst galaxies M82 and NGC 253. The total fluxes of the sources are consistent with gamma-ray emission originating from the interaction of cosmic rays with local interstellar gas and radiation fields and constitute evidence for a link between massive star formation and gamma-ray emission in star-forming galaxies.Comment: Submitted to ApJ Letter