Why sensitive bacteria are resistant to hospital infection control.

Background: Large reductions in the incidence of antibiotic-resistant strains of Staphylococcus aureus and Clostridium difficile have been observed in response to multifaceted hospital-based interventions. Reductions in antibiotic-sensitive strains have been smaller or non-existent. It has been argued that since infection control measures, such as hand hygiene, should affect resistant and sensitive strains equally, observed changes must have largely resulted from other factors, including changes in antibiotic use. We used a mathematical model to test the validity of this reasoning. Methods: We developed a mechanistic model of resistant and sensitive strains in a hospital and its catchment area. We assumed the resistant strain had a competitive advantage in the hospital and the sensitive strain an advantage in the community. We simulated a hospital hand hygiene intervention that directly affected resistant and sensitive strains equally. The annual incidence rate ratio ( IRR) associated with the intervention was calculated for hospital- and community-acquired infections of both strains. Results: For the resistant strain, there were large reductions in hospital-acquired infections (0.1 ≤ IRR ≤ 0.6) and smaller reductions in community-acquired infections (0.2 ≤ IRR ≤  0.9). These reductions increased in line with increasing importance of nosocomial transmission of the strain. For the sensitive strain, reductions in hospital acquisitions were much smaller (0.6 ≤ IRR ≤ 0.9), while communityacquisitions could increase or decrease (0.9 ≤ IRR ≤ 1.2). The greater the importance of the community environment for the transmission of the sensitive strain, the smaller the reductions. Conclusions: Counter-intuitively, infection control interventions, including hand hygiene, can have strikingly discordant effects on resistant and sensitive strains even though they target them equally, following differences in their adaptation to hospital and community-based transmission. Observed lack of effectiveness of control measures for sensitive strains does not provide evidence that infection control interventions have been ineffective in reducing resistant strains

Self-Gravitating Strings In 2+1 Dimensions

We present a family of classical spacetimes in 2+1 dimensions. Such a spacetime is produced by a Nambu-Goto self-gravitating string. Due to the special properties of three-dimensional gravity, the metric is completely described as a Minkowski space with two identified worldsheets. In the flat limit, the standard string is recovered. The formalism is developed for an open string with massive endpoints, but applies to other boundary conditions as well. We consider another limit, where the string tension vanishes in geometrical units but the end-masses produce finite deficit angles. In this limit, our open string reduces to the free-masses solution of Gott, which possesses closed timelike curves when the relative motion of the two masses is sufficiently rapid. We discuss the possible causal structures of our spacetimes in other regimes. It is shown that the induced worldsheet Liouville mode obeys ({\it classically}) a differential equation, similar to the Liouville equation and reducing to it in the flat limit. A quadratic action formulation of this system is presented. The possibility and significance of quantizing the self-gravitating string, is discussed.Comment: 55 page

High gene expression of inflammatory markers and IL-17A correlates with severity of injection site reactions of Atlantic salmon vaccinated with oil-adjuvanted vaccines

<p>Abstract</p> <p>Background</p> <p>Two decades after the introduction of oil-based vaccines in the control of bacterial and viral diseases in farmed salmonids, the mechanisms of induced side effects manifested as intra-abdominal granulomas remain unresolved. Side effects have been associated with generation of auto-antibodies and autoimmunity but the underlying profile of inflammatory and immune response has not been characterized. This study was undertaken with the aim to elucidate the inflammatory and immune mechanisms of granuloma formation at gene expression level associated with high and low side effect (granuloma) indices.</p> <p>Groups of Atlantic salmon parr were injected intraperitoneally with oil-adjuvanted vaccines containing either high or low concentrations of <it>Aeromonas salmonicida </it>or <it>Moritella viscosa </it>antigens in order to induce polarized (severe and mild) granulomatous reactions. The established granulomatous reactions were confirmed by gross and histological methods at 3 months post vaccination when responses were known to have matured. The corresponding gene expression patterns in the head kidneys were profiled using salmonid cDNA microarrays followed by validation by real-time quantitative PCR (qPCR). qPCR was also used to examine the expression of additional genes known to be important in the adaptive immune response.</p> <p>Results</p> <p>Granulomatous lesions were observed in all vaccinated fish. The presence of severe granulomas was associated with a profile of up-regulation of innate immunity-related genes such as complement factors C1q and C6, mannose binding protein, lysozyme C, C-type lectin receptor, CD209, Cathepsin D, CD63, LECT-2, CC chemokine and metallothionein. In addition, TGF-β (p = 0.001), IL-17A (p = 0.007) and its receptor (IL-17AR) (p = 0.009) representing T_H17 were significantly up-regulated in the group with severe granulomas as were arginase and IgM. None of the genes directly reflective of T_H1 T cell lineage (IFN-γ, CD4) or T_H2 (GATA-3) responses were differentially expressed.</p> <p>Conclusions</p> <p>Granulomatous reactions following vaccination with oil-based vaccines in Atlantic salmon have the profile of strong expression of genes related to innate immune responses. The expression of TGF-β, IL-17A and its receptor suggests an involvement of T_H17 T cell lineage and is in conformity with strong infiltration of neutrophils and macrophages into inflamed areas. Arginase upregulation shows that macrophages in these reactions are alternatively activated, indicating also a T_H2-profile. To what extent the expression of IL-17A and its receptor reflects an autoimmune vaccine-based reaction remains elusive but would be in conformity with previous observations of autoimmune reactions in salmon when vaccinated with oil-based vaccines.</p

Addition-Deletion Networks

We study structural properties of growing networks where both addition and deletion of nodes are possible. Our model network evolves via two independent processes. With rate r, a node is added to the system and this node links to a randomly selected existing node. With rate 1, a randomly selected node is deleted, and its parent node inherits the links of its immediate descendants. We show that the in-component size distribution decays algebraically, c_k ~ k^{-beta}, as k-->infty. The exponent beta=2+1/(r-1) varies continuously with the addition rate r. Structural properties of the network including the height distribution, the diameter of the network, the average distance between two nodes, and the fraction of dangling nodes are also obtained analytically. Interestingly, the deletion process leads to a giant hub, a single node with a macroscopic degree whereas all other nodes have a microscopic degree.Comment: 8 pages, 5 figure

Concepts of mental disorders in the United Kingdom : Similarities and differences between the lay public and psychiatrists

BACKGROUND: The lay public often conceptualise mental disorders in a different way to mental health professionals, and this can negatively impact on outcomes when in treatment. AIMS: This study explored which disorders the lay public are familiar with, which theoretical models they understand, which they endorse and how they compared to a sample of psychiatrists. METHODS: The Maudsley Attitude Questionnaire (MAQ), typically used to assess mental health professional's concepts of mental disorders, was adapted for use by a lay community sample (N = 160). The results were compared with a sample of psychiatrists (N = 76). RESULTS: The MAQ appeared to be accessible to the lay public, providing some interesting preliminary findings: in order, the lay sample reported having the best understanding of depression followed by generalised anxiety, schizophrenia and finally antisocial personality disorder. They best understood spiritualist, nihilist and social realist theoretical models of these disorders, but were most likely to endorse biological, behavioural and cognitive models. The lay public were significantly more likely to endorse some models for certain disorders suggesting a nuanced understanding of the cause and likely cure, of various disorders. Ratings often differed significantly from the sample of psychiatrists who were relatively steadfast in their endorsement of the biological model. CONCLUSION: The adapted MAQ appeared accessible to the lay sample. Results suggest that the lay public are generally aligned with evidence-driven concepts of common disorders, but may not always understand or agree with how mental health professionals conceptualise them. The possible causes of these differences, future avenues for research and the implications for more collaborative, patient-clinician conceptualisations are discussed.Peer reviewedFinal Accepted Versio

Post-assembly Modification of Tetrazine-Edged Fe(II)4L6 Tetrahedra.

Post-assembly modification (PAM) is a powerful tool for the modular functionalization of self-assembled structures. We report a new family of tetrazine-edged Fe(II)4L6 tetrahedral cages, prepared using different aniline subcomponents, which undergo rapid and efficient PAM by inverse electron-demand Diels-Alder (IEDDA) reactions. Remarkably, the electron-donating or -withdrawing ability of the para-substituent on the aniline moiety influences the IEDDA reactivity of the tetrazine ring 11 bonds away. This effect manifests as a linear free energy relationship, quantified using the Hammett equation, between σ(para) and the rate of the IEDDA reaction. The rate of PAM can thus be adjusted by varying the aniline subcomponent.This work was supported by the UK Engineering and Physical Sciences Research Council (EPSRC). The au-thors thank Diamond Light Source (UK) for synchro-tron beamtime on I19 (MT8464), the Department of Chemistry NMR facility, University of Cambridge, and the EPSRC UK National Mass Spectrometry Facility at Swansea University. D.A.R. acknowledges the Gates Cambridge Trust for Ph.D. funding. B.S.P. acknowledges the Herchel Smith Research Fellowship from the University of Cambridge and the Fellowship from Corpus Christi College, Cambridge.This is the final version of the article. It first appeared from the American Chemical Society via http://dx.doi.org/10.1021/jacs.5b0508

Structural and functional determination of homologs of the Mycobacterium tuberculosis N-acetylglucosamine-6-phosphate deacetylase (NagA)

The (Mtb) pathogen encodes an -acetylglucosamine-6-phosphate deacetylase enzyme, NagA (Rv3332), that belongs to the amidohydrolase superfamily. NagA enzymes catalyze the deacetylation of -acetylglucosamine-6-phosphate (GlcNAc6P) to glucosamine-6-phosphate (GlcN6P). NagA is a potential anti-tubercular drug target because it represents the key enzymatic step in the generation of essential amino-sugar precursors required for cell wall biosynthesis and also influences recycling of cell wall peptidoglycan fragments. Here, we report the structural and functional characterization of NagA from (MSNagA) and (MMNagA), close relatives of Using a combination of X-ray crystallography, site-directed mutagenesis, and biochemical and biophysical assays, we show that these mycobacterial NagA enzymes are selective for GlcNAc6P. Site-directed mutagenesis studies revealed crucial roles of conserved residues in the active site that underpin stereo-selective recognition, binding, and catalysis of substrates. Moreover, we report the crystal structure of MSNagA in both ligand-free form and in complex with the GlcNAc6P substrate at 2.6 Å and 2.0 Å resolutions, respectively. The GlcNAc6P-complex structure disclosed the precise mode of GlcNAc6P binding and the structural framework of the active site, including two divalent metals located in the α/β binuclear site. Furthermore, we observed a cysteine residue located on a flexible loop region that occludes the active site. This cysteine is unique to mycobacteria and may represent a unique subsite for targeting mycobacterial NagA enzymes. Our results provide critical insights into the structural and mechanistic properties of mycobacterial NagA enzymes having an essential role in amino-sugar and nucleotide metabolism in mycobacteria

First Passage Properties of the Erdos-Renyi Random Graph

We study the mean time for a random walk to traverse between two arbitrary sites of the Erdos-Renyi random graph. We develop an effective medium approximation that predicts that the mean first-passage time between pairs of nodes, as well as all moments of this first-passage time, are insensitive to the fraction p of occupied links. This prediction qualitatively agrees with numerical simulations away from the percolation threshold. Near the percolation threshold, the statistically meaningful quantity is the mean transit rate, namely, the inverse of the first-passage time. This rate varies non-monotonically with p near the percolation transition. Much of this behavior can be understood by simple heuristic arguments.Comment: 10 pages, 9 figures, 2-column revtex4 forma

Low intensity shockwave treatment modulates macrophage functions beneficial to healing chronic wounds

Acknowledgments: We acknowledge the University of Aberdeen Microscopy and Histology Facility and the qPCR facility for use of facilities and advice. We acknowledge Ehab Husain for scoring the patient wound biopsies. Funding: This research was funded by NHS Grampian Endowments, grant number 17/004 and by personal funding from JSH.Peer reviewedPublisher PD