Development of primary invasive pneumococcal disease caused by serotype 1 pneumococci is driven by early increased type I interferon response in the lung

The pneumococcus is the world's foremost respiratory pathogen, but the mechanisms allowing this pathogen to proceed from initial asymptomatic colonization to invasive disease are poorly understood. We have examined the early stages of invasive pneumococcal disease (IPD) by comparing host transcriptional responses to an invasive strain and a noninvasive strain of serotype 1 Streptococcus pneumoniae in the mouse lung. While the two strains were present in equal numbers in the lung 6 h after intranasal challenge, only the invasive strain (strain 1861) had invaded the pleural cavity at that time point; this correlated with subsequent development of bacteremia in mice challenged with strain 1861 but not the noninvasive strain (strain 1). Progression beyond the lung was associated with stronger induction of the type I interferon (IFN-I) response in the lung at 6 h. Suppression of the IFN-I response through administration of neutralizing antibody to IFNAR1 (the receptor for type I interferons) led to significantly reduced invasion of the pleural cavity by strain 1861 at 6 h postchallenge. Our data suggest that strong induction of the IFN-I response is a key factor in early progression of invasive serotype 1 strain 1861 beyond the lung during development of IPD

Overlapping functionality of the Pht proteins in zinc homeostasis of streptococcus pneumoniae

Streptococcus pneumoniae is a globally significant pathogen that causes a range of diseases, including pneumonia, sepsis, meningitis, and otitis media. Its ability to cause disease depends upon the acquisition of nutrients from its environment, including transition metal ions such as zinc. The pneumococcus employs a number of surface proteins to achieve this, among which are four highly similar polyhistidine triad (Pht) proteins. It has previously been established that these proteins collectively aid in the delivery of zinc to the ABC transporter substrate-binding protein AdcAII. Here we have investigated the contribution of each individual Pht protein to pneumococcal zinc homeostasis by analyzing mutant strains expressing only one of the four pht genes. Under conditions of low zinc availability, each of these mutants showed superior growth and zinc accumulation profiles relative to a mutant strain lacking all four genes, indicating that any of the four Pht proteins are able to facilitate delivery of zinc to AdcAII. However, optimal growth and zinc accumulation in vitro and pneumococcal survival and proliferation in vivo required production of all four Pht proteins, indicating that, despite their overlapping functionality, the proteins are not dispensable without incurring a fitness cost. We also show that surface-attached forms of the Pht proteins are required for zinc recruitment and that they do not contribute to defense against extracellular zinc stress

Standards of lithium monitoring in mental health trusts in the UK

Background Lithium is a commonly prescribed drug with a narrow therapeutic index, and recognised adverse effects on the kidneys and thyroid. Clinical guidelines for the management of bipolar affective disorder published by The National Institute for Health and Clinical Excellence (NICE) recommend checks of renal and thyroid function before lithium is prescribed. They further recommend that all patients who are prescribed lithium should have their renal and thyroid function checked every six months, and their serum lithium checked every three months. Adherence to these recommendations has not been subject to national UK audit. Methods The Prescribing Observatory for Mental Health (POMH-UK) invited all National Health Service Mental Health Trusts in the UK to participate in a benchmarking audit of lithium monitoring against recommended standards. Data were collected retrospectively from clinical records and submitted electronically. Results 436 clinical teams from 38 Trusts submitted data for 3,373 patients. In patients recently starting lithium, there was a documented baseline measure of renal or thyroid function in 84% and 82% respectively. For patients prescribed lithium for a year or more, the NICE standards for monitoring lithium serum levels, and renal and thyroid function were met in 30%, 55% and 50% of cases respectively. Conclusions The quality of lithium monitoring in patients who are in contact with mental health services falls short of recognised standards and targets. Findings from this audit, along with reports of harm received by the National Patient Safety Agency, prompted a Patient Safety Alert mandating primary care, mental health and acute Trusts, and laboratory staff to work together to ensure systems are in place to support recommended lithium monitoring by December 2010

How to increase earthquake and home fire preparedness: the fix-it intervention

Published, evaluated community intervention studies concerning natural hazard preparedness are rare. Most lack a rigorous methodology, thereby hampering the development of evidence-based interventions. This paper describes the rationale and methodology of a cross-cultural, longitudinal intervention study on earthquake and home fire preparedness, termed fix-it. The aim is to evaluate whether and how the intervention brings about behaviour change in the targeted communities in two coastal cities with high seismic risk: Seattle, USA and Izmir, Turkey. Participants are adult residents of these cities. The intervention group attends a 6-h workshop, which focuses on securing items in the household. The control group does not attend the workshop. All participants complete baseline and post-intervention, as well as 3- and 12-month follow-up assessments. The primary outcome measure is an observational measure of nine preparedness items for earthquake and fire in participants’ homes. This is evaluated alongside participants’ self-reports concerning their preparedness levels. Secondary outcomes are changes in levels of self-efficacy, perceived outcome, trust, corruption, empowerment, anxiety and social cohesion. Results from the first of the studies, conducted in Seattle in September 2015, indicate that while the fix-it intervention is effective, in the longer term, multi-hazard preparedness is increased by the mere act of going into people’s homes to observe their preparedness levels along with assessing self-reported preparedness and sociopsychological orientation towards natural hazards. This protocol and study aim to augment the empirical literature on natural hazard preparedness, informing national and international policy on delivery of evidence-based community interventions to promote multi-hazard preparedness in households

The first histidine triad motif of phtd is critical for zinc homeostasis in Streptococcus pneumoniae

Streptococcus pneumoniae is the world's foremost human pathogen. Acquisition of the first row transition metal ion zinc is essential for pneumococcal colonization and disease. Zinc is acquired via the ATP-binding cassette transporter AdcCB and two zinc-binding proteins, AdcA and AdcAII. We have previously shown that AdcAII is reliant upon the polyhistidine triad (Pht) proteins to aid in zinc recruitment. Pht proteins generally contain five histidine (His) triad motifs that are believed to facilitate zinc binding and therefore play a significant role in pneumococcal metal ion homeostasis. However, the importance and potential redundancy of these motifs have not been addressed. We examined the effects of mutating each of the five His triad motifs of PhtD. The combination of in vitro growth assays, active zinc uptake, and PhtD expression studies show that the His triad closest to the protein's amino terminus is the most important for zinc acquisition. Intriguingly, in vivo competitive infection studies investigating the amino- and carboxyl-terminal His triad mutants indicate that the motifs have similar importance in colonization. Collectively, our new insights into the contributions of the individual His triad motifs of PhtD, and by extension the other Pht proteins, highlight the crucial role of the first His triad site in zinc acquisition. This study also suggests that the Pht proteins likely play a role beyond zinc acquisition in pneumococcal virulence

Implementation and adoption of nationwide electronic health records in secondary care in England: Final qualitative results from prospective national evaluation in "early adopter" hospitals

This is an open-access article distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits use, distribution, and reproduction in any medium, provided the original work is properly cited, the use is non commercial and is otherwise in compliance with the license. See: http://creativecommons.org/licenses/by-nc/2.0/ and http://creativecommons.org/licenses/by-nc/2.0/legalcode.Objectives: To evaluate the implementation and adoption of the NHS detailed care records service in “early adopter” hospitals in England. Design: Theoretically informed, longitudinal qualitative evaluation based on case studies. Setting: 12 “early adopter” NHS acute hospitals and specialist caresettings studied over two and a half years. Data sources: Data were collected through in depth interviews, observations, and relevant documents relating directly to case study sites and to wider national developments that were perceived to impact on the implementation strategy. Data were thematically analysed, initially within and then across cases. The dataset consisted of 431 semistructured interviews with key stakeholders, including hospital staff, developers, and governmental stakeholders; 590 hours of observations of strategic meetings and use of the software in context; 334 sets of notes from observations, researcher’ field notes, and notes from national conferences; 809 NHS documents; and 58 regional and national documents. Results: Implementation has proceeded more slowly, with a narrower scope and substantially less clinical functionality than was originally planned. The national strategy had considerable local consequences (summarised under five key themes), and wider national developments impacted heavily on implementation and adoption. More specifically, delays related to unrealistic expectations about the capabilities of systems; the time needed to build, configure, and customise the software; the work needed to ensure that systems were supporting provision of care; and the needs of end users for training and support. Other factors hampering progress included the changing milieu of NHS policy and priorities; repeatedly renegotiated national contracts; different stages of development of diverse NHS care records service systems; and a complex communication process between different stakeholders, along with contractual arrangements that largely excluded NHS providers. There was early evidence that deploying systems resulted in important learning within and between organisations and the development of relevant competencies within NHS hospitals. Conclusions: Implementation of the NHS Care Records Service in “early adopter” sites proved time consuming and challenging, with as yet limited discernible benefits for clinicians and no clear advantages for patients. Although our results might not be directly transferable to later adopting sites because the functionalities we evaluated were new and untried in the English context, they shed light on the processes involved in implementing major new systems. The move to increased local decision making that we advocated based on our interim analysis has been pursued and welcomed by the NHS, but it is important that policymakers do not lose sight of the overall goal of an integrated interoperable solution

No triangles on the moduli space of maximally supersymmetric gauge theory

Maximally supersymmetric gauge theory in four dimensions has a remarkably simple S-matrix at the origin of its moduli space at both tree and loop level. This leads to the question what, if any, of this structure survives at the complement of this one point. Here this question is studied in detail at one loop for the branch of the moduli space parameterized by a vacuum expectation value for one complex scalar. Motivated by the parallel D-brane picture of spontaneous symmetry breaking a simple relation is demonstrated between the Lagrangian of broken super Yang-Mills theory and that of its higher dimensional unbroken cousin. Using this relation it is proven both through an on- as well as an off-shell method there are no so-called triangle coefficients in the natural basis of one-loop functions at any finite point of the moduli space for the theory under study. The off-shell method yields in addition absence of rational terms in a class of theories on the Coulomb branch which includes the special case of maximal supersymmetry. The results in this article provide direct field theory evidence for a recently proposed exact dual conformal symmetry motivated by the AdS/CFT correspondence.Comment: 39 pages, 4 figure