A host type I interferon response is induced by cytosolic sensing of the bacterial second messenger cyclic-di-GMP

The innate immune system responds to unique molecular signatures that are widely conserved among microbes but that are not normally present in host cells. Compounds that stimulate innate immune pathways may be valuable in the design of novel adjuvants, vaccines, and other immunotherapeutics. The cyclic dinucleotide cyclic-di–guanosine monophosphate (c-di-GMP) is a recently appreciated second messenger that plays critical regulatory roles in many species of bacteria but is not produced by eukaryotic cells. In vivo and in vitro studies have previously suggested that c-di-GMP is a potent immunostimulatory compound recognized by mouse and human cells. We provide evidence that c-di-GMP is sensed in the cytosol of mammalian cells via a novel immunosurveillance pathway. The potency of cytosolic signaling induced by c-di-GMP is comparable to that induced by cytosolic delivery of DNA, and both nucleic acids induce a similar transcriptional profile, including triggering of type I interferons and coregulated genes via induction of TBK1, IRF3, nuclear factor κB, and MAP kinases. However, the cytosolic pathway that senses c-di-GMP appears to be distinct from all known nucleic acid–sensing pathways. Our results suggest a novel mechanism by which host cells can induce an inflammatory response to a widely produced bacterial ligand

Identification of Host Cytosolic Sensors and Bacterial Factors Regulating the Type I Interferon Response to Legionella pneumophila

Legionella pneumophila is a gram-negative bacterial pathogen that replicates in host macrophages and causes a severe pneumonia called Legionnaires' Disease. The innate immune response to L. pneumophila remains poorly understood. Here we focused on identifying host and bacterial factors involved in the production of type I interferons (IFN) in response to L. pneumophila. It was previously suggested that the delivery of L. pneumophila DNA to the host cell cytosol is the primary signal that induces the type I IFN response. However, our data are not easily reconciled with this model. We provide genetic evidence that two RNA-sensing proteins, RIG-I and MDA5, participate in the IFN response to L. pneumophila. Importantly, these sensors do not seem to be required for the IFN response to L. pneumophila DNA, whereas we found that RIG-I was required for the response to L. pneumophila RNA. Thus, we hypothesize that bacterial RNA, or perhaps an induced host RNA, is the primary stimulus inducing the IFN response to L. pneumophila. Our study also identified a secreted effector protein, SdhA, as a key suppressor of the IFN response to L. pneumophila. Although viral suppressors of cytosolic RNA-sensing pathways have been previously identified, analogous bacterial factors have not been described. Thus, our results provide new insights into the molecular mechanisms by which an intracellular bacterial pathogen activates and also represses innate immune responses

Serendipitous discovery of a dying Giant Radio Galaxy associated with NGC 1534, using the Murchison Widefield Array

This article has been accepted for publication in Monthly Notices of the Royal Astronomical Society. © 2015 The Authors. Published by Oxford University Press on behalf of the Royal Astronomical Society.Recent observations with the Murchison Widefield Array at 185~MHz have serendipitously unveiled a heretofore unknown giant and relatively nearby ($z = 0.0178$) radio galaxy associated with NGC\,1534. The diffuse emission presented here is the first indication that NGC\,1534 is one of a rare class of objects (along with NGC\,5128 and NGC\,612) in which a galaxy with a prominent dust lane hosts radio emission on scales of $\sim$700\,kpc. We present details of the radio emission along with a detailed comparison with other radio galaxies with disks. NGC1534 is the lowest surface brightness radio galaxy known with an estimated scaled 1.4-GHz surface brightness of just 0.2\,mJy\,arcmin$^{-2}$. The radio lobes have one of the steepest spectral indices yet observed: $\alpha=-2.1\pm0.1$, and the core to lobe luminosity ratio is $Peer reviewe

Study of redshifted H I from the epoch of reionization with drift scan

The detection of the Epoch of Reionization (EoR) in the redshifted 21-cm line is a challenging task. Here we formulate the detection of the EoR signal using the drift scan strategy. This method potentially has better instrumental stability as compared to the case where a single patch of sky is tracked. We demonstrate that the correlation time between measured visibilities could extend up to 1-2 hr for an interferometer array such as the Murchison Widefield Array (MWA), which has a wide primary beam. We estimate the EoR power based on cross-correlation of visibilities across time and show that the drift scan strategy is capable of the detection of the EoR signal with comparable/better signal-to-noise as compared to the tracking case. We also estimate the visibility correlation for a set of bright point sources and argue that the statistical inhomogeneity of bright point sources might allow their separation from the EoR signal

The prevention and reduction of weight loss in an acute tertiary care setting: Protocol for a pragmatic stepped wedge randomised cluster trial (the PRoWL Project)

Background: Malnutrition, with accompanying weight loss, is an unnecessary risk in hospitalised persons and often remains poorly recognised and managed. The study aims to evaluate a hospital-wide multifaceted intervention co-facilitated by clinical nurses and dietitians addressing the nutritional care of patients, particularly those at risk of malnutrition. Using the best available evidence on reducing and preventing unplanned weight loss, the intervention (introducing universal nutritional screening; the provision of oral nutritional supplements; and providing red trays and additional support for patients in need of feeding) will be introduced by local ward teams in a phased way in a large tertiary acute care hospital. Methods/Design: A pragmatic stepped wedge randomised cluster trial with repeated cross section design will be conducted. The unit of randomisation is the ward, with allocation by a random numbers table. Four groups of wards (n = 6 for three groups, n = 7 for one group) will be randomly allocated to each intervention time point over the trial. Two trained local facilitators (a nurse and dietitian for each group) will introduce the intervention. The primary outcome measure is change in patient’s body weight, secondary patient outcomes are: length of stay, all-cause mortality, discharge destinations, readmission rates and ED presentations. Patient outcomes will be measured on one ward per group, with 20 patients measured per ward per time period by an unblinded researcher. Including baseline, measurements will be conducted at five time periods. Staff perspectives on the context of care will be measured with the Alberta Context Tool. Discussion: Unplanned and unwanted weight loss in hospital is common. Despite the evidence and growing concern about hospital nutrition there are very few evaluations of system-wide nutritional implementation programs. This project will test the implementation of a nutritional intervention across one hospital system using a staged approach, which will allow sequential rolling out of facilitation and project support. This project is one of the first evidence implementation projects to use the stepped wedge design in acute care and we will therefore be testing the appropriateness of the stepped wedge design to evaluate such interventions.Alison L Kitson, Timothy J Schultz, Leslye Long, Alison Shanks, Rick Wiechula, Ian Chapman and Stijn Soene

A systematic review of mental disorder, suicide, and deliberate self harm in lesbian, gay and bisexual people

Background: Lesbian, gay and bisexual (LGB) people may be at higher risk of mental disorders than heterosexual people.Method: We conducted a systematic review and meta-analysis of the prevalence of mental disorder, substance misuse, suicide, suicidal ideation and deliberate self harm in LGB people. We searched Medline, Embase, PsycInfo, Cinahl, the Cochrane Library Database, the Web of Knowledge, the Applied Social Sciences Index and Abstracts, the International Bibliography of the Social Sciences, Sociological Abstracts, the Campbell Collaboration and grey literature databases for articles published January 1966 to April 2005. We also used Google and Google Scholar and contacted authors where necessary. We searched all terms related to homosexual, lesbian and bisexual people and all terms related to mental disorders, suicide, and deliberate self harm. We included papers on population based studies which contained concurrent heterosexual comparison groups and valid definition of sexual orientation and mental health outcomes.Results: Of 13706 papers identified, 476 were initially selected and 28 (25 studies) met inclusion criteria. Only one study met all our four quality criteria and seven met three of these criteria. Data was extracted on 214,344 heterosexual and 11,971 non heterosexual people. Meta-analyses revealed a two fold excess in suicide attempts in lesbian, gay and bisexual people [ pooled risk ratio for lifetime risk 2.47 (CI 1.87, 3.28)]. The risk for depression and anxiety disorders (over a period of 12 months or a lifetime) on meta-analyses were at least 1.5 times higher in lesbian, gay and bisexual people (RR range 1.54-2.58) and alcohol and other substance dependence over 12 months was also 1.5 times higher (RR range 1.51-4.00). Results were similar in both sexes but meta analyses revealed that lesbian and bisexual women were particularly at risk of substance dependence (alcohol 12 months: RR 4.00, CI 2.85, 5.61; drug dependence: RR 3.50, CI 1.87, 6.53; any substance use disorder RR 3.42, CI 1.97-5.92), while lifetime prevalence of suicide attempt was especially high in gay and bisexual men (RR 4.28, CI 2.32, 7.88).Conclusion: LGB people are at higher risk of mental disorder, suicidal ideation, substance misuse, and deliberate self harm than heterosexual people

The complex genetics of gait speed:Genome-wide meta-analysis approach

Emerging evidence suggests that the basis for variation in late-life mobility is attributable, in part, to genetic factors, which may become increasingly important with age. Our objective was to systematically assess the contribution of genetic variation to gait speed in older individuals. We conducted a meta-analysis of gait speed GWASs in 31,478 older adults from 17 cohorts of the CHARGE consortium, and validated our results in 2,588 older adults from 4 independent studies. We followed our initial discoveries with network and eQTL analysis of candidate signals in tissues. The meta-analysis resulted in a list of 536 suggestive genome wide significant SNPs in or near 69 genes. Further interrogation with Pathway Analysis placed gait speed as a polygenic complex trait in five major networks. Subsequent eQTL analysis revealed several SNPs significantly associated with the expression of PRSS16, WDSUB1 and PTPRT, which in addition to the meta-analysis and pathway suggested that genetic effects on gait speed may occur through synaptic function and neuronal development pathways. No genome-wide significant signals for gait speed were identified from this moderately large sample of older adults, suggesting that more refined physical function phenotypes will be needed to identify the genetic basis of gait speed in aging

The Murchison Widefield Array: The Square Kilometre Array Precursor at Low Radio Frequencies

The Murchison Widefield Array (MWA) is one of three Square Kilometre Array Precursor telescopes and is located at the Murchison Radio-astronomy Observatory in the Murchison Shire of the mid-west of Western Australia, a location chosen for its extremely low levels of radio frequency interference. The MWA operates at low radio frequencies, 80–300 MHz, with a processed bandwidth of 30.72 MHz for both linear polarisations, and consists of 128 aperture arrays (known as tiles) distributed over a ~3-km diameter area. Novel hybrid hardware/software correlation and a real-time imaging and calibration systems comprise the MWA signal processing backend. In this paper, the as-built MWA is described both at a system and sub-system level, the expected performance of the array is presented, and the science goals of the instrument are summarised

IMPRoving Outcomes for children exposed to domestic ViolencE (IMPROVE): an evidence synthesis

BackgroundExposure to domestic violence and abuse (DVA) during childhood and adolescence increases the risk of negative outcomes across the lifespan.ObjectivesTo synthesise evidence on the clinical effectiveness, cost-effectiveness and acceptability of interventions for children exposed to DVA, with the aim of making recommendations for further research.Design(1) A systematic review of controlled trials of interventions; (2) a systematic review of qualitative studies of participant and professional experience of interventions; (3) a network meta-analysis (NMA) of controlled trials and cost-effectiveness analysis; (4) an overview of current UK provision of interventions; and (5) consultations with young people, parents, service providers and commissioners.SettingsNorth America (11), the Netherlands (1) and Israel (1) for the systematic review of controlled trials of interventions; the USA (4) and the UK (1) for the systematic review of qualitative studies of participant and professional experience of interventions; and the UK for the overview of current UK provision of interventions and consultations with young people, parents, service providers and commissioners.ParticipantsA total of 1345 children for the systematic review of controlled trials of interventions; 100 children, 202 parents and 39 professionals for the systematic review of qualitative studies of participant and professional experience of interventions; and 16 young people, six parents and 20 service providers and commissioners for the consultation with young people, parents, service providers and commissioners.InterventionsPsychotherapeutic, advocacy, parenting skills and advocacy, psychoeducation, psychoeducation and advocacy, guided self-help.Main outcome measuresInternalising symptoms and externalising behaviour, mood, depression symptoms and diagnosis, post-traumatic stress disorder symptoms and self-esteem for the systematic review of controlled trials of interventions and NMA; views about and experience of interventions for the systematic review of qualitative studies of participant and professional experience of interventions and consultations.Data sourcesMEDLINE, Cumulative Index to Nursing and Allied Health Literature, PsycINFO, EMBASE, Cochrane Central Register of Controlled Trials, Science Citation Index, Applied Social Sciences Index and Abstracts, International Bibliography of the Social Sciences, Social Services Abstracts, Social Care Online, Sociological Abstracts, Social Science Citation Index, World Health Organization trials portal and clinicaltrials.gov.Review methodsA narrative review; a NMA and incremental cost-effectiveness analysis; and a qualitative synthesis.ResultsThe evidence base on targeted interventions was small, with limited settings and types of interventions; children were mostly &lt; 14 years of age, and there was an absence of comparative studies. The interventions evaluated in trials were mostly psychotherapeutic and psychoeducational interventions delivered to the non-abusive parent and child, usually based on the child’s exposure to DVA (not specific clinical or broader social needs). Qualitative studies largely focused on psychoeducational interventions, some of which included the abusive parent. The evidence for clinical effectiveness was as follows: 11 trials reported improvements in behavioural or mental health outcomes, with modest effect sizes but significant heterogeneity and high or unclear risk of bias. Psychoeducational group-based interventions delivered to the child were found to be more effective for improving mental health outcomes than other types of intervention. Interventions delivered to (non-abusive) parents and to children were most likely to be effective for improving behavioural outcomes. However, there is a large degree of uncertainty around comparisons, particularly with regard to mental health outcomes. In terms of evidence of cost-effectiveness, there were no economic studies of interventions. Cost-effectiveness was modelled on the basis of the NMA, estimating differences between types of interventions. The outcomes measured in trials were largely confined to children’s mental health and behavioural symptoms and disorders, although stakeholders’ concepts of success were broader, suggesting that a broader range of outcomes should be measured in trials. Group-based psychoeducational interventions delivered to children and non-abusive parents in parallel were largely acceptable to all stakeholders. There is limited evidence for the acceptability of other types of intervention. In terms of the UK evidence base and service delivery landscape, there were no UK-based trials, few qualitative studies and little widespread service evaluation. Most programmes are group-based psychoeducational interventions. However, the funding crisis in the DVA sector is significantly undermining programme delivery.ConclusionsThe evidence base regarding the acceptability, clinical effectiveness and cost-effectiveness of interventions to improve outcomes for children exposed to DVA is underdeveloped. There is an urgent need for more high-quality studies, particularly trials, that are designed to produce actionable, generalisable findings that can be implemented in real-world settings and that can inform decisions about which interventions to commission and scale. We suggest that there is a need to pause the development of new interventions and to focus on the systematic evaluation of existing programmes. With regard to the UK, we have identified three types of programme that could be justifiably prioritised for further study: psycho-education delivered to mothers and children, or children alone; parent skills training in combination with advocacy: and interventions involving the abusive parent/caregiver. We also suggest that there is need for key stakeholders to come together to explicitly identify and address the structural, practical and cultural barriers that may have hampered the development of the UK evidence base to date.Future work recommendationsThere is a need for well-designed, well-conducted and well-reported UK-based randomised controlled trials with cost-effectiveness analyses and nested qualitative studies. Development of consensus in the field about core outcome data sets is required. There is a need for further exploration of the acceptability and effectiveness of interventions for specific groups of children and young people (i.e. based on ethnicity, age, trauma exposure and clinical profile). There is also a need for an investigation of the context in which interventions are delivered, including organisational setting and the broader community context, and the evaluation of qualities, qualifications and disciplines of personnel delivering interventions. We recommend prioritisation of psychoeducational interventions and parent skills training delivered in combination with advocacy in the next phase of trials, and exploratory trials of interventions that engage both the abusive and the non-abusive parent.Study registrationThis study is registered as PROSPERO CRD42013004348 and PROSPERO CRD420130043489.FundingThe National Institute for Health Research Public Health Research programme.</jats:sec

Cerebral small vessel disease genomics and its implications across the lifespan

White matter hyperintensities (WMH) are the most common brain-imaging feature of cerebral small vessel disease (SVD), hypertension being the main known risk factor. Here, we identify 27 genome-wide loci for WMH-volume in a cohort of 50,970 older individuals, accounting for modification/confounding by hypertension. Aggregated WMH risk variants were associated with altered white matter integrity (p = 2.5×10-7) in brain images from 1,738 young healthy adults, providing insight into the lifetime impact of SVD genetic risk. Mendelian randomization suggested causal association of increasing WMH-volume with stroke, Alzheimer-type dementia, and of increasing blood pressure (BP) with larger WMH-volume, notably also in persons without clinical hypertension. Transcriptome-wide colocalization analyses showed association of WMH-volume with expression of 39 genes, of which four encode known drug targets. Finally, we provide insight into BP-independent biological pathways underlying SVD and suggest potential for genetic stratification of high-risk individuals and for genetically-informed prioritization of drug targets for prevention trials.Peer reviewe