The regulation of host defences to infection by the microbiota

The skin and mucosal epithelia of humans and other mammals are permanently colonised by large microbial communities (the microbiota). Due to this life-long association with the microbiota, these microbes have an extensive influence over the physiology of their host organism. It is now becoming apparent that nearly all tissues and organ systems, whether in direct contact with the microbiota, or in deeper host sites, are under microbial influence. The immune system is perhaps the most profoundly affected, with the microbiota programming both its innate and adaptive arms. The regulation of immunity by the microbiota helps protect the host against intestinal and extra-intestinal infection by many classes of pathogen. In this review, we will discuss the experimental evidence supporting a role for the microbiota in regulating host defences to extra-intestinal infection, draw together common mechanistic themes, including the central role of pattern recognition receptors, and outline outstanding questions which need to be answered. This article is protected by copyright. All rights reserved

Overcoming the barriers to walking for children

This paper is an output from the project CAPABLE (Children?s Activities,Perceptions and Behaviour in the Local Environment) being carried out at UCL,jointly between the Centre for Transport Studies, the Department of Psychology, theBartlett School of Planning and the Centre for Advanced Spatial Analysis. The overallaim of the project, which runs from 1 August 2004 to 31 July 2006, is to examine theinteraction between children and the local environment, including identifying howchildren use open space and streets, and why they go to some places but not others.This paper draws on results from questionnaires completed by children about theextent to which they are allowed out unaccompanied by an adult. The surveys werecarried out in four schools, two in Hertfordshire, the area immediately north ofLondon, and two in the London Borough of Lewisham. The purpose is to establish theextent to which the children are allowed by their parents to go out unaccompanied byadults. The issues covered include whether the children go out walking or cyclingwithout an adult, whether they are allowed out alone to visit friends houses, go outafter dark or to cross main roads. The results are considered in terms of the children?sage and gender, and in terms of the households? car ownership level and the strengthof its local social networks. It is found that more of the children in Hertfordshire areallowed out alone, despite the fact that the factors that seem to correlate with beingallowed out unaccompanied are stronger in Lewisham. It is concluded that this maywell be due to environmental factors, real and perceived

Setting Children Free: Children’s Independent Movement in the Local Environment

Parental concerns about children’s safety and security are restricting children’s independent exploration of the local environment. Children are being denied important opportunities to exercise, to acquire decision-making skills, such as crossing the road safely, and to develop social skills through interaction with their peers. This paper presents findings from the project CAPABLE (Children’s Activities, Perceptions And Behaviour in the Local Environment) being carried out at University College London. Based on findings from fieldwork carried out with children aged 8-11 in Cheshunt, Hertfordshire, the paper shows the effect of factors such as the number of adults at home, having an older sibling, having a car or garden at home and living near to a park on the propensity to be allowed out alone. Then it considers how being allowed out alone affects the amount of time children spend outdoors, playing with friends and watching television. The paper then uses data from children who have been fitted with physical activity monitors and GPS (Global Positioning Satellite) monitors and asked to keep diaries, to show how children’s travel behaviour differs when they are with adults from when they are not

Calculating the random guess scores of multiple-response and matching test items

For achievement tests, the guess score is often used as a baseline for the lowest possible grade for score to grade transformations and setting the cut scores. For test item types such as multiple-response, matching and drag-and-drop, determin-ing the guess score requires more elaborate calculations than the more straight-forward calculation of the guess score for True-False and multiple-choice test item formats. For various variants of multiple-response and matching types with respect to dichotomous and polytomous scoring, methods for determining the guess score are presented and illustrated with practical applications. The implica-tions for theory and practice are discussed

Correlates of genetic monogamy in socially monogamous mammals: insights from Azara's owl monkeys

Understanding the evolution of mating systems, a central topic in evolutionary biology for more than 50 years, requires examining the genetic consequences of mating and the relationships between social systems and mating systems. Among pair-living mammals, where genetic monogamy is extremely rare, the extent of extra-group paternity rates has been associated withmale participation in infant care, strength of the pair bond and length of the breeding season. This study evaluated the relationship between two of those factors and the genetic mating system of socially monogamous mammals, testing predictions that male care and strength of pair bond would be negatively correlated with rates of extra-pair paternity (EPP). Autosomal microsatellite analyses provide evidence for genetic monogamy in a pair-living primate with bi-parental care, the Azara’s owl monkey (Aotus azarae). A phylogenetically corrected generalized least square analysis was used to relate male care and strength of the pair bond to their genetic mating system (i.e. proportions of EPP) in 15 socially monogamous mammalian species. The intensity of male care was correlated with EPP rates in mammals, while strength of pair bond failed to reach statistical significance. Our analyses showthat, once social monogamy has evolved, paternal care, and potentially also close bonds, may facilitate the evolution of genetic monogamy.German Science Foundation (HU 1746/2-1); Wenner-Gren Foundation; L.S.B. Leakey Foundation;National Geographic Society; National Science Foundation (BCS-0621020, 1219368, and 1232349); the University of Pennsylvania Research Foundation; the Zoological Society of San Dieg

Signs of deterioration in infants discharged home following congenital heart surgery in the first year of life: a qualitative study

AIMS: To describe the ways in which parents recognise and make decisions about their child's symptoms following discharge home after congenital heart interventions in the first year of life and their experiences of seeking help. METHODS: This was a qualitative study involving semistructured interviews with parents. Twenty-one parents were recruited to the study. Parents all had a child who had congenital heart surgery in their first year of life between September 2009 and October 2013 at one of three UK cardiac centres; the children had either died or were readmitted as an emergency following initial discharge. RESULTS: Some parents were unable to identify any early warning signs. Others described symptoms of deterioration including changes in feeding and appearance, respiratory distress and subtle behavioural changes that may not be routinely highlighted to parents at discharge. Several barriers to accessing prompt medical assistance were identified including parents feeling that their concerns were not taken seriously, long wait times and lack of protocols at A&E. CONCLUSIONS: Our study highlights behavioural symptoms as being a potentially underemphasised sign of deterioration and identifies a number of barriers to parents accessing support when they are concerned. It is important that parents are encouraged to seek advice at the earliest opportunity and that those health professionals at the front line have access to the information they need in order to respond in an appropriate and timely way. A role for home monitoring was also noted as potentially useful in identifying at risk children who appear clinically well

Composite nature of fresh skin revealed during compression

Biological systems are subjected to moderate-to-high strain rates in blast-type traumatic injuries. An improved understanding of the responses of cells and tissues to extreme mechanical stresses could improve mitigation and post-injury treatment strategies. A key aim of this research is to create biologically meaningful injury models of soft tissues. Here the authors examine the material and cellular properties of freshly harvested porcine skin in compression. The data presented suggest that fresh skin differentially responds low to moderate strain rates as a composite rather than that of a homogeneous polymer. The implications of this work are discussed in terms of creating improved analytical models to describe the material properties of fresh skin. The Centre for Blast Injury Studies acknowledges The Royal British Legion for its support, as well as Imperial College London. The Institute of Shock Physics acknowledges the support of the Atomic Weapon Establishment, Aldermaston, UK and Imperial College London.This is the accepted manuscript. The final version is available at http://www.icevirtuallibrary.com/content/article/10.1680/bbn.14.00028

Solar cycle variation in solar f-mode frequencies and radius

Using data from the Global Oscillation Network Group (GONG) covering the period from 1995 to 1998, we study the change with solar activity in solar f-mode frequencies. The results are compared with similar changes detected from the Michelson Doppler Imager (MDI) data. We find variations in f-mode frequencies which are correlated with solar activity indices. If these changes are due to variation in solar radius then the implications are that the solar radius decreases by about 5 km from minimum to maximum activity.Comment: To appear in Solar Physic

Carotid artery stenting compared with endarterectomy in patients with symptomatic carotid stenosis (International Carotid Stenting Study): a randomised controlled trial with cost-effectiveness analysis

BACKGROUND: Carotid artery stenting (CAS) is an alternative to carotid endarterectomy (CEA) for the treatment of carotid stenosis, but safety and long-term efficacy were uncertain. OBJECTIVE: To compare the risks, benefits and cost-effectiveness of CAS versus CEA for symptomatic carotid stenosis. DESIGN: International, multicentre, randomised controlled, open, prospective clinical trial. SETTING: Hospitals at 50 centres worldwide. PARTICIPANTS: Patients older than 40 years of age with symptomatic atheromatous carotid artery stenosis. INTERVENTIONS: Patients were randomly allocated stenting or endarterectomy using a computerised service and followed for up to 10 years. MAIN OUTCOME MEASURES: The primary outcome measure was the long-term rate of fatal or disabling stroke, analysed by intention to treat (ITT). Disability was assessed using the modified Rankin Scale (mRS). A cost–utility analysis estimating mean costs and quality-adjusted life-years (QALYs) was calculated over a 5-year time horizon. RESULTS: A total of 1713 patients were randomised but three withdrew consent immediately, leaving 1710 for ITT analysis (853 were assigned to stenting and 857 were assigned to endarterectomy). The incidence of stroke, death or procedural myocardial infarction (MI) within 120 days of treatment was 8.5% in the CAS group versus 5.2% in the CEA group (72 vs. 44 events) [hazard ratio (HR) 1.69, 95% confidence interval (CI) 1.16 to 2.45; p = 0.006]. In the analysis restricted to patients who completed stenting, age independently predicted the risk of stroke, death or MI within 30 days of CAS (relative risk increase 1.17% per 5 years of age, 95% CI 1.01% to 1.37%). Use of an open-cell stent conferred higher risk than a closed-cell stent (relative risk 1.92, 95% CI 1.11 to 3.33), but use of a cerebral protection device did not modify the risk. CAS was associated with a higher risk of stroke in patients with an age-related white-matter changes score of 7 or more (HR 2.98, 95% CI 1.29 to 6.93; p = 0.011). After completion of follow-up with a median of 4.2 years, the number of patients with fatal or disabling stroke in the CAS and CEA groups (52 vs. 49), and the cumulative 5-year risk did not differ significantly (6.4% vs. 6.5%) (HR 1.06, 95% CI 0.72 to 1.57; p = 0.776). Stroke of any severity was more frequent in the CAS group (15.2% vs. 9.4% in the CEA group) (HR 1.712, 95% CI 1.280 to 2.300; p < 0.001). There was no significant difference in long-term rates of severe carotid restenosis or occlusion (10.8% in the CAS group vs. 8.6% in the CEA group) (HR 1.25, 95% CI 0.89 to 1.75; p = 0.20). There was no difference in the distribution of mRS scores at 1-year, 5-year or final follow-up. There were no differences in costs or QALYs between the treatments. LIMITATIONS: Patients and investigators were not blinded to treatment allocation. Interventionists’ experience of stenting was less than that of surgeons with endarterectomy. Data on costs of managing strokes were not collected. CONCLUSIONS: The functional outcome after stenting is similar to endarterectomy, but stenting is associated with a small increase in the risk of non-disabling stroke. The choice between stenting and endarterectomy should take into account the procedural risks related to individual patient characteristics. Future studies should include measurement of cognitive function, assessment of carotid plaque morphology and identification of clinical characteristics that determine benefit from revascularisation

Semiparametric Multivariate Accelerated Failure Time Model with Generalized Estimating Equations

The semiparametric accelerated failure time model is not as widely used as the Cox relative risk model mainly due to computational difficulties. Recent developments in least squares estimation and induced smoothing estimating equations provide promising tools to make the accelerate failure time models more attractive in practice. For semiparametric multivariate accelerated failure time models, we propose a generalized estimating equation approach to account for the multivariate dependence through working correlation structures. The marginal error distributions can be either identical as in sequential event settings or different as in parallel event settings. Some regression coefficients can be shared across margins as needed. The initial estimator is a rank-based estimator with Gehan's weight, but obtained from an induced smoothing approach with computation ease. The resulting estimator is consistent and asymptotically normal, with a variance estimated through a multiplier resampling method. In a simulation study, our estimator was up to three times as efficient as the initial estimator, especially with stronger multivariate dependence and heavier censoring percentage. Two real examples demonstrate the utility of the proposed method