Filter exchange imaging with crusher gradient modelling detects increased blood–brain barrier water permeability in response to mild lung infection

Blood–brain barrier (BBB) dysfunction occurs in many brain diseases, and there is increasing evidence to suggest that it is an early process in dementia which may be exacerbated by peripheral infection. Filter-exchange imaging (FEXI) is an MRI technique for measuring trans-membrane water exchange. FEXI data is typically analysed using the apparent exchange rate (AXR) model, yielding estimates of the AXR. Crusher gradients are commonly used to remove unwanted coherence pathways arising from longitudinal storage pulses during the mixing period. We first demonstrate that when using thin slices, as is needed for imaging the rodent brain, crusher gradients result in underestimation of the AXR. To address this, we propose an extended crusher-compensated exchange rate (CCXR) model to account for diffusion-weighting introduced by the crusher gradients, which is able to recover ground truth values of BBB water exchange (kin) in simulated data. When applied to the rat brain, kin estimates obtained using the CCXR model were 3.10 s−1 and 3.49 s−1 compared to AXR estimates of 1.24 s−1 and 0.49 s−1 for slice thicknesses of 4.0 mm and 2.5 mm respectively. We then validated our approach using a clinically relevant Streptococcus pneumoniae lung infection. We observed a significant 70 ± 10% increase in BBB water exchange in rats during active infection (kin = 3.78 ± 0.42 s−1) compared to before infection (kin = 2.72 ± 0.30 s−1; p = 0.02). The BBB water exchange rate during infection was associated with higher levels of plasma von Willebrand factor (VWF), a marker of acute vascular inflammation. We also observed 42% higher expression of perivascular aquaporin-4 (AQP4) in infected animals compared to non-infected controls, while levels of tight junction proteins remain consistent between groups. In summary, we propose a modelling approach for FEXI data which removes the bias in estimated water-exchange rates associated with the use of crusher gradients. Using this approach, we demonstrate the impact of peripheral infection on BBB water exchange, which appears to be mediated by endothelial dysfunction and associated with an increase in perivascular AQP4

Securitization and Community-Based Protection Among Chin Refugees in Kuala Lumpur

This article examines refugee-led community organizations among Chin refugees from Myanmar in Kuala Lumpur. It uses a structuration analysis that recognizes refugee-led organizations as complex governance entities engaged in a dynamic relationship with (among others) national policies of securitization of forced migration and international humanitarian governance. This approach expands the existing literature on the securitization of forced migration by exploring refugees’ lived experiences in a context of south–south migration. It expands the literature on community-based protection by going beyond recognizing the existence of refugee-led organizations to analyse their construction, constitution and consequences. Three primary areas of work by Chin refugee groups are analysed in relation to their immediate activity and longer term effects: organization (‘building ethnic unity in adversity’), documentation (‘asserting a bureaucratic identity’) and socialization (‘learning to be illegal’). These long-term effects indicate the possible impact of local protection activities on macrostructural processes such as identity construction and migration choices.construction, constitution and consequences. Three primary areas of work by Chin refugee groups are analysed in relation to their immediate activity and longer term effects: organization (‘building ethnic unity in adversity’), documentation (‘asserting a bureaucratic identity’) and socialization (‘learning to be illegal’). These long-term effects indicate the possible impact of local protection activities on macrostructural processes such as identity construction and migration choices

Conventional versus hypofractionated high-dose intensity-modulated radiotherapy for prostate cancer: 5-year outcomes of the randomised, non-inferiority, phase 3 CHHiP trial

SummaryBackgroundProstate cancer might have high radiation-fraction sensitivity that would give a therapeutic advantage to hypofractionated treatment. We present a pre-planned analysis of the efficacy and side-effects of a randomised trial comparing conventional and hypofractionated radiotherapy after 5 years follow-up.MethodsCHHiP is a randomised, phase 3, non-inferiority trial that recruited men with localised prostate cancer (pT1b–T3aN0M0). Patients were randomly assigned (1:1:1) to conventional (74 Gy delivered in 37 fractions over 7·4 weeks) or one of two hypofractionated schedules (60 Gy in 20 fractions over 4 weeks or 57 Gy in 19 fractions over 3·8 weeks) all delivered with intensity-modulated techniques. Most patients were given radiotherapy with 3–6 months of neoadjuvant and concurrent androgen suppression. Randomisation was by computer-generated random permuted blocks, stratified by National Comprehensive Cancer Network (NCCN) risk group and radiotherapy treatment centre, and treatment allocation was not masked. The primary endpoint was time to biochemical or clinical failure; the critical hazard ratio (HR) for non-inferiority was 1·208. Analysis was by intention to treat. Long-term follow-up continues. The CHHiP trial is registered as an International Standard Randomised Controlled Trial, number ISRCTN97182923.FindingsBetween Oct 18, 2002, and June 17, 2011, 3216 men were enrolled from 71 centres and randomly assigned (74 Gy group, 1065 patients; 60 Gy group, 1074 patients; 57 Gy group, 1077 patients). Median follow-up was 62·4 months (IQR 53·9–77·0). The proportion of patients who were biochemical or clinical failure free at 5 years was 88·3% (95% CI 86·0–90·2) in the 74 Gy group, 90·6% (88·5–92·3) in the 60 Gy group, and 85·9% (83·4–88·0) in the 57 Gy group. 60 Gy was non-inferior to 74 Gy (HR 0·84 [90% CI 0·68–1·03], pNI=0·0018) but non-inferiority could not be claimed for 57 Gy compared with 74 Gy (HR 1·20 [0·99–1·46], pNI=0·48). Long-term side-effects were similar in the hypofractionated groups compared with the conventional group. There were no significant differences in either the proportion or cumulative incidence of side-effects 5 years after treatment using three clinician-reported as well as patient-reported outcome measures. The estimated cumulative 5 year incidence of Radiation Therapy Oncology Group (RTOG) grade 2 or worse bowel and bladder adverse events was 13·7% (111 events) and 9·1% (66 events) in the 74 Gy group, 11·9% (105 events) and 11·7% (88 events) in the 60 Gy group, 11·3% (95 events) and 6·6% (57 events) in the 57 Gy group, respectively. No treatment-related deaths were reported.InterpretationHypofractionated radiotherapy using 60 Gy in 20 fractions is non-inferior to conventional fractionation using 74 Gy in 37 fractions and is recommended as a new standard of care for external-beam radiotherapy of localised prostate cancer.FundingCancer Research UK, Department of Health, and the National Institute for Health Research Cancer Research Network

Antenatal corticosteroids and cardio-metabolic outcomes in adolescents born with very low birth weight

Exposure to antenatal corticosteroids (ANCS) is associated with adverse cardio-metabolic outcomes in animal models; however long-term outcomes in clinical studies are not well characterized. We hypothesized that exposure to ANCS would be associated with markers of increased cardio-metabolic risk in adolescents born with very low birth weight (VLBW)

Providing education on evidence-based practice improved knowledge but did not change behaviour: a before and after study

BACKGROUND: Many health professionals lack the skills to find and appraise published research. This lack of skills and associated knowledge needs to be addressed, and practice habits need to change, for evidence-based practice to occur. The aim of this before and after study was to evaluate the effect of a multifaceted intervention on the knowledge, skills, attitudes and behaviour of allied health professionals. METHODS: 114 self-selected occupational therapists were recruited. The intervention included a 2-day workshop combined with outreach support for eight months. Support involved email and telephone contact and a workplace visit. Measures were collected at baseline, post-workshop, and eight months later. The primary outcome was knowledge, measured using the Adapted Fresno Test of Evidence-Based Practice (total score 0 to 156). Secondary outcomes were attitude to evidence-based practice (% reporting improved skills and confidence; % reporting barriers), and behaviour measured using an activity diary (% engaging/not engaging in search and appraisal activities), and assignment completion. RESULTS: Post-workshop, there were significant gains in knowledge which were maintained at follow-up. The mean difference in the Adapted Fresno Test total score was 20.6 points (95% CI, 15.6 to 25.5). The change from post-workshop to follow-up was small and non-significant (mean difference 1.2 points, 95% CI, -6.0 to 8.5). Fewer participants reported lack of searching and appraisal skills as barriers to evidence-based practice over time (searching = 61%, 53%, 24%; appraisal 60%, 65%, 41%). These differences were statistically significant (p = 0.0001 and 0.010 respectively). Behaviour changed little. Pre-workshop, 6% engaged in critical appraisal increasing to 18% post-workshop and 18% at follow-up. Nearly two thirds (60%) were not reading any research literature at follow-up. Twenty-three participants (20.2%) completed their assignment. CONCLUSION: Evidence-based practice skills and knowledge improved markedly with a targetted education intervention and outreach support. However, changes in behaviour were small, based on the frequency of searching and appraisal activities. Allied health educators should focus more on post-workshop skill development, particularly appraisal, and help learners to establish new routines and priorities around evidence-based practice. Learners also need to know that behaviour change of this nature may take months, even years

Shallow waters: social science research in South Africa's marine environment

This paper provides an overview of social science research in the marine environment of South Africa for the period 1994–2012. A bibliography based on a review of relevant literature and social science projects funded under the SEAChange programme of the South African Network for Coastal and Oceanic Research (SANCOR) was used to identify nine main themes that capture the knowledge generated in the marine social science field. Within these themes, a wide diversity of topics has been explored, covering a wide geographic area. The review suggests that there has been a steady increase in social science research activities and outputs over the past 18 years, with a marked increase in postgraduate dissertations in this field. The SEAChange programme has contributed to enhancing understanding of certain issues and social interactions in the marine environment but this work is limited. Furthermore, there has been limited dissemination of these research results amongst the broader marine science community and incorporation of this information into policy and management decisions has also been limited. However, marine scientists are increasingly recognising the importance of taking a more holistic and integrated approach to management, and are encouraging further social science research, as well as interdisciplinary research across the natural and social sciences. Possible reasons for the lack of communication and coordination amongst natural and social scientists, as well as the limited uptake of research results in policy and management decisions, are discussed and recommendations are proposed.Web of Scienc

Human papillomavirus prevalence, viral load and pre-cancerous lesions of the cervix in women initiating highly active antiretroviral therapy in South Africa: a cross-sectional study

Background Cervical cancer and infection with human immunodeficiency virus (HIV) are both important public health problems in South Africa (SA). The aim of this study was to determine the prevalence of cervical squamous intraepithelial lesions (SILs), high-risk human papillomavirus (HR-HPV), HPV viral load and HPV genotypes in HIV positive women initiating anti-retroviral (ARV) therapy. Methods A cross-sectional survey was conducted at an anti-retroviral (ARV) treatment clinic in Cape Town, SA in 2007. Cervical specimens were taken for cytological analysis and HPV testing. The Digene Hybrid Capture 2 (HC2) test was used to detect HR-HPV. Relative light units (RLU) were used as a measure of HPV viral load. HPV types were determined using the Roche Linear Array HPV Genotyping test. Crude associations with abnormal cytology were tested and multiple logistic regression was used to determine independent risk factors for abnormal cytology. Results The median age of the 109 participants was 31 years, the median CD4 count was 125/mm3, 66.3% had an abnormal Pap smear, the HR-HPV prevalence was 78.9% (Digene), the median HPV viral load was 181.1 RLU (HC2 positive samples only) and 78.4% had multiple genotypes. Among women with abnormal smears the most prevalent HR-HPV types were HPV types 16, 58 and 51, all with a prevalence of 28.5%. On univariate analysis HR-HPV, multiple HPV types and HPV viral load were significantly associated with the presence of low and high-grade SILs (LSIL/HSIL). The multivariate logistic regression showed that HPV viral load was associated with an increased odds of LSIL/HSIL, odds ratio of 10.7 (95% CI 2.0 – 57.7) for those that were HC2 positive and had a viral load of ≤ 181.1 RLU (the median HPV viral load), and 33.8 (95% CI 6.4 – 178.9) for those that were HC2 positive with a HPV viral load > 181.1 RLU. Conclusion Women initiating ARVs have a high prevalence of abnormal Pap smears and HR-HPV. Our results underscore the need for locally relevant, rigorous screening protocols for the increasing numbers of women accessing ARV therapy so that the benefits of ARVs are not partially offset by an excess risk in cervical cancer

Search for new phenomena in final states with an energetic jet and large missing transverse momentum in pp collisions at √ s = 8 TeV with the ATLAS detector

Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses 20.3 fb−1 of √ s = 8 TeV data collected in 2012 with the ATLAS detector at the LHC. Events are required to have at least one jet with pT > 120 GeV and no leptons. Nine signal regions are considered with increasing missing transverse momentum requirements between Emiss T > 150 GeV and Emiss T > 700 GeV. Good agreement is observed between the number of events in data and Standard Model expectations. The results are translated into exclusion limits on models with either large extra spatial dimensions, pair production of weakly interacting dark matter candidates, or production of very light gravitinos in a gauge-mediated supersymmetric model. In addition, limits on the production of an invisibly decaying Higgs-like boson leading to similar topologies in the final state are presente

Search for the neutral Higgs bosons of the minimal supersymmetric standard model in pp collisions at root s=7 TeV with the ATLAS detector

A search for neutral Higgs bosons of the Minimal Supersymmetric Standard Model (MSSM) is reported. The analysis is based on a sample of proton-proton collisions at a centre-of-mass energy of 7TeV recorded with the ATLAS detector at the Large Hadron Collider. The data were recorded in 2011 and correspond to an integrated luminosity of 4.7 fb-1 to 4.8 fb-1. Higgs boson decays into oppositely-charged muon or τ lepton pairs are considered for final states requiring either the presence or absence of b-jets. No statistically significant excess over the expected background is observed and exclusion limits at the 95% confidence level are derived. The exclusion limits are for the production cross-section of a generic neutral Higgs boson, φ, as a function of the Higgs boson mass and for h/A/H production in the MSSM as a function of the parameters mA and tan β in the mhmax scenario for mA in the range of 90GeV to 500 GeV. Copyright CERN