Supernatants derived from chemotherapy-treated cancer cell lines can modify angiogenesis

BACKGROUND: There is evidence that tumours produce substances such as cytokines and microvesicular bodies bearing bioactive molecules, which support the carcinogenic process. Furthermore, chemotherapy has also been shown to modify these exudates and in doing so, neutralise their tumourigenic influence. METHODS: In the current study, we have investigated the effect of chemotherapy agents on modifying the cytokine profile and microvesicular cargo of supernatants derived from cancer cell lines. In addition, we have explored the effect of these tumour-derived supernatants on angiogenesis, and how chemotherapy can alter the supernatants rendering them less pro-angiogenic. RESULTS: Herein, we show that supernatants contain a rich cocktail of cytokines, a number of which are potent modulators of angiogenesis. They also contain microvesicular bodies containing RNA transcripts that code for proteins involved in transcription, immune modulation and angiogenesis. These supernatants altered intracellular signalling molecules in endothelial cells and significantly enhanced their tubulogenic character; however, this was severely compromised when supernatants from tumours treated with chemotherapy was used instead. CONCLUSION: This study suggests tumour exudates and bioactive material from tumours can influence cellular functions, and that treatment with some chemotherapy can serve to negate these pro-tumourigenic processes

Minimizing gravitational lensing contributions to the primordial bispectrum covariance

The next generation of ground-based cosmic microwave background (CMB) experiments aim to measure temperature and polarization fluctuations up to ℓmax≈5000 over half of the sky. Combined with Planck data on large scales, this will provide improved constraints on primordial non-Gaussianity. However, the impressive resolution of these experiments will come at a price. Besides signal confusion from galactic foregrounds, extragalactic foregrounds, and late-time gravitational effects, gravitational lensing will introduce large non-Gaussianity that can become the leading contribution to the bispectrum covariance through the connected four-point function. Here, we compute this effect analytically for the first time on the full sky for both temperature and polarization. We compare our analytical results with those obtained directly from map-based simulations of the CMB sky for several levels of instrumental noise. Of the standard shapes considered in the literature, the local shape is most affected, resulting in a 35% increase of the estimator standard deviation for an experiment such as the Simons Observatory (SO) and a 110% increase for a cosmic-variance limited experiment, including both temperature and polarization modes up to ℓmax=3800. Because of the nature of the lensing four-point function, the impact on other shapes is reduced while still non-negligible for the orthogonal shape. Two possible avenues to reduce the non-Gaussian contribution to the covariance are proposed: First by marginalizing over lensing contributions, such as the Integrated Sachs Wolfe (ISW)-lensing three-point function in temperature, and second by delensing the CMB. We show the latter method can remove almost all extra covariance, reducing the effect to below <5% for local bispectra. At the same time, delensing would remove signal biases from secondaries induced by lensing, such as ISW lensing. We aim to apply both techniques directly to the forthcoming SO data when searching for primordial non-Gaussianity

The Effectiveness of Alcohol Screening and Brief Intervention in Emergency Departments: A Multicentre Pragmatic Cluster Randomized Controlled Trial

BACKGROUND: Alcohol misuse is common in people attending emergency departments (EDs) and there is some evidence of efficacy of alcohol screening and brief interventions (SBI). This study investigated the effectiveness of SBI approaches of different intensities delivered by ED staff in nine typical EDs in England: the SIPS ED trial. METHODS AND FINDINGS: Pragmatic multicentre cluster randomized controlled trial of SBI for hazardous and harmful drinkers presenting to ED. Nine EDs were randomized to three conditions: a patient information leaflet (PIL), 5 minutes of brief advice (BA), and referral to an alcohol health worker who provided 20 minutes of brief lifestyle counseling (BLC). The primary outcome measure was the Alcohol Use Disorders Identification Test (AUDIT) status at 6 months. Of 5899 patients aged 18 or more presenting to EDs, 3737 (63·3%) were eligible to participate and 1497 (40·1%) screened positive for hazardous or harmful drinking, of whom 1204 (80·4%) gave consent to participate in the trial. Follow up rates were 72% (n?=?863) at six, and 67% (n?=?810) at 12 months. There was no evidence of any differences between intervention conditions for AUDIT status or any other outcome measures at months 6 or 12 in an intention to treat analysis. At month 6, compared to the PIL group, the odds ratio of being AUDIT negative for brief advice was 1·103 (95% CI 0·328 to 3·715). The odds ratio comparing BLC to PIL was 1·247 (95% CI 0·315 to 4·939). A per protocol analysis confirmed these findings. CONCLUSIONS: SBI is difficult to implement in typical EDs. The results do not support widespread implementation of alcohol SBI in ED beyond screening followed by simple clinical feedback and alcohol information, which is likely to be easier and less expensive to implement than more complex interventions

Pharmaceutical care for elderly patients shared between community pharmacists and general practitioners: A randomised evaluation. RESPECT (Randomised Evaluation of Shared Prescribing for Elderly people in the Community over Time) [ISRCTN16932128]

Background: This trial aims to investigate the effectiveness and cost implications of 'pharmaceutical care' provided by community pharmacists to elderly patients in the community. As the UK government has proposed that by 2004 pharmaceutical care services should extend nationwide, this provides an opportunity to evaluate the effect of pharmaceutical care for the elderly. Design: The trial design is a randomised multiple interrupted time series. We aim to recruit 700 patients from about 20 general practices, each associated with about three community pharmacies, from each of the five Primary Care Trusts in North and East Yorkshire. We shall randomise the five resulting groups of practices, pharmacies and patients to begin pharmaceutical care in five successive phases. All five will act as controls until they receive the intervention in a random sequence. Until they receive training community pharmacists will provide their usual dispensing services and so act as controls. The community pharmacists and general practitioners will receive training in pharmaceutical care for the elderly. Once trained, community pharmacists will meet recruited patients, either in their pharmacies (in a consultation room or dispensary to preserve confidentiality) or at home. They will identify drug-related issues/problems, and design a pharmaceutical care plan in conjunction with both the GP and the patient. They will implement, monitor, and update this plan monthly. The primary outcome measure is the 'Medication Appropriateness Index'. Secondary measures include adverse events, quality of life, and patient knowledge and compliance. We shall also investigate the cost of pharmaceutical care to the NHS, to patients and to society as a whole.published_or_final_versio

Apolipoprotein E O-glycosylation is associated with amyloid plaques and APOE genotype

Although the APOE ε4 allele is the strongest genetic risk factor for sporadic Alzheimer\u27s disease (AD), the relationship between apolipoprotein (apoE) and AD pathophysiology is not yet fully understood. Relatively little is known about the apoE protein species, including post-translational modifications, that exist in the human periphery and CNS. To better understand these apoE species, we developed a LC-MS/MS assay that simultaneously quantifies both unmodified and O-glycosylated apoE peptides. The study cohort included 47 older individuals (age 75.6 ± 5.7 years [mean ± standard deviation]), including 23 individuals (49%) with cognitive impairment. Paired plasma and cerebrospinal fluid samples underwent analysis. We quantified O-glycosylation of two apoE protein residues - one in the hinge region and one in the C-terminal region - and found that glycosylation occupancy of the hinge region in the plasma was significantly correlated with plasma total apoE levels, APOE genotype and amyloid status as determined by CSF Aβ42/Aβ40. A model with plasma glycosylation occupancy, plasma total apoE concentration, and APOE genotype distinguished amyloid status with an AUROC of 0.89. These results suggest that plasma apoE glycosylation levels could be a marker of brain amyloidosis, and that apoE glycosylation may play a role in the pathophysiology of AD

AESOPS: a randomised controlled trial of the clinical effectiveness and cost-effectiveness of opportunistic screening and stepped care interventions for older hazardous alcohol users in primary care

BACKGROUND: There is clear evidence of the detrimental impact of hazardous alcohol consumption on the physical and mental health of the population. Estimates suggest that hazardous alcohol consumption annually accounts for 150,000 hospital admissions and between 15,000 and 22,000 deaths in the UK. In the older population, hazardous alcohol consumption is associated with a wide range of physical, psychological and social problems. There is evidence of an association between increased alcohol consumption and increased risk of coronary heart disease, hypertension and haemorrhagic and ischaemic stroke, increased rates of alcohol-related liver disease and increased risk of a range of cancers. Alcohol is identified as one of the three main risk factors for falls. Excessive alcohol consumption in older age can also contribute to the onset of dementia and other age-related cognitive deficits and is implicated in one-third of all suicides in the older population. OBJECTIVE: To compare the clinical effectiveness and cost-effectiveness of a stepped care intervention against a minimal intervention in the treatment of older hazardous alcohol users in primary care. DESIGN: A multicentre, pragmatic, two-armed randomised controlled trial with an economic evaluation. SETTING: General practices in primary care in England and Scotland between April 2008 and October 2010. PARTICIPANTS: Adults aged ≥ 55 years scoring ≥ 8 on the Alcohol Use Disorders Identification Test (10-item) (AUDIT) were eligible. In total, 529 patients were randomised in the study. INTERVENTIONS: The minimal intervention group received a 5-minute brief advice intervention with the practice or research nurse involving feedback of the screening results and discussion regarding the health consequences of continued hazardous alcohol consumption. Those in the stepped care arm initially received a 20-minute session of behavioural change counselling, with referral to step 2 (motivational enhancement therapy) and step 3 (local specialist alcohol services) if indicated. Sessions were recorded and rated to ensure treatment fidelity. MAIN OUTCOME MEASURES: The primary outcome was average drinks per day (ADD) derived from extended AUDIT--Consumption (3-item) (AUDIT-C) at 12 months. Secondary outcomes were AUDIT-C score at 6 and 12 months; alcohol-related problems assessed using the Drinking Problems Index (DPI) at 6 and 12 months; health-related quality of life assessed using the Short Form Questionnaire-12 items (SF-12) at 6 and 12 months; ADD at 6 months; quality-adjusted life-years (QALYs) (for cost-utility analysis derived from European Quality of Life-5 Dimensions); and health and social care resource use associated with the two groups. RESULTS: Both groups reduced alcohol consumption between baseline and 12 months. The difference between groups in log-transformed ADD at 12 months was very small, at 0.025 [95% confidence interval (CI)--0.060 to 0.119], and not statistically significant. At month 6 the stepped care group had a lower ADD, but again the difference was not statistically significant. At months 6 and 12, the stepped care group had a lower DPI score, but this difference was not statistically significant at the 5% level. The stepped care group had a lower SF-12 mental component score and lower physical component score at month 6 and month 12, but these differences were not statistically significant at the 5% level. The overall average cost per patient, taking into account health and social care resource use, was £488 [standard deviation (SD) £826] in the stepped care group and £482 (SD £826) in the minimal intervention group at month 6. The mean QALY gains were slightly greater in the stepped care group than in the minimal intervention group, with a mean difference of 0.0058 (95% CI -0.0018 to 0.0133), generating an incremental cost-effectiveness ratio (ICER) of £1100 per QALY gained. At month 12, participants in the stepped care group incurred fewer costs, with a mean difference of -£194 (95% CI -£585 to £198), and had gained 0.0117 more QALYs (95% CI -0.0084 to 0.0318) than the control group. Therefore, from an economic perspective the minimal intervention was dominated by stepped care but, as would be expected given the effectiveness results, the difference was small and not statistically significant. CONCLUSIONS: Stepped care does not confer an advantage over minimal intervention in terms of reduction in alcohol consumption at 12 months post intervention when compared with a 5-minute brief (minimal) intervention. TRIAL REGISTRATION: This trial is registered as ISRCTN52557360. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 17, No. 25. See the HTA programme website for further project information

'Countries in the Air': Travel and Geomodernism in Louis MacNeice's BBC Features

In the middle stretch of his twenty-two-year BBC career, the poet and producer Louis MacNeice earned a reputation as one of the ‘undisputed masters of creative sound broadcasting’, a reputation derived, in part, from a huge range of radio features that were founded upon his journeys abroad. Through close examination of some of his most significant overseas soundscapes – including Portrait of Rome (1947) and Portrait of Delhi (1948) – this article will consider the role and function of travel in shaping MacNeice’s engagement with the radio feature as a modernist form at a particular transcultural moment when Britain moved through the end of the Second World War and the eventual disintegration of its empire

Multicentre individual randomised controlled trial of screening and brief alcohol intervention to prevent risky drinking in young people aged 14-15 in a high school setting (SIPS JR-HIGH): study protocol.

INTRODUCTION: Drinking has adverse impacts on health, well-being, education and social outcomes for adolescents. Adolescents in England are among the heaviest drinkers in Europe. Recently, the proportion of adolescents who drink alcohol has fallen, although consumption among those who do drink has actually increased. This trial seeks to investigate how effective and efficient an alcohol brief intervention is with 11-15 years olds to encourage lower alcohol consumption. METHODS AND ANALYSIS: This is an individually randomised two-armed trial incorporating a control arm of usual school-based practice and a leaflet on a healthy lifestyle (excl. alcohol), and an intervention arm that combines usual practice with a 30 min brief intervention delivered by school learning mentors and a leaflet on alcohol. At least 30 schools will be recruited from four regions in England (North East, North West, London, Kent and Medway) to follow-up 235 per arm. The primary outcome is total alcohol consumed in the last 28 days, using the 28 day Timeline Follow Back questionnaire measured at the 12-month follow-up. The analysis of the intervention will consider effectiveness and cost-effectiveness. A qualitative study will explore, via 1:1 in-depth interviews with (n=80) parents, young people and school staff, intervention experience, intervention fidelity and acceptability issues, using thematic narrative synthesis to report qualitative data. ETHICS AND DISSEMINATION: Ethical approval was granted by Teesside University. Dissemination plans include academic publications, conference presentations, disseminating to local and national education departments and the wider public health community, including via Fuse, and engaging with school staff and young people to comment on whether and how the project can be improved. TRIAL REGISTRATION TRIAL: ISRCTN45691494; Pre-results

Inflation and Dark Energy from spectroscopy at z > 2

The expansion of the Universe is understood to have accelerated during two epochs: in its very first moments during a period of Inflation and much more recently, at z < 1, when Dark Energy is hypothesized to drive cosmic acceleration. The undiscovered mechanisms behind these two epochs represent some of the most important open problems in fundamental physics. The large cosmological volume at 2 < z < 5, together with the ability to efficiently target high-$z$ galaxies with known techniques, enables large gains in the study of Inflation and Dark Energy. A future spectroscopic survey can test the Gaussianity of the initial conditions up to a factor of ~50 better than our current bounds, crossing the crucial theoretical threshold of $\sigma(f_{NL}^{\rm local})$ of order unity that separates single field and multi-field models. Simultaneously, it can measure the fraction of Dark Energy at the percent level up to $z = 5$, thus serving as an unprecedented test of the standard model and opening up a tremendous discovery space