BackgroundNon-invasive ventilation (NIV), in the form of continuous positive airway pressure (CPAP) or bilevel inspiratory positive airway pressure (BiPAP), is used in hospital to treat patients with acute respiratory failure. Pre-hospital NIV may be more effective than in-hospital NIV but requires additional ambulance service resources.ObjectivesWe aimed to determine the clinical effectiveness and cost-effectiveness of pre-hospital NIV compared with usual care for adults presenting to the emergency services with acute respiratory failure and to identify priorities for future research.Data sourcesFourteen electronic databases and research registers (including MEDLINE In-Process & Other Non-Indexed Citations, MEDLINE, EMBASE, and Cumulative Index to Nursing and Allied Health Literature) were searched from inception to August 2013, supplemented by hand-searching reference lists and contacting experts in the field.Review methodsWe included all randomised or quasi-randomised controlled trials of pre-hospital NIV in patients with acute respiratory failure. Methodological quality was assessed according to established criteria. An aggregate data network meta-analysis (NMA) of mortality and intubation was used to jointly estimate intervention effects relative to usual care. A NMA, using individual patient-level data (IPD) and aggregate data where IPD were not available, was carried out to assess whether or not covariates were treatment effect modifiers. A de novo economic model was developed to explore the costs and health outcomes when pre-hospital NIV (specifically CPAP provided by paramedics) and standard care (in-hospital NIV) were applied to a hypothetical cohort of patients with acute respiratory failure.ResultsThe literature searches identified 2284 citations. Of the 10 studies that met the inclusion criteria, eight were randomised controlled trials and two were quasi-randomised trials (six CPAP; four BiPAP; sample sizes 23–207 participants). IPD were available from seven trials (650 patients). The aggregate data NMA suggested that CPAP was the most effective treatment in terms of mortality (probability = 0.989) and intubation rate (probability = 0.639), and reduced both mortality [odds ratio (OR) 0.41, 95% credible interval (CrI) 0.20 to 0.77] and intubation rate (OR 0.32, 95% CrI 0.17 to 0.62) compared with standard care. The effect of BiPAP on mortality (OR 1.94, 95% CrI 0.65 to 6.14) and intubation rate (OR 0.40, 95% CrI 0.14 to 1.16) compared with standard care was uncertain. The combined IPD and aggregate data NMA suggested that sex was a statistically significant treatment effect modifier for mortality. The economic analysis showed that pre-hospital CPAP was more effective and more expensive than standard care, with an incremental cost-effectiveness ratio of £20,514 per quality-adjusted life-year (QALY) and a 49.5% probability of being cost-effective at the £20,000-per-QALY threshold. Variation in the incidence of eligible patients had a marked impact on cost-effectiveness and the expected value of sample information for a future randomised trial.LimitationsThe meta-analysis lacked power to detect potentially important differences in outcome (particularly for BiPAP), the intervention was not always compared with the best alternative care (in-hospital NIV) in the primary studies and findings may not be generalisable.ConclusionsPre-hospital CPAP can reduce mortality and intubation rates, but cost-effectiveness is uncertain and the value of further randomised evaluation depends on the incidence of suitable patients. A feasibility study is required to determine if a large pragmatic trial of clinical effectiveness and cost-effectiveness is appropriate.Study registrationThe study is registered as PROSPERO CRD42012002933.FundingThe National Institute for Health Research Health Technology Assessment programme.

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Globally populations are ageing and mental health disorders, including dementia and depression, are reported as the leading cause of disability and ill health in older people (1). Epidemiological and randomised trial evidence supports potential roles for folate and the metabolically related B-vitamins in preventing cognitive dysfunction and depression in ageing, but the evidence is inconsistent (2). The aim of this study was to investigate the effect of supplementation with folate and related B-vitamins, over a 2 year period, on cognitive function (primary outcome) and depression (secondary outcome) in older adults. The B-vitamins and Brain Health in Older People (BrainHOP) randomised controlled trial was conducted in adults aged 70 years and older. Participants were randomised to receive a supplement containing folic acid (400 µg), vitamin B12 (10 µg), vitamin B6 (10 mg) and riboflavin (10 mg) or placebo daily. Cognitive function was assessed before and after the 2-year intervention using the Frontal Assessment Battery (FAB) and the Repeatable Battery of the Assessment of Neuropsychological Status (RBANS). Depression was assessed using the Centre for Epidemiological Studies Depression (CES-D) scale. Of the 328 participants initially recruited, 249 (74%) participants completed the intervention. Results showed that B-vitamin intervention appeared to have no significant effect on either frontal lobe or global cognitive function (as measured by FAB and RBANS, respectively). However, when specific domains within global cognition (i.e. RBANS index scores) were examined separately, B-vitamin intervention was found to protect against visuospatial cognitive decline over the two year period (Table).

The GLI (GLI1/GLI2) transcription factors have been implicated in the development and progression of prostate cancer although our understanding of how they actually contribute to the biology of these common tumours is limited. We observed that GLI reporter activity was higher in normal (PNT-2) and tumourigenic (DU145 and PC-3) androgen-independent cells compared to androgen-dependent LNCaP prostate cancer cells and, accordingly, GLI mRNA levels were also elevated. Ectopic expression of GLI1 or the constitutively active ΔNGLI2 mutant induced a distinct cobblestone-like morphology in LNCaP cells that, regarding the former, correlated with increased GLI2 as well as expression of the basal/stem-like markers CD44, β1-integrin, ΔNp63 and BMI1, and decreased expression of the luminal marker AR (androgen receptor). LNCaP-GLI1 cells were viable in the presence of the AR inhibitor bicalutamide and gene expression profiling revealed that the transcriptome of LNCaP-GLI1 cells was significantly closer to DU145 and PC-3 cells than to control LNCaP-pBP (empty vector) cells, as well as identifying LCN2/NGAL as a highly induced transcript which is associated with hormone independence in breast and prostate cancer. Functionally, LNCaP-GLI1 cells displayed greater clonal growth and were more invasive than control cells but they did not form colonies in soft agar or prostaspheres in suspension suggesting that they do not possess inherent stem cell properties. Moreover, targeted suppression of GLI1 or GLI2 with siRNA did not reverse the transformed phenotype of LNCaP-GLI1 cells nor did double GLI1/GLI2 knockdowns activate AR expression in DU145 or PC-3 cells. As such, early targeting of the GLI oncoproteins may hinder progression to a hormone independent state but a more detailed understanding of the mechanisms that maintain this phenotype is required to determine if their inhibition will enhance the efficacy of anti-hormonal therapy through the induction of a luminal phenotype and increased dependency upon AR function.