Decline in effectiveness of antenatal corticosteroids with time to birth : real or artefact?

The effectiveness of antenatal corticosteroids to prevent neonatal lung disease in women at risk of preterm birth was established by systematic reviews. In addition, subgroup analyses suggested that treatment was most effective in babies born one to seven days after administration. This belief led to widespread use of repeated courses of corticosteroids in women who did not deliver within a week or two of initial treatment. However, the notion that effectiveness declines after seven days may be incorrect, as the analyses that it is based on are unreliable. Here, we discuss the methodological problems of these analyses and their relevance to current randomised controlled trials of repeated versus single courses

Mechanical chest-compression devices: current and future roles

Purpose of review: It is recognised that the quality of CPR is an important predictor of outcome from cardiac arrest yet studies consistently demonstrate that the quality of CPR performed in real life is frequently sub-optimal. Mechanical chest compression devices provide an alternative to manual CPR. This review will consider the evidence and current indications for the use of these devices. Recent findings: Physiological and animal data suggest that mechanical chest compression devices are more effective than manual CPR. However there is no high quality evidence showing improved outcomes in humans. There are specific circumstances where it may not be possible to perform manual CPR effectively e.g. during ambulance transport to hospital, en-route to and during cardiac catheterisation, prior to organ donation and during diagnostic imaging where using these devices may be advantageous. Summary: There is insufficient evidence to recommend the routine use of mechanical chest compression devices. There may be specific circumstances when CPR is difficult or impossible where mechanical devices may play an important role in maintaining circulation. There is an urgent need for definitive clinical and cost effectiveness trials to confirm or refute the place of mechanical chest compression devices during resuscitation

Comparison of Bayesian and frequentist group-sequential clinical trial designs

Background: There is a growing interest in the use of Bayesian adaptive designs in late-phase clinical trials. This includes the use of stopping rules based on Bayesian analyses in which the frequentist type I error rate is controlled as in frequentist group-sequential designs. Methods: This paper presents a practical comparison of Bayesian and frequentist group-sequential tests. Focussing on the setting in which data can be summarised by normally distributed test statistics, we evaluate and compare boundary values and operating characteristics. Results: Although Bayesian and frequentist group-sequential approaches are based on fundamentally different paradigms, in a single arm trial or two-arm comparative trial with a prior distribution specified for the treatment difference, Bayesian and frequentist group-sequential tests can have identical stopping rules if particular critical values with which the posterior probability is compared or particular spending function values are chosen. If the Bayesian critical values at different looks are restricted to be equal, O’Brien and Fleming’s design corresponds to a Bayesian design with an exceptionally informative negative prior, Pocock’s design to a Bayesian design with a non-informative prior and frequentist designs with a linear alpha spending function are very similar to Bayesian designs with slightly informative priors. This contrasts with the setting of a comparative trial with independent prior distributions specified for treatment effects in different groups. In this case Bayesian and frequentist group-sequential tests cannot have the same stopping rule as the Bayesian stopping rule depends on the observed means in the two groups and not just on their difference. In this setting the Bayesian test can only be guaranteed to control the type I error for a specified range of values of the control group treatment effect. Conclusions: Comparison of frequentist and Bayesian designs can encourage careful thought about design parameters and help to ensure appropriate design choices are made

Scoping exercise on fallers’ clinics : report to the National Co-ordinating Centre for NHS Service Delivery and Organisation R & D (NCCSDO)

The National Service Framework for Older People has stated the need for fall-prevention programmes. An appraisal of fallers’ clinics launched by the National Institute for Health and Clinical Excellence (NICE) was suspended because of a lack of information regarding existing services and typology. This project aimed to determine the feasibility of conducting economic modelling to appraise fallers’ clinics. To achieve this a national survey of services and reviews of the evidence of effectiveness of various models of fallers’ clinics and screening tools were undertaken

Does a monetary incentive improve the response to a postal questionnaire in a randomised controlled trial? : the MINT incentive study

Background: Sending a monetary incentive with postal questionnaires has been found to improve the proportion of responders, in research in non-healthcare settings. However, there is little research on use of incentives to improve follow-up rates in clinical trials, and existing studies are inconclusive. We conducted a randomised trial among participants in the Managing Injuries of the Neck Trial (MINT) to investigate the effects on the proportion of questionnaires returned and overall non-response of sending a £5 gift voucher with a follow-up questionnaire. Methods: Participants in MINT were randomised to receive either: (a) a £5 gift voucher (incentive group) or (b) no gift voucher (no incentive group), with their 4 month or 8 month follow-up questionnaire. We recorded, for each group, the number of questionnaires returned, the number returned without any chasing from the study office, the overall number of non-responders (after all chasing efforts by the study office), and the costs of following up each group. Results: 2144 participants were randomised, 1070 to the incentive group and 1074 to the no incentive group. The proportion of questionnaires returned (RR 1.10 (95% CI 1.05, 1.16)) and the proportion returned without chasing (RR 1.14 (95% CI 1.05, 1.24) were higher in the incentive group, and the overall non-response rate was lower (RR 0.68 (95% CI 0.53, 0.87)). Adjustment for injury severity and hospital of recruitment to MINT made no difference to these results, and there were no differences in results between the 4-month and 8-month follow up questionnaires. Analysis of costs suggested a cost of £67.29 per additional questionnaire returned. Conclusion: Monetary incentives may be an effective way to increase the proportion of postal questionnaires returned and minimise loss to follow-up in clinical trials

Is protocolised weaning that includes early extubation onto non-invasive ventilation more cost effective than protocolised weaning without non-invasive ventilation? Findings from the Breathe Study

Background Optimising techniques to wean patients from invasive mechanical ventilation (IMV) remains a key goal of intensive care practice. The use of non-invasive ventilation (NIV) as a weaning strategy (transitioning patients who are difficult to wean to early NIV) may reduce mortality, ventilator-associated pneumonia and intensive care unit (ICU) length of stay. Objectives Our objectives were to determine the cost effectiveness of protocolised weaning, including early extubation onto NIV, compared with weaning without NIV in a UK National Health Service setting. Methods We conducted an economic evaluation alongside a multicentre randomised controlled trial. Patients were randomised to either protocol-directed weaning from mechanical ventilation or ongoing IMV with daily spontaneous breathing trials. The primary efficacy outcome was time to liberation from ventilation. Bivariate regression of costs and quality-adjusted life-years (QALYs) provided estimates of the incremental cost per QALY and incremental net monetary benefit (INMB) overall and for subgroups [presence/absence of chronic obstructive pulmonary disease (COPD) and operative status]. Long-term cost effectiveness was determined through extrapolation of survival curves using flexible parametric modelling. Results NIV was associated with a mean INMB of £620 ($US885) (cost-effectiveness threshold of £20,000 per QALY) with a corresponding probability of 58$US6594 per QALY gained). Conclusions The probability of NIV being cost effective relative to weaning without NIV ranged between 57 and 59% overall and between 82 and 87% for the COPD subgroup

Differential efficacy of vaccinia virus envelope proteins administered by DNA immunisation in protection of BALB/c mice from a lethal intranasal poxvirus challenge

DNA vaccines might offer an alternative to the live smallpox vaccine in providing protective efficacy in an orthopoxvirus (OPV) lethal respiratory challenge model. BALB/c mice were immunised with DNA vaccines coding for 10 different single vaccinia virus (VACV) membrane proteins. After an intranasal challenge with the VACV IHD strain, three gene candidates B5R, A33R and A27L produced > or =66% survival. The B5R DNA vaccine consistently produced 100% protection and exhibited greatest efficacy after three 50 microg intramuscular doses in this model. Sero-conversion to these vaccines was often inconsistent, implying that antibody itself was not a correlate of protection. The B5R DNA vaccine induced a strong and consistent gamma interferon (IFNgamma) response in BALB/c mice given a single DNA vaccine dose. Strong IFNgamma responses were also measured in pTB5R immunised C57BL6 mice deficient for MHC class I molecules, suggesting that the memory response was mediated by a CD4+ T cell population