Advantages of Bayesian monitoring methods in deciding whether and when to stop a clinical trial: an example of a neonatal cooling trial.

BackgroundDecisions to stop randomized trials are often based on traditional P value thresholds and are often unconvincing to clinicians. To familiarize clinical investigators with the application and advantages of Bayesian monitoring methods, we illustrate the steps of Bayesian interim analysis using a recent major trial that was stopped based on frequentist analysis of safety and futility.MethodsWe conducted Bayesian reanalysis of a factorial trial in newborn infants with hypoxic-ischemic encephalopathy that was designed to investigate whether outcomes would be improved by deeper (32 °C) or longer cooling (120 h), as compared with those achieved by standard whole body cooling (33.5 °C for 72 h). Using prior trial data, we developed neutral and enthusiastic prior probabilities for the effect on predischarge mortality, defined stopping guidelines for a clinically meaningful effect, and derived posterior probabilities for predischarge mortality.ResultsBayesian relative risk estimates for predischarge mortality were closer to 1.0 than were frequentist estimates. Posterior probabilities suggested increased predischarge mortality (relative risk > 1.0) for the three intervention groups; two crossed the Bayesian futility threshold.ConclusionsBayesian analysis incorporating previous trial results and different pre-existing opinions can help interpret accruing data and facilitate informed stopping decisions that are likely to be meaningful and convincing to clinicians, meta-analysts, and guideline developers.Trial registrationClinicalTrials.gov NCT01192776 . Registered on 31 August 2010

Greenhouse Gas Emissions Payback for Lightweighted Vehicles Using Aluminum and High-Strength Steel

In this article we consider interactions between life cycle emissions and materials flows associated with lightweighting (LW) automobiles. Both aluminum and high-strength steel (HSS) lightweighting are considered, with LW ranging from 6% to 23% on the basis of literature references and input from industry experts. We compare the increase in greenhouse gas (GHG) emissions associated with producing lightweight vehicles with the saved emissions during vehicle use. This yields a calculation of how many years of vehicle use are required to offset the added GHG emissions from the production stage. Payback periods for HSS are shorter than for aluminum. Nevertheless, achieving significant LW with HSS comparable to aluminum-intensive vehicles requires not only material substitution but also the achievement of secondary LW by downsizing of other vehicle components in addition to the vehicle structure. GHG savings for aluminum LW varies strongly with location where the aluminum is produced and whether secondary aluminum can be utilized instead of primary. HSS is less sensitive to these parameters. In principle, payback times for vehicles lightweighted with aluminum can be shortened by closed-loop recycling of wrought aluminum (i.e., use of secondary wrought aluminum). Over a 15-year time horizon, however, it is unlikely that this could significantly reduce emissions from the automotive industry, given the challenges involved with enabling a closed-loop aluminum infrastructure without downcycling automotive body structures.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/79236/1/j.1530-9290.2010.00283.x.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/79236/2/JIEC_283_sm_SuppMatS1.pd

Does social disadvantage over the life-course account for alcohol and tobacco use in Irish people? Birth cohort study

Medical Research Council (MRC) training fellowship awarded to J.D-M; Grant number: G0701595/

Prolonged duration of early antibiotic therapy in extremely premature infants.

BackgroundProlonged early antibiotics in extremely premature infants may have negative effects. We aimed to assess prevalence and outcomes of provision of prolonged early antibiotics to extremely premature infants in the absence of culture-confirmed infection or NEC.MethodsCohort study of infants from 13 centers born without a major birth defect from 2008-2014 who were 401-1000 grams birth weight, 22-28 weeks gestation, and survived ≥5 days without culture-confirmed infection, NEC, or spontaneous intestinal perforation. We determined the proportion of infants who received prolonged early antibiotics, defined as ≥5 days of antibiotic therapy started at ≤72 h of age, by center and over time. Associations between prolonged early antibiotics and adverse outcomes were assessed using multivariable logistic regression.ResultsA total of 5730 infants were included. The proportion of infants receiving prolonged early antibiotics varied from 30-69% among centers and declined from 49% in 2008 to 35% in 2014. Prolonged early antibiotics was not significantly associated with death (adjusted odds ratio 1.17 [95% CI: 0.99-1.40], p = 0.07) and was not associated with NEC.ConclusionsThe proportion of extremely premature infants receiving prolonged early antibiotics decreased, but significant center variation persists. Prolonged early antibiotics were not significantly associated with increased odds of death or NEC

A meta-synthesis of qualitative research on perceptions of people with long-term neurological conditions about group-based memory rehabilitation

The effectiveness of memory rehabilitation based on randomised controlled trials and meta-analyses has been inconclusive, but patient reports based on qualitative studies have been largely positive. We conducted a meta-synthesis of qualitative studies of group-based memory rehabilitation programmes for people with neurological conditions. Based on systematic searches of electronic databases and reference lists, five papers (87 participants) were selected. Quality appraisal of papers was conducted by two independent reviewers using the Critical Appraisal Skills Programme tool. Data synthesis was guided by the meta-ethnography approach. Fiver higher order themes were elicited. These suggested that memory rehabilitation was associated with insight and acceptance of participants’ neurological condition and resultant cognitive deficits. The therapeutic effects of the groups, with social support and leisure activities, helped with participants’ confidence. There were improvements in memory related to better self-awareness and learning to use new skills and strategies to compensate for memory deficits. These improvements also related to other psychological effects, in terms of positively affected mood, confidence and fatigue. Ultimately, these changes had a positive impact on daily life, with changes seen in the personal, inter-personal and professional spheres. Therefore, this synthesis of qualitative studies suggests that memory rehabilitation offers positive outcomes for people with long-term neurological conditions

Inhaled PGE1 in neonates with hypoxemic respiratory failure: two pilot feasibility randomized clinical trials.

BackgroundInhaled nitric oxide (INO), a selective pulmonary vasodilator, has revolutionized the treatment of neonatal hypoxemic respiratory failure (NHRF). However, there is lack of sustained improvement in 30 to 46% of infants. Aerosolized prostaglandins I2 (PGI2) and E1 (PGE1) have been reported to be effective selective pulmonary vasodilators. The objective of this study was to evaluate the feasibility of a randomized controlled trial (RCT) of inhaled PGE1 (IPGE1) in NHRF.MethodsTwo pilot multicenter phase II RCTs are included in this report. In the first pilot, late preterm and term neonates with NHRF, who had an oxygenation index (OI) of ≥15 and <25 on two arterial blood gases and had not previously received INO, were randomly assigned to receive two doses of IPGE1 (300 and 150 ng/kg/min) or placebo. The primary outcome was the enrollment of 50 infants in six to nine months at 10 sites. The first pilot was halted after four months for failure to enroll a single infant. The most common cause for non-enrollment was prior initiation of INO. In a re-designed second pilot, co-administration of IPGE1 and INO was permitted. Infants with suboptimal response to INO received either aerosolized saline or IPGE1 at a low (150 ng/kg/min) or high dose (300 ng/kg/min) for a maximum duration of 72 hours. The primary outcome was the recruitment of an adequate number of patients (n = 50) in a nine-month-period, with fewer than 20% protocol violations.ResultsNo infants were enrolled in the first pilot. Seven patients were enrolled in the second pilot; three in the control, two in the low-dose IPGE1, and two in the high-dose IPGE1 groups. The study was halted for recruitment futility after approximately six months as enrollment targets were not met. No serious adverse events, one minor protocol deviation and one pharmacy protocol violation were reported.ConclusionsThese two pilot RCTs failed to recruit adequate eligible newborns with NHRF. Complex management RCTs of novel therapies for persistent pulmonary hypertension of the newborn (PPHN) may require novel study designs and a longer period of time from study approval to commencement of enrollment.Trial registrationCLINICALTRIALS.GOV: Pilot one: NCT number: 00598429 registered on 10 January 2008. Last updated: 3 February 2011. Pilot two: NCT number: 01467076 17 October 2011. Last updated: 13 February 2013

Do changes to the local street environment alter behaviour and quality of life of older adults? The ‘DIY Streets’ intervention

<p>Background: The burden of ill-health due to inactivity has recently been highlighted. Better studies on environments that support physical activity are called for, including longitudinal studies of environmental interventions. A programme of residential street improvements in the UK (Sustrans ‘DIY Streets’) allowed a rare opportunity for a prospective, longitudinal study of the effect of such changes on older adults’ activities, health and quality of life.</p> <p>Methods: Pre–post, cross-sectional surveys were carried out in locations across England, Wales and Scotland; participants were aged 65+ living in intervention or comparison streets. A questionnaire covered health and quality of life, frequency of outdoor trips, time outdoors in different activities and a 38-item scale on neighbourhood open space. A cohort study explored changes in self-report activity and well-being postintervention. Activity levels were also measured by accelerometer and accompanying diary records.</p> <p>Results: The cross-sectional surveys showed outdoor activity predicted by having a clean, nuisance-free local park, attractive, barrier-free routes to it and other natural environments nearby. Being able to park one's car outside the house also predicted time outdoors. The environmental changes had an impact on perceptions of street walkability and safety at night, but not on overall activity levels, health or quality of life. Participants’ moderate-to-vigorous activity levels rarely met UK health recommendations.</p> <p>Conclusions: Our study contributes to methodology in a longitudinal, pre–post design and points to factors in the built environment that support active ageing. We include an example of knowledge exchange guidance on age-friendly built environments for policy-makers and planners.</p&gt

Probing the neutrino mass hierarchy with CMB weak lensing

We forecast constraints on cosmological parameters with primary CMB anisotropy information and weak lensing reconstruction with a future post-Planck CMB experiment, the Cosmic Origins Explorer (COrE), using oscillation data on the neutrino mass splittings as prior information. Our MCMC simulations in flat models with a non-evolving equation-of-state of dark energy w give typical 68% upper bounds on the total neutrino mass of 0.136 eV and 0.098 eV for the inverted and normal hierarchies respectively, assuming the total summed mass is close to the minimum allowed by the oscillation data for the respective hierarchies (0.10 eV and 0.06 eV). Including information from future baryon acoustic oscillation measurements with the complete BOSS, Type 1a supernovae distance moduli from WFIRST, and a realistic prior on the Hubble constant, these upper limits shrink to 0.118 eV and 0.080 eV for the inverted and normal hierarchies, respectively. Addition of these distance priors also yields percent-level constraints on w. We find tension between our MCMC results and the results of a Fisher matrix analysis, most likely due to a strong geometric degeneracy between the total neutrino mass, the Hubble constant, and w in the unlensed CMB power spectra. If the minimal-mass, normal hierarchy were realised in nature, the inverted hierarchy should be disfavoured by the full data combination at typically greater than the 2-sigma level. For the minimal-mass inverted hierarchy, we compute the Bayes' factor between the two hierarchies for various combinations of our forecast datasets, and find that the future probes considered here should be able to provide `strong' evidence (odds ratio 12:1) for the inverted hierarchy. Finally, we consider potential biases of the other cosmological parameters from assuming the wrong hierarchy and find that all biases on the parameters are below their 1-sigma marginalised errors.Comment: 16 pages, 13 figures; minor changes to match the published version, references adde

Designing a complex intervention for dementia case management in primary care

Background: Community-based support will become increasingly important for people with dementia, but currently services are fragmented and the quality of care is variable. Case management is a popular approach to care co-ordination, but evidence to date on its effectiveness in dementia has been equivocal. Case management interventions need to be designed to overcome obstacles to care co-ordination and maximise benefit. A successful case management methodology was adapted from the United States (US) version for use in English primary care, with a view to a definitive trial. Medical Research Council guidance on the development of complex interventions was implemented in the adaptation process, to capture the skill sets, person characteristics and learning needs of primary care based case managers. Methods: Co-design of the case manager role in a single NHS provider organisation, with external peer review by professionals and carers, in an iterative technology development process. Results: The generic skills and personal attributes were described for practice nurses taking up the case manager role in their workplaces, and for social workers seconded to general practice teams, together with a method of assessing their learning needs. A manual of information material for people with dementia and their family carers was also created using the US intervention as its source. Conclusions: Co-design produces rich products that have face validity and map onto the complexities of dementia and of health and care services. The feasibility of the case manager role, as described and defined by this process, needs evaluation in ‘real life’ settings