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1.  Initiating change locally in bullying and aggression through the school environment (INCLUSIVE): study protocol for a cluster randomised controlled trial 
Trials  2014;15(1):381.
Background
Systematic reviews suggest that interventions that address school organisation are effective in reducing victimisation and bullying. We successfully piloted a school environment intervention modified from international studies to incorporate ‘restorative justice’ approaches. This trial aims to establish the effectiveness and cost-effectiveness of the INCLUSIVE intervention in reducing aggression and bullying in English secondary schools.
Methods
Design: cluster randomised trial.
Participants: 40 state-supported secondary schools. Outcomes assessed among the cohort of students in year 8 (n = approximately 6,000) in intervention year 1.
Intervention: INCLUSIVE is a school-led intervention which combines changes to the school environment with the promotion of social and emotional skills and restorative practices through: the formation of a school action group involving students and staff supported by an external facilitator to review local data on needs, determine priorities, and develop and implement an action plan for revising relevant school policies/rules and other actions to improve relationships at school and reduce aggression; staff training in restorative practices; and a new social and emotional skills curriculum. The intervention will be delivered by schools supported in the first two years by educational facilitators independent of the research team, with a third locally facilitated intervention year.
Comparator: normal practice.
Outcomes: primary: 2 primary outcomes at student level assessed at baseline and at 36 months: Aggressive behaviours in school: Edinburgh Study of Youth Transitions and Crime school misbehaviour subscale (ESYTC)Bullying and victimisation: Gatehouse Bullying Scale (GBS)
Secondary outcomes assessed at baseline, 24 and 36 months will include measures relating to the economic evaluation, psychosocial outcomes in students and staff and school-level truancy and exclusion rates.
Sample size: 20 schools per arm will provide 90% power to identify an effect size of 0.25 SD with a 5% significance level.
Randomisation: eligible consenting schools will be randomised stratified for single sex versus mixed sex schools, school-level deprivation and measures of school attainment.
Discussion
The trial will be run by independent research and intervention teams and supervised by a Trial Steering Committee and a Data Monitoring Committee (DMC).
Trial registration
Current Controlled Trials ISRCTN10751359 (Registered 11 March 2014)
doi:10.1186/1745-6215-15-381
PMCID: PMC4197327  PMID: 25269491
Bullying; Cluster randomised trial; School intervention; Violence prevention; Adolescent
2.  Research participation effects: a skeleton in the methodological cupboard☆ 
Journal of Clinical Epidemiology  2014;67(8):845-849.
Objective
There have been concerns about impacts of various aspects of taking part in research studies for a century. The concerns have not, however, been sufficiently well conceptualized to form traditions of study capable of defining and elaborating the nature of these problems. In this article we present a new way of thinking about a set of issues attracting long-standing attention.
Study Design and Setting
We briefly review existing concepts and empirical work on well-known biases in surveys and cohort studies and propose that they are connected.
Results
We offer the construct of “research participation effects” (RPE) as a vehicle for advancing multi-disciplinary understanding of biases. Empirical studies are needed to identify conditions in which RPE may be sufficiently large to warrant modifications of study design, analytic methods, or interpretation. We consider the value of adopting a more participant-centred view of the research process as a way of thinking about these issues, which may also have benefits in relation to research methodology more broadly.
Conclusion
Researchers may too readily overlook the extent to which research studies are unusual contexts, and that people may react in unexpected ways to what we invite them to do, introducing a range of biases.
doi:10.1016/j.jclinepi.2014.03.002
PMCID: PMC4236591  PMID: 24766858
Research participation; Bias; Research methods; Hawthorne effect; Research assessment; Mixed methods; Surveys; Cohort studies
3.  In randomization we trust? There are overlooked problems in experimenting with people in behavioral intervention trials☆ 
Journal of Clinical Epidemiology  2014;67(3):247-253.
Objectives
Behavioral intervention trials may be susceptible to poorly understood forms of bias stemming from research participation. This article considers how assessment and other prerandomization research activities may introduce bias that is not fully prevented by randomization.
Study Design and Setting
This is a hypothesis-generating discussion article.
Results
An additivity assumption underlying conventional thinking in trial design and analysis is problematic in behavioral intervention trials. Postrandomization sources of bias are somewhat better known within the clinical epidemiological and trials literatures. Neglect of attention to possible research participation effects means that unintended participant behavior change stemming from artifacts of the research process has unknown potential to bias estimates of behavioral intervention effects.
Conclusion
Studies are needed to evaluate how research participation effects are introduced, and we make suggestions for how research in this area may be taken forward, including how these issues may be addressed in the design and conduct of trials. It is proposed that attention to possible research participation effects can improve the design of trials evaluating behavioral and other interventions and inform the interpretation of existing evidence.
doi:10.1016/j.jclinepi.2013.09.004
PMCID: PMC3969092  PMID: 24314401
Behavior; Trials; Bias; Research participation; Intervention; Hawthorne effect
4.  Systematic review of the Hawthorne effect: New concepts are needed to study research participation effects☆ 
Journal of Clinical Epidemiology  2014;67(3):267-277.
Objectives
This study aims to (1) elucidate whether the Hawthorne effect exists, (2) explore under what conditions, and (3) estimate the size of any such effect.
Study Design and Setting
This systematic review summarizes and evaluates the strength of available evidence on the Hawthorne effect. An inclusive definition of any form of research artifact on behavior using this label, and without cointerventions, was adopted.
Results
Nineteen purposively designed studies were included, providing quantitative data on the size of the effect in eight randomized controlled trials, five quasiexperimental studies, and six observational evaluations of reporting on one's behavior by answering questions or being directly observed and being aware of being studied. Although all but one study was undertaken within health sciences, study methods, contexts, and findings were highly heterogeneous. Most studies reported some evidence of an effect, although significant biases are judged likely because of the complexity of the evaluation object.
Conclusion
Consequences of research participation for behaviors being investigated do exist, although little can be securely known about the conditions under which they operate, their mechanisms of effects, or their magnitudes. New concepts are needed to guide empirical studies.
doi:10.1016/j.jclinepi.2013.08.015
PMCID: PMC3969247  PMID: 24275499
Hawthorne effect; Reactivity; Observation; Research methods; Research participation; Assessment
9.  First steps: study protocol for a randomized controlled trial of the effectiveness of the Group Family Nurse Partnership (gFNP) program compared to routine care in improving outcomes for high-risk mothers and their children and preventing abuse 
Trials  2013;14:285.
Background
Evidence from the USA suggests that the home-based Family Nurse Partnership program (FNP), extending from early pregnancy until infants are 24 months, can reduce the risk of child abuse and neglect throughout childhood. FNP is now widely available in the UK. A new variant, Group Family Nurse Partnership (gFNP) offers similar content but in a group context and for a shorter time, until infants are 12 months old. Each group comprises 8 to 12 women with similar expected delivery dates and their partners. Its implementation has been established but there is no evidence of its effectiveness.
Methods/Design
The study comprises a multi-site randomized controlled trial designed to identify the benefits of gFNP compared to standard care. Participants (not eligible for FNP) must be either aged < 20 years at their last menstrual period (LMP) with one or more previous live births, or aged 20 to 24 at LMP with low educational qualifications and no previous live births. ‘Low educational qualifications’ is defined as not having both Maths and English Language GCSE at grade C or higher or, if they have both, no more than four in total at grade C or higher. Exclusions are: under 20 years and previously received home-based FNP and, in either age group, severe psychotic mental illness or not able to communicate in English. Consenting women are randomly allocated (minimized by site and maternal age group) when between 10 and 16 weeks pregnant to either to the 44 session gFNP program or to standard care after the collection of baseline information. Researchers are blind to group assignment.
The primary outcomes at 12 months are child abuse potential based on the revised Adult-Adolescent Parenting Inventory and parent/infant interaction coded using the CARE Index based on a video-taped interaction. Secondary outcomes are maternal depression, parenting stress, health related quality of life, social support, and use of services.
Discussion
This is the first study of the effectiveness of gFNP in the UK. Results should inform decision-making about its delivery alongside universal services, potentially enabling a wider range of families to benefit from the FNP curriculum and approach to supporting parenting.
Trial registration
ISRCTN78814904.
doi:10.1186/1745-6215-14-285
PMCID: PMC3846406  PMID: 24011061
Early intervention; Child abuse; Nurse; Young parents
10.  The Good Schools Toolkit to prevent violence against children in Ugandan primary schools: study protocol for a cluster randomised controlled trial 
Trials  2013;14:232.
Background
We aim to evaluate the effectiveness of the Good School Toolkit, developed by Raising Voices, in preventing violence against children attending school and in improving child mental health and educational outcomes.
Methods/design
We are conducting a two-arm cluster randomised controlled trial with parallel assignment in Luwero District, Uganda. We will also conduct a qualitative study, a process evaluation and an economic evaluation. A total of 42 schools, representative of Luwero District, Uganda, were allocated to receive the Toolkit plus implementation support, or were allocated to a wait-list control condition. Our main analysis will involve a cross-sectional comparison of the prevalence of past-week violence from school staff as reported by children in intervention and control primary schools at follow-up.
At least 60 children per school and all school staff members will be interviewed at follow-up. Data collection involves a combination of mobile phone-based, interviewer-completed questionnaires and paper-and-pen educational tests. Survey instruments include the ISPCAN Child Abuse Screening Tools to assess experiences of violence; the Strengths and Difficulties Questionnaire to measure symptoms of common childhood mental disorders; and word recognition, reading comprehension, spelling, arithmetic and sustained attention tests adapted from an intervention trial in Kenya.
Discussion
To our knowledge, this is the first study to rigorously investigate the effects of any intervention to prevent violence from school staff to children in primary school in a low-income setting. We hope the results will be informative across the African region and in other settings.
Trial registration
clinicaltrials.gov NCT01678846
doi:10.1186/1745-6215-14-232
PMCID: PMC3734010  PMID: 23883138
Corporal punishment; Primary school; Violence; Uganda; Mental health; Education
11.  The Support to Rural India's Public Education System (STRIPES) Trial: A Cluster Randomised Controlled Trial of Supplementary Teaching, Learning Material and Material Support 
PLoS ONE  2013;8(7):e65775.
Background
The aim of the STRIPES trial was to assess the effectiveness of providing supplementary, remedial teaching and learning materials (and an additional ‘kit’ of materials for girls) on a composite of language and mathematics test scores for children in classes two, three and four in public primary schools in villages in the Nagarkurnool division of Andhra Pradesh, India.
Methods
STRIPES was a cluster randomised trial in which 214 villages were allocated either to the supplementary teaching intervention (n = 107) or to serve as controls (n = 107). 54 of the intervention villages were further randomly allocated to receive additional kit for girls. The study was not blinded. Analysis was conducted on the intention to treat principle, allowing for clustering.
Results
Composite test scores were significantly higher in the intervention group (107 villages; 2364 children) than in the control group (106 villages; 2014 children) at the end of the trial (mean difference on a percentage scale 15.8; 95% CI 13.1 to 18.6; p<0.001; 0.75 Standard Deviation (SD) difference). Composite test scores were not significantly different in the 54 villages (614 girls) with the additional kits for girls compared to the 53 villages (636 girls) without these kits at the end of the trial (mean difference on a percentage scale 0.5; 95% CI -4.34 to 5.4; p = 0.84). The cost per 0.1 SD increase in composite test score for intervention without kits is Rs. 382.97 (£4.45, $7.13), and Rs.480.59 (£5.58, $8.94) for the intervention with kits.
Conclusions
A 18 month programme of supplementary remedial teaching and learning materials had a substantial impact on language and mathematics scores of primary school students in rural Andhra Pradesh, yet providing a ‘kit’ of materials to girls in these villages did not lead to any measured additional benefit.
Trial Registration
Controlled-Trials.com ISRCTN69951502
doi:10.1371/journal.pone.0065775
PMCID: PMC3712986  PMID: 23874383
12.  Investigating the relationship between predictability and imbalance in minimisation: a simulation study 
Trials  2013;14:86.
Background
The use of restricted randomisation methods such as minimisation is increasing. This paper investigates under what conditions it is preferable to use restricted randomisation in order to achieve balance between treatment groups at baseline with regard to important prognostic factors and whether trialists should be concerned that minimisation may be considered deterministic.
Methods
Using minimisation as the randomisation algorithm, treatment allocation was simulated for hypothetical patients entering a theoretical study having values for prognostic factors randomly assigned with a stipulated probability. The number of times the allocation could have been determined with certainty and the imbalances which might occur following randomisation using minimisation were examined.
Results
Overall treatment balance is relatively unaffected by reducing the probability of allocation to optimal treatment group (P) but within-variable balance can be affected by any P <1. This effect is magnified by increased numbers of prognostic variables, the number of categories within them and the prevalence of these categories within the study population.
Conclusions
In general, for smaller trials, probability of treatment allocation to the treatment group with fewer numbers requires a larger value P to keep treatment and variable groups balanced. For larger trials probability of allocation values from P = 0.5 to P = 0.8 can be used while still maintaining balance. For one prognostic variable there is no significant benefit in terms of predictability in reducing the value of P. However, for more than one prognostic variable, significant reduction in levels of predictability can be achieved with the appropriate choice of P for the given trial design.
doi:10.1186/1745-6215-14-86
PMCID: PMC3652769  PMID: 23537389
Randomisation; Minimisation; Allocation imbalance; Allocation predictability
13.  Use of randomisation in clinical trials: a survey of UK practice 
Trials  2012;13:198.
Background
In healthcare research the randomised controlled trial is seen as the gold standard because it ensures selection bias is minimised. However, there is uncertainty as to which is the most preferred method of randomisation in any given setting and to what extent more complex methods are actually being implemented in the field.
Methods
In this paper we describe the results of a survey of UK academics and publicly funded researchers to examine the extent of the use of various methods of randomisation in clinical trials.
Results
Trialists reported using simple randomisation, permuted blocks and stratification more often than more complex methods such as minimisation. Most trialists believed that simple randomisation is suitable for larger trials but there is a high probability of possible imbalance between treatment groups in small trials. It was thought that groups should be balanced at baseline to avoid imbalance and help face-validity. However, very few respondents considered that more complex methods offer any advantages.
Conclusions
This paper demonstrates that for most UK trialists the preferred method of randomisation is using permuted blocks of varying random length within strata. This method eliminates the problem of predictability while maintaining balance across combinations of factors. If the number of prognostic factors is large, then minimisation can be used to provide treatment balance as well as balance over these factors. However, only those factors known to affect outcome should be considered.
doi:10.1186/1745-6215-13-198
PMCID: PMC3522058  PMID: 23101457
Survey; Randomisation; Minimisation
14.  Inhaled Nitric Oxide in Preterm Infants: An Individual-Patient Data Meta-analysis of Randomized Trials 
Pediatrics  2011;128(4):729-739.
BACKGROUND:
Inhaled nitric oxide (iNO) is an effective therapy for pulmonary hypertension and hypoxic respiratory failure in term infants. Fourteen randomized controlled trials (n = 3430 infants) have been conducted on preterm infants at risk for chronic lung disease (CLD). The study results seem contradictory.
DESIGN/METHODS:
Individual-patient data meta-analysis included randomized controlled trials of preterm infants (<37 weeks' gestation). Outcomes were adjusted for trial differences and correlation between siblings.
RESULTS:
Data from 3298 infants in 12 trials (96%) were analyzed. There was no statistically significant effect of iNO on death or CLD (59% vs 61%: relative risk [RR]: 0.96 [95% confidence interval (CI): 0.92–1.01]; P = .11) or severe neurologic events on imaging (25% vs 23%: RR: 1.12 [95% CI: 0.98–1.28]; P = .09). There were no statistically significant differences in iNO effect according to any of the patient-level characteristics tested. In trials that used a starting iNO dose of >5 vs ≤5 ppm there was evidence of improved outcome (interaction P = .02); however, these differences were not observed at other levels of exposure to iNO. This result was driven primarily by 1 trial, which also differed according to overall dose, duration, timing, and indication for treatment; a significant reduction in death or CLD (RR: 0.85 [95% CI: 0.74–0.98]) was found.
CONCLUSIONS:
Routine use of iNO for treatment of respiratory failure in preterm infants cannot be recommended. The use of a higher starting dose might be associated with improved outcome, but because there were differences in the designs of these trials, it requires further examination.
doi:10.1542/peds.2010-2725
PMCID: PMC3387905  PMID: 21930540
inhaled nitric oxide; chronic lung disease; respiratory disease; preterm infants; individual-patient data meta-analysis
15.  The efficacy of a brief intervention in reducing hazardous drinking in working age men in Russia: the HIM (Health for Izhevsk men) individually randomised parallel group exploratory trial 
Trials  2011;12:238.
Background
Russia has particularly low life expectancy for an industrialised country, with mortality at working ages having fluctuated dramatically over the past few decades, particularly among men. Alcohol has been identified as the most likely cause of these temporal variations. One approach to reducing the alcohol problem in Russia is 'brief interventions' which seek to change views of the personal acceptability of excessive drinking and to encourage self-directed behaviour change. Very few studies to evaluate the efficacy of brief interventions in Russia have been conducted. Motivational Interviewing (MI) is a person-centred counselling style which can be adapted to brief interventions in which help is offered in thinking through behaviour in the context of values and goals, to decide whether change is needed, and if so, how it may best be achieved.
Methods
This paper reports on an individually randomised two-armed parallel group exploratory trial. The primary hypothesis is that a brief adaptation of MI will be effective in reducing self-reported hazardous and harmful drinking at 3 months. Participants were drawn from the Izhevsk Family Study II, with eligibility determined based on proxy reports of hazardous and harmful drinking in the past year. All participants underwent a health check, with MI subsequently delivered to those in the intervention arm. Signed consent was obtained from those in the intervention arm only at this point. Both groups were then invited for 3 and 12 month follow ups. The control group did not receive any additional intervention.
Results
441 men were randomised. Of these 61 did not have a health check leaving 190 in each trial arm. Follow up at 3 months was high (97% of those having a health check), and very similar in the two trial arms (183 in the intervention and 187 in the control).
No significant differences were detected between the randomised groups in either the primary or the secondary outcomes at three months in the intention to treat analyses. The unadjusted odds ratio (95% CI) for the effect of MI on hazardous and harmful drinking was 0.77 (0.51, 1.16). An adjusted odds ratio of 0.52 (0.28, 0.94) was obtained in the pre-specified per protocol analysis.
Conclusions
This trial demonstrates that it is possible to engage Russian men who drink hazardously in a brief intervention aimed at reducing alcohol related harm. However the results with respect to the efficacy are equivocal and further, larger-scale trials are warranted.
Trial Registration
ISRCTN: ISRCTN82405938
doi:10.1186/1745-6215-12-238
PMCID: PMC3222605  PMID: 22053775
16.  Can Research Assessments Themselves Cause Bias in Behaviour Change Trials? A Systematic Review of Evidence from Solomon 4-Group Studies 
PLoS ONE  2011;6(10):e25223.
Background
The possible effects of research assessments on participant behaviour have attracted research interest, especially in studies with behavioural interventions and/or outcomes. Assessments may introduce bias in randomised controlled trials by altering receptivity to intervention in experimental groups and differentially impacting on the behaviour of control groups. In a Solomon 4-group design, participants are randomly allocated to one of four arms: (1) assessed experimental group; (2) unassessed experimental group (3) assessed control group; or (4) unassessed control group. This design provides a test of the internal validity of effect sizes obtained in conventional two-group trials by controlling for the effects of baseline assessment, and assessing interactions between the intervention and baseline assessment. The aim of this systematic review is to evaluate evidence from Solomon 4-group studies with behavioural outcomes that baseline research assessments themselves can introduce bias into trials.
Methodology/Principal Findings
Electronic databases were searched, supplemented by citation searching. Studies were eligible if they reported appropriately analysed results in peer-reviewed journals and used Solomon 4-group designs in non-laboratory settings with behavioural outcome measures and sample sizes of 20 per group or greater. Ten studies from a range of applied areas were included. There was inconsistent evidence of main effects of assessment, sparse evidence of interactions with behavioural interventions, and a lack of convincing data in relation to the research question for this review.
Conclusions/Significance
There were too few high quality completed studies to infer conclusively that biases stemming from baseline research assessments do or do not exist. There is, therefore a need for new rigorous Solomon 4-group studies that are purposively designed to evaluate the potential for research assessments to cause bias in behaviour change trials.
doi:10.1371/journal.pone.0025223
PMCID: PMC3198466  PMID: 22039407
17.  Alcohol and fatal life trajectories in Russia: understanding narrative accounts of premature male death in the family 
BMC Public Health  2011;11:481.
Background
In the post-Soviet period, Russian working-age men have suffered unusually high mortality rates. Earlier quantitative work found that part of this is attributable to hazardous and harmful patterns of alcohol consumption, which increased in the period of transition at a time of massive social and economic disruption and uncertainty. However, there has been very little work done to document and understand in detail the downward life trajectories of individual men who died prematurely from alcohol-related conditions. Building on an earlier case-control study, this unique qualitative study investigates the perceived interplay between men's drinking careers, their employment and family history, health and eventual death.
Methods
In-depth interviews were conducted with close relatives (most often the widow) of 19 men who died between 2003 and 2005 aged 25-54 years whose close relatives reported that alcohol contributed to their death. The study was conducted in a typical medium-sized Russian city. The relative's accounts were analysed using thematic content analysis.
Results
The accounts describe how hazardous drinking both contributed to serious employment, family and health problems, and was simultaneously used as a coping mechanism to deal with life crises and a decline in social status. The interviews highlighted the importance of the workplace and employment status for shaping men's drinking patterns. Common themes emerged around a culture of drinking in the workplace, peer pressure from colleagues to drink, use of alcohol as remuneration, consuming non-beverage alcohols, Russian-specific drinking patterns, attitudes to treatment, and passive attitudes towards health and drinking.
Conclusions
The study provides a unique insight into the personal decline that lies behind the extremely high working-age mortality due to heavy drinking in Russia, and highlights how health status and hazardous drinking are often closely intertwined with economic and social functioning. Descriptions of the development of drinking careers, hazardous drinking patterns and treatment experiences can be used to plan effective interventions relevant in the Russian context.
doi:10.1186/1471-2458-11-481
PMCID: PMC3144462  PMID: 21689451
18.  Pilot randomized trial of therapeutic hypothermia with serial cranial ultrasound and 18-22 month follow-up for neonatal encephalopathy in a low resource hospital setting in uganda: study protocol 
Trials  2011;12:138.
Background
There is now convincing evidence that in industrialized countries therapeutic hypothermia for perinatal asphyxial encephalopathy increases survival with normal neurological function. However, the greatest burden of perinatal asphyxia falls in low and mid-resource settings where it is unclear whether therapeutic hypothermia is safe and effective.
Aims
Under the UCL Uganda Women's Health Initiative, a pilot randomized controlled trial in infants with perinatal asphyxia was set up in the special care baby unit in Mulago Hospital, a large public hospital with ~20,000 births in Kampala, Uganda to determine:
(i) The feasibility of achieving consent, neurological assessment, randomization and whole body cooling to a core temperature 33-34°C using water bottles
(ii) The temperature profile of encephalopathic infants with standard care
(iii) The pattern, severity and evolution of brain tissue injury as seen on cranial ultrasound and relation with outcome
(iv) The feasibility of neurodevelopmental follow-up at 18-22 months of age
Methods/Design
Ethical approval was obtained from Makerere University and Mulago Hospital. All infants were in-born. Parental consent for entry into the trial was obtained. Thirty-six infants were randomized either to standard care plus cooling (target rectal temperature of 33-34°C for 72 hrs, started within 3 h of birth) or standard care alone. All other aspects of management were the same. Cooling was performed using water bottles filled with tepid tap water (25°C). Rectal, axillary, ambient and surface water bottle temperatures were monitored continuously for the first 80 h. Encephalopathy scoring was performed on days 1-4, a structured, scorable neurological examination and head circumference were performed on days 7 and 17. Cranial ultrasound was performed on days 1, 3 and 7 and scored. Griffiths developmental quotient, head circumference, neurological examination and assessment of gross motor function were obtained at 18-22 months.
Discussion
We will highlight differences in neonatal care and infrastructure that need to be taken into account when considering a large safety and efficacy RCT of therapeutic hypothermia in low and mid resource settings in the future.
Trial registration
Current controlled trials ISRCTN92213707
doi:10.1186/1745-6215-12-138
PMCID: PMC3127769  PMID: 21639927
19.  Effect of a Nutrition Supplement and Physical Activity Program on Pneumonia and Walking Capacity in Chilean Older People: A Factorial Cluster Randomized Trial 
PLoS Medicine  2011;8(4):e1001023.
Alan Dangour and colleagues report results from the CENEX (Cost-effectiveness Evaluation of a Nutritional supplement and EXercise program for older people) trial, which evaluates a nutritional and exercise program aiming to prevent pneumonia and physical decline in Chilean people.
Background
Ageing is associated with increased risk of poor health and functional decline. Uncertainties about the health-related benefits of nutrition and physical activity for older people have precluded their widespread implementation. We investigated the effectiveness and cost-effectiveness of a national nutritional supplementation program and/or a physical activity intervention among older people in Chile.
Methods and Findings
We conducted a cluster randomized factorial trial among low to middle socioeconomic status adults aged 65–67.9 years living in Santiago, Chile. We randomized 28 clusters (health centers) into the study and recruited 2,799 individuals in 2005 (∼100 per cluster). The interventions were a daily micronutrient-rich nutritional supplement, or two 1-hour physical activity classes per week, or both interventions, or neither, for 24 months. The primary outcomes, assessed blind to allocation, were incidence of pneumonia over 24 months, and physical function assessed by walking capacity 24 months after enrolment. Adherence was good for the nutritional supplement (∼75%), and moderate for the physical activity intervention (∼43%). Over 24 months the incidence rate of pneumonia did not differ between intervention and control clusters (32.5 versus 32.6 per 1,000 person years respectively; risk ratio = 1.00; 95% confidence interval 0.61–1.63; p = 0.99). In intention-to-treat analysis, after 24 months there was a significant difference in walking capacity between the intervention and control clusters (mean difference 33.8 meters; 95% confidence interval 13.9–53.8; p = 0.001). The overall cost of the physical activity intervention over 24 months was US$164/participant; equivalent to US$4.84/extra meter walked. The number of falls and fractures was balanced across physical activity intervention arms and no serious adverse events were reported for either intervention.
Conclusions
Chile's nutritional supplementation program for older people is not effective in reducing the incidence of pneumonia. This trial suggests that the provision of locally accessible physical activity classes in a transition economy population can be a cost-effective means of enhancing physical function in later life.
Trial registration
Current Controlled Trials ISRCTN 48153354
Please see later in the article for the Editors' Summary
Editors' Summary
Background
By 2050, about a quarter of the world's population will be aged 60 years or over, with Asia and Latin America experiencing the most dramatic increases in the proportion of older people. For example, in Chile, which has recently undergone rapid demographic transition, the proportion of the population aged 60 years or over has increased from 8% to 12% over the past 25 years.
Current global policy initiatives that promote healthy ageing include an emphasis on adequate nutrient intakes, as longitudinal studies (conducted in high-income countries) suggest that achieving nutritional sufficiency and maintaining moderate levels of physical activity both decrease risk of mortality by preserving immune function and lean body mass and so reduce the numerous risk factors for disability and chronic disease in later life. Such interventions may also decrease the risk of infection, particularly pneumonia, a common cause of death in older people. However, older people in low- and middle-income countries frequently have diets with insufficient calories (energy) and/or micronutrients.
Why Was This Study Done?
Currently, there is no high-quality evidence to support the benefits of improved nutrition and increased physical activity levels from low-income or transition economies, where the ongoing demographic trends suggest that the needs are greatest. National policies aimed at preserving health and function in older people with interventions such as cash-transfers and provision of “food baskets” are often used in Latin American countries, such as Chile, but are rarely formally evaluated. Therefore, the purpose of this study (the Cost-effectiveness Evaluation of a Nutritional supplement and EXercise program for older people—CENEX) was to evaluate Chile's national nutritional supplementation program and/or physical exercise, to investigate whether this program prevented pneumonia and physical functional decline in older people in Santiago, and also to investigate whether these interventions were cost-effective.
What Did the Researchers Do and Find?
The researchers randomly allocated 28 participating health centers in Santiago, Chile, into one of four arms: (1) nutritional supplementation; (2) nutritional supplementation+physical activity; (3) physical activity alone; (4) control. From May to December 2005, 2,799 eligible adults aged 65–67.9 years and living in low to middle socioeconomic circumstances, who attended each health center, were recruited into the study and received the allocated intervention—daily micronutrient-rich nutritional supplement, or two 1-hour physical activity classes per week, or both interventions or neither—for 24 months. The researchers did not know the allocation arm of each patient and over the course of the study assessed the incidence of pneumonia (viral and bacterial as based on diagnosis at the health center or hospital) and physical function was measured by walking capacity (meters walked in 6 minutes). The researchers used administrative records and interviews with staff and patients to estimate the cost-effectiveness of the interventions.
Participant retention in the study was 84%, although only three-quarters of patients receiving the nutritional intervention and less than half (43%) of patients in the physical activity intervention arm adhered to their respective programs. Over 24 months, the incidence rate of pneumonia did not differ between intervention and control groups (32.5 versus 32.6 per 1,000 person years, respectively), but at the end of the study period, there was a significant difference in walking capacity between the intervention and control clusters (mean difference 33.8 meters). The number of falls and fractures in the study arms were similar. The overall costs over 24 months were US$91.00 and US$163.70 per participant for the nutritional supplement and physical activity interventions, respectively. The cost of the physical activity intervention per extra meter walked at 24 months was US$4.84.
What Do These Findings Mean?
The results of this trial suggest that there is little evidence to support the effectiveness of Chile's national nutritional supplementation program in reducing the incidence of pneumonia for 65.0–67.9 year olds. Therefore, given Chile's high burden of infectious and nutrition-related chronic diseases and the associated high health costs, this program should not be considered as a priority preventive public health intervention. However, the provision of locally available physical activity classes to older people could be of clinical benefit, especially in urban settings such as Santiago, although future challenges include increasing the uptake of, and retention to, such programs.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001023.
The World Health Organization provides information about the state of health in Chile
Wikipedia also provides information about health and health care in Chile (please note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
doi:10.1371/journal.pmed.1001023
PMCID: PMC3079648  PMID: 21526229
20.  A randomised controlled trial investigating the effect of vitamin B12 supplementation on neurological function in healthy older people: the Older People and Enhanced Neurological function (OPEN) study protocol [ISRCTN54195799] 
Nutrition Journal  2011;10:22.
Background
Vitamin B12 deficiency is common in older people and the prevalence increases with age. Vitamin B12 deficiency may present as macrocytic anaemia, subacute combined degeneration of the spinal cord, or as neuropathy, but is often asymptomatic in older people. The diagnosis and indications for treatment are clear for individuals with low plasma levels of vitamin B12 in the setting of megaloblastic anaemia and neuropathy, but the relevance of treatment of vitamin B12 deficiency in the absence of such clinical signs is uncertain.
Methods
The aim of the present study is to assess whether dietary supplementation with crystalline vitamin B12 will improve electrophysiological indices of neurological function in older people who have biochemical evidence of vitamin B12 insufficiency in the absence of anaemia. To test this hypothesis we designed a randomized double-blind placebo-controlled trial involving 200 older people aged 75 years or greater who were randomly allocated to receive either a daily oral tablet containing 1 mg vitamin B12 or a matching placebo tablet. The primary outcome assessed at 12 months is change in electrophysiological indices of peripheral and central neurosensory responses required for mobility and sensory function. We here report the detailed study protocol.
Conclusions
In view of the high prevalence of vitamin B12 deficiency in later life, the present trial could have considerable significance for public health.
doi:10.1186/1475-2891-10-22
PMCID: PMC3062585  PMID: 21396086
21.  The BRACELET Study: surveys of mortality in UK neonatal and paediatric intensive care trials 
Trials  2010;11:65.
Background
The subject of death and bereavement in the context of randomised controlled trials in neonatal or paediatric intensive care is under-researched. The objectives of this phase of the Bereavement and RAndomised ControlLEd Trials (BRACELET) Study were to determine trial activity in UK neonatal and paediatric intensive care (2002-06); numbers of deaths before hospital discharge; and variation in mortality across intensive care units and trials and to determine whether bereavement support policies were available within trials. These are essential prerequisites to considering the implications of future policies and practice subsequent to bereavement following a child's enrolment in a trial.
Methods
The units survey involved neonatal units providing level 2 or 3 care, and paediatric units providing level II care or above; the trials survey involved trials where allocation was randomized and interventions were delivered to intensive care patients, or to parents but designed to affect patient outcomes.
Results
Information was available from 191/220 (87%) neonatal units (149 level 2 or 3 care); and 28/32 (88%) paediatric units. 90/177 (51%) eligible responding units participated in one or more trial (76 neonatal, 14 paediatric) and 54 neonatal units and 6 paediatric units witnessed at least one death. 50 trials were identified (36 neonatal, 14 paediatric). 3,137 babies were enrolled in neonatal trials, 210 children in paediatric trials. Deaths ranged 0-278 (median [IQR interquartile range] 2 [1, 14.5]) per neonatal trial, 0-4 (median [IQR] 1 [0, 2.5]) per paediatric trial. 534 (16%) participants died post-enrolment: 522 (17%) in neonatal trials, 12 (6%) in paediatric trials. Trial participants ranged 1-236 (median [IQR] 21.5 [8, 39.8]) per neonatal unit, 1-53 (median [IQR] 11.5 [2.3, 33.8]) per paediatric unit. Deaths ranged 0-37 (median [IQR] 3.5 [0.3, 8.8]) per neonatal unit, 0-7 (median [IQR] 0.5 [0, 1.8]) per paediatric unit. Three trials had a formal policy for responding to bereavement.
Conclusions
A substantial number of deaths after trial enrolment were identified, distributed over many trials and units. Few trial teams had responses to bereavement in place. Those with the largest numbers of deaths might be best placed to collaborate in developing and assessing responses to bereavement.
doi:10.1186/1745-6215-11-65
PMCID: PMC2896344  PMID: 20504341
22.  The WOMAN Trial (World Maternal Antifibrinolytic Trial): tranexamic acid for the treatment of postpartum haemorrhage: an international randomised, double blind placebo controlled trial 
Trials  2010;11:40.
Background
Each year, worldwide about 530,000 women die from causes related to pregnancy and childbirth. Of the deaths 99% are in low and middle income countries. Obstetric haemorrhage is the leading cause of maternal mortality, most occurring in the postpartum period. Systemic antifibrinolytic agents are widely used in surgery to prevent clot breakdown (fibrinolysis) in order to reduce surgical blood loss. At present there is little reliable evidence from randomised trials on the effectiveness of tranexamic acid in the treatment of postpartum haemorrhage.
Methods
The Trial aims to determine the effect of early administration of tranexamic acid on mortality, hysterectomy and other morbidities (surgical interventions, blood transfusion, risk of non-fatal vascular events) in women with clinically diagnosed postpartum haemorrhage. The use of health services and safety, especially thromboembolic effect, on breastfed babies will also be assessed. The trial will be a large, pragmatic, randomised, double blind, placebo controlled trial among 15,000 women with a clinical diagnosis of postpartum haemorrhage. All legally adult women with clinically diagnosed postpartum haemorrhage following vaginal delivery of a baby or caesarean section will potentially be eligible. The fundamental eligibility criterion is the responsible clinician's 'uncertainty' as to whether or not to use an antifibrinolytic agent in a particular woman with postpartum haemorrhage. Treatment will entail a dose of tranexamic acid (1 gram by intravenous injection) or placebo (sodium chloride 0.9%) will be given as soon as possible after randomisation. A second dose may be given if after 30 minutes bleeding continues, or if it stops and restarts within 24 hours after the first dose.
The main analyses will be on an 'intention to treat' basis, irrespective of whether the allocated treatment was received or not. Subgroup analyses for the primary outcome will be based on type of delivery; administration or not of prophylactic uterotonics; and on whether the clinical decision to consider trial entry was based primarily on estimated blood loss alone or on haemodynamic instability. A study with 15,000 women will have over 90% power to detect a 25% reduction from 4% to 3% in the primary endpoint of mortality or hysterectomy.
Trial registration
Current Controlled Trials: ISRCTN76912190 and Clinicaltrials.gov ID: NCT00872469
doi:10.1186/1745-6215-11-40
PMCID: PMC2864262  PMID: 20398351
24.  Inhaled Nitric Oxide in preterm infants: a systematic review and individual patient data meta-analysis 
BMC Pediatrics  2010;10:15.
Background
Preterm infants requiring assisted ventilation are at significant risk of both pulmonary and cerebral injury. Inhaled Nitric Oxide, an effective therapy for pulmonary hypertension and hypoxic respiratory failure in the full term infant, has also been studied in preterm infants. The most recent Cochrane review of preterm infants includes 11 studies and 3,370 participants. The results show a statistically significant reduction in the combined outcome of death or chronic lung disease (CLD) in two studies with routine use of iNO in intubated preterm infants. However, uncertainty remains as a larger study (Kinsella 2006) showed no significant benefit for iNO for this combined outcome. Also, trials that included very ill infants do not demonstrate significant benefit. One trial of iNO treatment at a later postnatal age reported a decrease in the incidence of CLD. The aim of this individual patient meta-analysis is to confirm or refute these potentially conflicting results and to determine the extent to which patient or treatment characteristics may explain the results and/or may predict benefit from inhaled Nitric Oxide in preterm infants.
Methods/Design
The Meta-Analysis of Preterm Patients on inhaled Nitric Oxide (MAPPiNO) Collaboration will perform an individual patient data meta-analysis to answer these important clinical questions. Studies will be included if preterm infants receiving assisted ventilation are randomized to receive inhaled Nitric Oxide or to a control group. The individual patient data provided by the Collaborators will be analyzed on an intention-to-treat basis where possible. Binary outcomes will be analyzed using log-binomial regression models and continuous outcomes will be analyzed using linear fixed effects models. Adjustments for trial differences will be made by including the trial variable in the model specification.
Discussion
Thirteen (13) trials, with a total of 3567 infants are eligible for inclusion in the MAPPiNO systematic review. To date 11 trials (n = 3298, 92% of available patients) have agreed to participate. Funding was successfully granted from Ikaria Inc as an unrestricted grant. A collaborative group was formed in 2006 with data collection commencing in 2007. It is anticipated that data analysis will commence in late 2009 with results being publicly available in 2010.
doi:10.1186/1471-2431-10-15
PMCID: PMC2860486  PMID: 20331899
25.  Control of hyperglycaemia in paediatric intensive care (CHiP): study protocol 
BMC Pediatrics  2010;10:5.
Background
There is increasing evidence that tight blood glucose (BG) control improves outcomes in critically ill adults. Children show similar hyperglycaemic responses to surgery or critical illness. However it is not known whether tight control will benefit children given maturational differences and different disease spectrum.
Methods/Design
The study is an randomised open trial with two parallel groups to assess whether, for children undergoing intensive care in the UK aged ≤ 16 years who are ventilated, have an arterial line in-situ and are receiving vasoactive support following injury, major surgery or in association with critical illness in whom it is anticipated such treatment will be required to continue for at least 12 hours, tight control will increase the numbers of days alive and free of mechanical ventilation at 30 days, and lead to improvement in a range of complications associated with intensive care treatment and be cost effective.
Children in the tight control group will receive insulin by intravenous infusion titrated to maintain BG between 4 and 7.0 mmol/l. Children in the control group will be treated according to a standard current approach to BG management.
Children will be followed up to determine vital status and healthcare resources usage between discharge and 12 months post-randomisation. Information regarding overall health status, global neurological outcome, attention and behavioural status will be sought from a subgroup with traumatic brain injury (TBI).
A difference of 2 days in the number of ventilator-free days within the first 30 days post-randomisation is considered clinically important. Conservatively assuming a standard deviation of a week across both trial arms, a type I error of 1% (2-sided test), and allowing for non-compliance, a total sample size of 1000 patients would have 90% power to detect this difference. To detect effect differences between cardiac and non-cardiac patients, a target sample size of 1500 is required. An economic evaluation will assess whether the costs of achieving tight BG control are justified by subsequent reductions in hospitalisation costs.
Discussion
The relevance of tight glycaemic control in this population needs to be assessed formally before being accepted into standard practice.
Trial Registration
Current Controlled Trials ISRCTN61735247
doi:10.1186/1471-2431-10-5
PMCID: PMC2830203  PMID: 20137090

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