A Bayesian spatio-temporal study of the association between meteorological factors and the spread of COVID-19.

BACKGROUND: The spread of COVID-19 has brought challenges to health, social and economic systems around the world. With little to no prior immunity in the global population, transmission has been driven primarily by human interaction. However, as with common respiratory illnesses such as influenza some authors have suggested COVID-19 may become seasonal as immunity grows. Despite this, the effects of meteorological conditions on the spread of COVID-19 are poorly understood. Previous studies have produced contrasting results, due in part to limited and inconsistent study designs. METHODS: This study investigates the effects of meteorological conditions on COVID-19 infections in England using a Bayesian conditional auto-regressive spatio-temporal model. Our data consists of daily case counts from local authorities in England during the first lockdown from March-May 2020. During this period, legal restrictions limiting human interaction remained consistent, minimising the impact of changes in human interaction. We introduce a lag from weather conditions to daily cases to accommodate an incubation period and delays in obtaining test results. By modelling spatio-temporal random effects we account for the nature of a human transmissible virus, allowing the model to isolate meteorological effects. RESULTS: Our analysis considers cases across England's 312 local authorities for a 55-day period. We find relative humidity is negatively associated with COVID-19 cases, with a 1% increase in relative humidity corresponding to a reduction in relative risk of 0.2% [95% highest posterior density (HPD): 0.1-0.3%]. However, we find no evidence for temperature, wind speed, precipitation or solar radiation being associated with COVID-19 spread. The inclusion of weekdays highlights systematic under reporting of cases on weekends with between 27.2-43.7% fewer cases reported on Saturdays and 26.3-44.8% fewer cases on Sundays respectively (based on 95% HPDs). CONCLUSION: By applying a Bayesian conditional auto-regressive model to COVID-19 case data we capture the underlying spatio-temporal trends present in the data. This enables us to isolate the main meteorological effects and make robust claims about the association of weather variables to COVID-19 incidence. Overall, we find no strong association between meteorological factors and COVID-19 transmission.

Cluster randomized controlled trial analysis at the cluster level: The clan command.

In this article, we introduce a new command, clan, that conducts a cluster-level analysis of cluster randomized trials. The command simplifies adjusting for individual- and cluster-level covariates and can also account for a stratified design. It can be used to analyze a continuous, binary, or rate outcome.

Understanding why EmpaTeach did not reduce teachers' use of violence in Nyarugusu Refugee Camp: A quantitative process evaluation of a school-based violence prevention intervention.

EmpaTeach was the first intervention to address teacher violence to be tested in a humanitarian setting and the first to focus on reducing impulsive use of violence, but a cluster randomised trial found no evidence that the intervention was effective in reducing physical and emotional violence from teachers. We aimed to understand why. We conducted a quantitative process evaluation to describe the intervention implementation process (what was implemented and how); examine teachers' adoption of positive teaching practices (was the content of the intervention taken up by participants), and test mechanisms of impact underlying the program theory (how the intervention was supposed to produce change). Despite participation in the intervention activities and adoption of intervention-recommended strategies (classroom management and positive disciplinary methods), we show that teachers who used more positive discipline did not appear to use less violence; and teachers in intervention schools did not experience gains in intermediate outcomes such as empathy, growth mindset, self-efficacy or social support. Our findings suggest that the intervention did not work due to the failure of some key hypothesised mechanisms, rather than because of implementation challenges.

Coach-Supported Versus Self-guided Digital Training Course for a Problem-solving Psychological Intervention for Nonspecialists: Protocol for a Pre-Post Nested Randomized Controlled Trial.

BACKGROUND: Psychosocial interventions delivered by nonspecialists can be effective at reducing common adolescent mental health problems in low-resource settings. However, there is a lack of evidence on resource-efficient methods for building capacity to deliver these interventions. OBJECTIVE: The objective of this study is to evaluate the effects of a digital training (DT) course, delivered in a self-guided format or with coaching, on nonspecialists' competency to deliver a problem-solving intervention intended for adolescents with common mental health problems in India. METHODS: We will conduct a pre-post study with a nested parallel, 2-arm, individually randomized controlled trial. The study aims to recruit 262 participants, randomized 1:1 to receive either a self-guided DT course or a DT course with weekly individualized coaching provided remotely by telephone. In both arms, the DT will be accessed over 4 to 6 weeks. Participants will be nonspecialists (ie, without prior practice-based training in psychological therapies) recruited from among university students and affiliates of nongovernmental organizations in Delhi and Mumbai, India. RESULTS: Outcomes will be assessed at baseline and 6 weeks post randomization using a knowledge-based competency measure that incorporates a multiple-choice quiz format. The primary hypothesis is that self-guided DT will lead to increased competency scores among novices with no prior experience of delivering psychotherapies. The secondary hypothesis is that digital training with coaching will have an incremental effect on competency scores compared with DT alone. The first participant was enrolled on April 4, 2022. CONCLUSIONS: The study will address an evidence gap on the effectiveness of training methods for nonspecialist providers of adolescent mental health interventions in low-resource settings. The findings from this study will be used to support wider efforts to scale up evidence-based mental health interventions for young people. TRIAL REGISTRATION: ClinicalTrials.gov NCT05290142; https://clinicaltrials.gov/ct2/show/NCT05290142. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/41981.

Developing knowledge-based psychotherapeutic competencies in non-specialist providers: A pre-post study with a nested randomised controlled trial of a coach-supported versus self-guided digital training course for a problem-solving psychological intervention in India.

We evaluated a digital learning programme for non-specialists to develop knowledge-based competencies in a problem-solving intervention for adolescents to examine the overall impact of training on knowledge-based competencies among learners; and to compare the effects of two training conditions (self-guided digital training with or without coaching) in a nested parallel, two-arm, individually randomised controlled trial. Eligible participants were 18 or older; fluent in Hindi or English; able to access digital training; and had no prior experience of delivering structured psychotherapies. 277 participants were enrolled from 31 March 2022 to 19 June 2022 of which 230 (83%) completed the study. There was a significant increase in competency score from pre-training (Mean = 7.01, SD = 3.29) to post-training (Mean = 8.88, SD = 3.80), 6 weeks after the pre-training assessment. Knowledge competency scores showed larger increase among participants randomised to the coaching arm (AMD = 1.09, 95% CI 0.26-1.92, p = 0.01) with an effect size (d) of 0.33 (95% CI 0.08-0.58). More participants completed training in the coaching arm (n = 96, 69.6%) compared to the self-guided training arm (n = 56, 40.3%). In conclusion, a coach-supported remote digital training intervention is associated with enhanced participation by learners and increased psychotherapeutic knowledge competencies.

Pilot randomised controlled trial of a remotely delivered online intervention for adolescent mental health problems in India: lessons learned about low acceptability and feasibility during the COVID-19 pandemic.

BACKGROUND: 'POD Adventures' is a gamified problem-solving intervention delivered via smartphone app, and supported by non-specialist counsellors for a target population of secondary school students in India during the COVID-19 pandemic. AIMS: To evaluate the feasibility and acceptability of undertaking a randomised controlled trial of POD Adventures when delivered online with telephone support from counsellors. METHOD: We conducted a parallel, two-arm, individually randomised pilot-controlled trial with 11 secondary schools in Goa, India. Participants received either the POD Adventures intervention delivered over 4 weeks or usual care comprising information about local mental health services and national helplines. Outcomes were assessed at two timepoints: baseline and 6 weeks post-randomisation. RESULTS: Seventy-nine classroom sensitisation sessions reaching a total of 1575 students were conducted. Ninety-two self-initiated study referrals (5.8%) were received, but only 11 participants enrolled in the study. No intervention arm participants completed the intervention. Outcomes at 6 weeks were not available for intervention arm participants (n = 5), and only four control arm participants completed outcomes. No qualitative interviews or participant satisfaction measures were completed because participants could not be reached by the study team. CONCLUSIONS: Despite modifications to address barriers arising from COVID-19 restrictions, online delivery was not feasible in the study context. Low recruitment and missing feasibility and acceptability data make it difficult to draw conclusions about intervention engagement and indicative clinical outcomes. Prior findings showing high uptake, adherence and engagement with POD Adventures when delivered in a school-based context suggest that an online study and delivery posed the biggest barriers to study participation and engagement.

School violence, depression symptoms, and school climate: a cross-sectional study of Congolese and Burundian refugee children.

Forcibly displaced children are at increased risk of violence and mental health disorders. In refugee contexts, schools are generally perceived as protective environments where children can build a sense of belonging and recover from trauma. Evidence shows that positive school climates can support student skills development and socio-emotional wellbeing and protect them against a host of adverse outcomes. However, schools are also places where children may experience violence, from both teachers and peers. Prevalence estimates of violence against children in humanitarian settings are scarce and evidence on the relationship between school climate and student outcomes in these contexts is non-existent. The aim of the study is to estimate the prevalence of school-based violence against children and to explore the association between perceptions of school climate and students' experiences and use of violence and their depression symptoms. We relied on data from a cross-sectional survey of students and teachers in all primary and secondary schools in Nyarugusu Refugee Camp in Tanzania, conducted as part of a cluster randomised controlled trial, to compute prevalence estimates and used mixed logistic regression analysis to assess the association between school climate and students' outcomes. We found that students in Nyarugusu experienced high levels of violence from both peers and teachers in both primary and secondary schools in the camp, with little difference between boys and girls. Nearly one in ten students screened positive for symptoms of depression. We found that opportunities for students and teachers to be involved in decision-making were associated with higher odds of violent discipline and teachers' self-efficacy was a significant protective factor against student depression symptoms. However, generally, school-level perceptions of school climate were not associated with student outcomes after adjusting for potential confounders. Our findings suggest that interventions to prevent and respond to teacher and peer violence in schools and to support students' mental health are urgently needed. Our results challenge the assumption that education environments are inherently protective for children and call for further investigation of norms around violence among students and teachers to better understand the role of school climate in refugee settings.

Linear mixed models to handle missing at random data in trial-based economic evaluations.

Trial-based cost-effectiveness analyses (CEAs) are an important source of evidence in the assessment of health interventions. In these studies, cost and effectiveness outcomes are commonly measured at multiple time points, but some observations may be missing. Restricting the analysis to the participants with complete data can lead to biased and inefficient estimates. Methods, such as multiple imputation, have been recommended as they make better use of the data available and are valid under less restrictive Missing At Random (MAR) assumption. Linear mixed effects models (LMMs) offer a simple alternative to handle missing data under MAR without requiring imputations, and have not been very well explored in the CEA context. In this manuscript, we aim to familiarize readers with LMMs and demonstrate their implementation in CEA. We illustrate the approach on a randomized trial of antidepressants, and provide the implementation code in R and Stata. We hope that the more familiar statistical framework associated with LMMs, compared to other missing data approaches, will encourage their implementation and move practitioners away from inadequate methods.

Designing Multi-arm Multistage Adaptive Trials for Neuroprotection in Progressive Multiple Sclerosis.

There are few treatments shown to slow disability progression in progressive multiple sclerosis (PMS). One challenge has been efficiently testing the pipeline of candidate therapies from preclinical studies in clinical trials. Multi-arm multistage (MAMS) platform trials may accelerate evaluation of new therapies compared to traditional sequential clinical trials. We describe a MAMS design in PMS focusing on selection of interim and final outcome measures, sample size, and statistical considerations. The UK MS Society Expert Consortium for Progression in MS Clinical Trials reviewed recent phase II and III PMS trials to inform interim and final outcome selection and design measures. Simulations were performed to evaluate trial operating characteristics under different treatment effect, recruitment rate, and sample size assumptions. People with MS formed a patient and public involvement group and contributed to the trial design, ensuring it would meet the needs of the MS community. The proposed design evaluates 3 experimental arms compared to a common standard of care arm in 2 stages. Stage 1 (interim) outcome will be whole brain atrophy on MRI at 18 months, assessed for 123 participants per arm. Treatments with sufficient evidence for slowing brain atrophy will continue to the second stage. The stage 2 (final) outcome will be time to 6-month confirmed disability progression, based on a composite clinical score comprising the Expanded Disability Status Scale, Timed 25-Foot Walk test, and 9-Hole Peg Test. To detect a hazard ratio of 0.75 for this primary final outcome with 90% power, 600 participants per arm are required. Assuming one treatment progresses to stage 2, the trial will recruit ≈1,900 participants and last ≈6 years. This is approximately two-thirds the size and half the time of separate 2-arm phase II and III trials. The proposed MAMS trial design will substantially reduce duration and sample size compared to traditional clinical trials, accelerating discovery of effective treatments for PMS. The design was well-received by people with multiple sclerosis. The practical and statistical principles of MAMS trial design may be applicable to other neurodegenerative conditions to facilitate efficient testing of new therapies.

Is positive school climate associated with better adolescent mental health? Longitudinal study of young people in England.

BACKGROUND AND OBJECTIVES: Studies suggest that individual student-reported connection to school is associated with better mental health. However, there is less evidence for associations between schools' overall school climate and the mental health of their students. This may reflect limitations in which mental health outcomes have been examined. We conducted a large longitudinal study in schools, hypothesising that we would find associations at both the student and school levels between student-reported positive school climate, and reduced student conduct and emotional problems and improved mental wellbeing. METHODS: We tracked students in 20 English secondary schools from near the end of the first year of secondary school (age 11/12) over 3 years using reliable measures of school climate and mental health. RESULTS: We found associations between student-level reports of positive school climate at baseline, and reduced conduct and emotional problems and better mental wellbeing at 3-year follow-up adjusting for various potential confounders. We also found some evidence of adjusted associations between baseline school-level measures of overall positive climate and better student mental health at follow-up. However, these student- and school-level associations reduced considerably when also adjusting for baseline mental health. CONCLUSIONS: Our findings suggest that there are associations between school climate and student mental health at both the student and school level but these associations are complex and not necessarily causal.

The EmpaTeach intervention for reducing physical violence from teachers to students in Nyarugusu Refugee Camp: A cluster-randomised controlled trial.

BACKGROUND: School-based violence prevention interventions offer enormous potential to reduce children's experience of violence perpetrated by teachers, but few have been rigorously evaluated globally and, to the best of our knowledge, none in humanitarian settings. We tested whether the EmpaTeach intervention could reduce physical violence from teachers to students in Nyarugusu Refugee Camp, Tanzania. METHODS AND FINDINGS: We conducted a 2-arm cluster-randomised controlled trial with parallel assignment. A complete sample of all 27 primary and secondary schools in Nyarugusu Refugee Camp were approached and agreed to participate in the study. Eligible students and teachers participated in cross-sectional baseline, midline, and endline surveys in November/December 2018, May/June 2019, and January/February 2020, respectively. Fourteen schools were randomly assigned to receive a violence prevention intervention targeted at teachers implemented in January-March 2019; 13 formed a wait-list control group. The EmpaTeach intervention used empathy-building exercises and group work to equip teachers with self-regulation, alternative discipline techniques, and classroom management strategies. Allocation was not concealed due to the nature of the intervention. The primary outcome was students' self-reported experience of physical violence from teachers, assessed at midline using a modified version of the ISPCAN Child Abuse Screening Tool-Child Institutional. Secondary outcomes included student reports of emotional violence, depressive symptoms, and school attendance. Analyses were by intention to treat, using generalised estimating equations adjusted for stratification factors. No schools left the study. In total, 1,493 of the 1,866 (80%) randomly sampled students approached for participation took part in the baseline survey; at baseline 54.1% of students reported past-week physical violence from school staff. In total, 1,619 of 1,978 students (81.9%) took part in the midline survey, and 1,617 of 2,032 students (79.6%) participated at endline. Prevalence of past-week violence at midline was not statistically different in intervention (408 of 839 students, 48.6%) and control schools (412 of 777 students, 53.0%; risk ratio = 0.91, 95% CI 0.80 to 1.02, p = 0.106). No effect was detected on secondary outcomes. A camp-wide educational policy change during intervention implementation resulted in 14.7% of teachers in the intervention arm receiving a compressed version of the intervention, but exploratory analyses showed no difference in our primary outcome by school-level adherence to the intervention. Main study limitations included the small number of schools in the camp, which limited statistical power to detect small differences between intervention and control groups. We also did not assess the test-retest reliability of our outcome measures, and interviewers were unmasked to intervention allocation. CONCLUSIONS: There was no evidence that the EmpaTeach intervention effectively reduced physical violence from teachers towards primary or secondary school students in Nyarugusu Refugee Camp. Further research is needed to develop and test interventions to prevent teacher violence in humanitarian settings. TRIAL REGISTRATION: clinicaltrials.gov (NCT03745573).

An Intervention Delivered by Mobile Phone Instant Messaging to Increase Acceptability and Use of Effective Contraception Among Young Women in Bolivia: Randomized Controlled Trial.

BACKGROUND: Although the most effective methods of contraception are available in Bolivia, unmet need for contraception among women aged 15 to 19 years is estimated to be 38% (2008), and the adolescent fertility rate is 71 per 1000 women (2016). Mobile phones are a popular mode to deliver health behavior support. We developed a contraceptive behavioral intervention for young Bolivian women delivered by mobile phone and guided by behavioral science. The intervention consists of short instant messages sent through an app over 4 months. OBJECTIVE: This trial aimed to evaluate the effect of the intervention on young Bolivian women's use of and attitudes toward the effective contraceptive methods available in Bolivia. METHODS: This was a parallel group, individually randomized superiority trial with a 1:1 allocation ratio. Women were eligible if they were aged 16 to 24 years, owned a personal Android mobile phone, lived in La Paz or El Alto, reported an unmet need for contraception, and could read Spanish. The target sample size was 1310 participants. Participants allocated to the intervention had access to an app with standard family planning information and intervention messages. Participants allocated to the control group had access to the same app and control messages. Coprimary outcomes were use of effective contraception and acceptability of at least one method of effective contraception at 4 months. Secondary outcomes were use of effective contraception during the study, acceptability of the individual methods, service uptake, unintended pregnancy, and abortion. Process outcomes included knowledge, perceived norms, personal agency, and intention. Outcomes were analyzed using logistic and linear regression. We also asked participants about physical violence. RESULTS: A total of 640 participants were enrolled, and 67.0% (429) of them contributed follow-up data for the coprimary outcome, the use of effective contraception. There was no evidence that use differed between the groups (33% control vs 37% intervention; adjusted odds ratio [OR] 1.19, 95% CI 0.80 to 1.77; P=.40). There was a borderline significant effect regarding acceptability (63% control vs 72% intervention; adjusted OR 1.49, 95% CI 0.98 to 2.28; P=.06). There were no statistically significant differences in any of the secondary or process outcomes. The intervention dose received was low. In the control group, 2.8% (6/207) reported experiencing physical violence compared with 1.9% (4/202) in the intervention group (Fisher exact test P=.75). CONCLUSIONS: This trial was unable to provide definitive conclusions regarding the effect of the intervention on use and acceptability of effective contraception because of under recruitment. Although we cannot strongly recommend implementation, the results suggest that it would be safe and may increase the acceptability of effective contraception if the intervention messages were offered alongside the download of the app. TRIAL REGISTRATION: ClinicalTrials.gov NCT02905526; https://clinicaltrials.gov/ct2/show/NCT02905526.

Drug therapy for delirium in terminally ill adults.

BACKGROUND: Delirium is a syndrome characterised by an acute disturbance of attention and awareness which develops over a short time period and fluctuates in severity over the course of the day. It is commonly experienced during inpatient admission in the terminal phase of illness. It can cause symptoms such as agitation and hallucinations and is distressing for terminally ill people, their families and staff. Delirium may arise from any number of causes and treatment should aim to address these causes. When this is not possible, or treatment is unsuccessful, drug therapy to manage the symptoms may become necessary. This is the second update of the review first published in 2004. OBJECTIVES: To evaluate the effectiveness and safety of drug therapies to manage delirium symptoms in terminally ill adults. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, CINAHL and PsycINFO from inception to July 2019, reference lists of retrieved papers, and online trial registries. SELECTION CRITERIA: We included randomised controlled trials of drug therapies in any dose by any route, compared to another drug therapy, a non-pharmacological approach, placebo, standard care or wait-list control, for the management of delirium symptoms in terminally ill adults (18 years or older). DATA COLLECTION AND ANALYSIS: We independently screened citations, extracted data and assessed risk of bias. Primary outcomes were delirium symptoms; agitation score; adverse events. Secondary outcomes were: use of rescue medication; cognitive status; survival. We applied the GRADE approach to assess the overall quality of the evidence for each outcome and we include eight 'Summary of findings' tables. MAIN RESULTS: We included four studies (three new to this update), with 399 participants. Most participants had advanced cancer or advanced AIDS, and mild- to moderate-severity delirium. Meta-analysis was not possible because no two studies examined the same comparison. Each study was at high risk of bias for at least one criterion. Most evidence was low to very low quality, downgraded due to very serious study limitations, imprecision or because there were so few data. Most studies reported delirium symptoms; two reported agitation scores; three reported adverse events with data on extrapyramidal effects; and none reported serious adverse events. 1. Haloperidol versus placebo There may be little to no difference between placebo and haloperidol in delirium symptoms within 24 hours (mean difference (MD) 0.34, 95% confidence interval (CI) -0.07 to 0.75; 133 participants). Haloperidol may slightly worsen delirium symptoms compared with placebo at 48 hours (MD 0.49, 95% CI 0.10 to 0.88; 123 participants with mild- to moderate-severity delirium). Haloperidol may reduce agitation slightly compared with placebo between 24 and 48 hours (MD -0.14, 95% -0.28 to -0.00; 123 participants with mild- to moderate-severity delirium). Haloperidol probably increases extrapyramidal adverse effects compared with placebo (MD 0.79, 95% CI 0.17 to 1.41; 123 participants with mild- to moderate-severity delirium). 2. Haloperidol versus risperidone There may be little to no difference in delirium symptoms with haloperidol compared with risperidone within 24 hours (MD -0.42, 95% CI -0.90 to 0.06; 126 participants) or 48 hours (MD -0.36, 95% CI -0.92 to 0.20; 106 participants with mild- to moderate-severity delirium). Agitation scores and adverse events were not reported for this comparison. 3. Haloperidol versus olanzapine We are uncertain whether haloperidol reduces delirium symptoms compared with olanzapine within 24 hours (MD 2.36, 95% CI -0.75 to 5.47; 28 participants) or 48 hours (MD 1.90, 95% CI -1.50 to 5.30, 24 participants). Agitation scores and adverse events were not reported for this comparison. 4. Risperidone versus placebo Risperidone may slightly worsen delirium symptoms compared with placebo within 24 hours (MD 0.76, 95% CI 0.30 to 1.22; 129 participants); and at 48 hours (MD 0.85, 95% CI 0.32 to 1.38; 111 participants with mild- to moderate-severity delirium). There may be little to no difference in agitation with risperidone compared with placebo between 24 and 48 hours (MD -0.05, 95% CI -0.19 to 0.09; 111 participants with mild- to moderate-severity delirium). Risperidone may increase extrapyramidal adverse effects compared with placebo (MD 0.73 95% CI 0.09 to 1.37; 111 participants with mild- to moderate-severity delirium). 5. Lorazepam plus haloperidol versus placebo plus haloperidol We are uncertain whether lorazepam plus haloperidol compared with placebo plus haloperidol improves delirium symptoms within 24 hours (MD 2.10, 95% CI -1.00 to 5.20; 50 participants with moderate to severe delirium), reduces agitation within 24 hours (MD 1.90, 95% CI 0.90 to 2.80; 52 participants), or increases adverse events (RR 0.70, 95% CI -0.19 to 2.63; 31 participants with moderate to severe delirium). 6. Haloperidol versus chlorpromazine We are uncertain whether haloperidol reduces delirium symptoms compared with chlorpromazine at 48 hours (MD 0.37, 95% CI -4.58 to 5.32; 24 participants). Agitation scores were not reported. We are uncertain whether haloperidol increases adverse events compared with chlorpromazine (MD 0.46, 95% CI -4.22 to 5.14; 24 participants). 7. Haloperidol versus lorazepam We are uncertain whether haloperidol reduces delirium symptoms compared with lorazepam at 48 hours (MD -4.88, 95% CI -9.70 to 0.06; 17 participants). Agitation scores were not reported. We are uncertain whether haloperidol increases adverse events compared with lorazepam (MD -6.66, 95% CI -14.85 to 1.53; 17 participants). 8. Lorazepam versus chlorpromazine We are uncertain whether lorazepam reduces delirium symptoms compared with chlorpromazine at 48 hours (MD 5.25, 95% CI 0.38 to 10.12; 19 participants), or increases adverse events (MD 7.12, 95% CI 1.08 to 15.32; 18 participants). Agitation scores were not reported. SECONDARY OUTCOMES: use of rescue medication, cognitive impairment, survival There were insufficient data to draw conclusions or assess GRADE. AUTHORS' CONCLUSIONS: We found no high-quality evidence to support or refute the use of drug therapy for delirium symptoms in terminally ill adults. We found low-quality evidence that risperidone or haloperidol may slightly worsen delirium symptoms of mild to moderate severity for terminally ill people compared with placebo. We found moderate- to low-quality evidence that haloperidol and risperidone may slightly increase extrapyramidal adverse events for people with mild- to moderate-severity delirium. Given the small number of studies and participants on which current evidence is based, further research is essential.

Reference-based multiple imputation for missing data sensitivity analyses in trial-based cost-effectiveness analysis.

Missing data are a common issue in cost-effectiveness analysis (CEA) alongside randomised trials and are often addressed assuming the data are 'missing at random'. However, this assumption is often questionable, and sensitivity analyses are required to assess the implications of departures from missing at random. Reference-based multiple imputation provides an attractive approach for conducting such sensitivity analyses, because missing data assumptions are framed in an intuitive way by making reference to other trial arms. For example, a plausible not at random mechanism in a placebo-controlled trial would be to assume that participants in the experimental arm who dropped out stop taking their treatment and have similar outcomes to those in the placebo arm. Drawing on the increasing use of this approach in other areas, this paper aims to extend and illustrate the reference-based multiple imputation approach in CEA. It introduces the principles of reference-based imputation and proposes an extension to the CEA context. The method is illustrated in the CEA of the CoBalT trial evaluating cognitive behavioural therapy for treatment-resistant depression. Stata code is provided. We find that reference-based multiple imputation provides a relevant and accessible framework for assessing the robustness of CEA conclusions to different missing data assumptions.

A randomized controlled trial of an intervention delivered by mobile phone text message to increase the acceptability of effective contraception among young women in Palestine.

BACKGROUND: Research has shown that mobile phone contraceptive behavioral interventions can increase knowledge and use of contraception, but other studies have failed to demonstrate a beneficial effect. The objective of this trial was to estimate the effect of a contraceptive behavioral intervention delivered by mobile phone text message on young Palestinian women's attitudes towards effective contraception. METHODS: We conducted a randomized controlled trial among women aged 18-24 years living in the West Bank, who were not using an effective method of contraception. The intervention group received zero to three messages per day (113 messages for female-not married and 120 messages for female-married) for 120 days. The control group received 16 messages over 120 days about trial participation. The primary outcome was acceptability of at least one method of effective contraception at 4 months. Secondary outcomes were use of effective contraception at 4 months and any use during the study, acceptability of individual methods, service uptake, unintended pregnancy and abortion. Process outcomes included knowledge, perceived norms, personal agency and intention. All outcomes were self-reported. We analyzed the outcomes using logistic and linear regression. RESULTS: A total of 578 participants were enrolled and 464 (80%) completed follow up at 4 months. Intervention group participants were more likely to find at least one method of effective contraception acceptable (31% in the intervention group versus 17% in the control group, adjusted OR 2.34, 95% CI 1.48-3.68, p < 0.001). They had a higher mean knowledge score, were more likely to find the intrauterine device, injection, implant and patch acceptable, to agree that their friends would use an effective method and to intend to use an effective method, compared to participants in the control group. While in the direction of intervention benefit, there were no differences between the groups in the use of effective contraception at 4 months and any use during the study, pill acceptability, service uptake, unintended pregnancy and induced abortion. CONCLUSIONS: The intervention can improve attitudes, knowledge-perceived norms and intention to use effective contraception among young women in Palestine. Research is needed to evaluate the efficacy of the intervention for contraceptive behavioral outcomes in Palestine. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02905461 . Registered on 14 September 2016. World Health Organization Trial Registration Data Set: http://apps.who.int/trialsearch/Trial2.aspx?TrialID=NCT02905461.

Correction to: Sensitivity Analysis for Not-at-Random Missing Data in Trial-Based Cost-Effectiveness Analysis: A Tutorial.

The Open Access license, which previously read.

Cost-effectiveness of habit-based advice for weight control versus usual care in general practice in the Ten Top Tips (10TT) trial: economic evaluation based on a randomised controlled trial.

OBJECTIVE: Ten Top Tips (10TT) is a primary care-led behavioural intervention which aims to help adults reduce and manage their weight by following 10 weight loss tips. The intervention promotes habit formation to encourage long-term behavioural changes. The aim of this study was to estimate the cost-effectiveness of 10TT in general practice from the perspective of the UK National Health Service. DESIGN: An economic evaluation was conducted alongside an individually randomised controlled trial. SETTING: 14 general practitioner practices in England. PARTICIPANTS: All patients were aged ≥18 years, with body mass index ≥30 kg/m2. A total of 537 patients were recruited; 270 received the usual care offered by their practices and 267 received the 10TT intervention. OUTCOMES MEASURES: Health service use and quality-adjusted life years (QALYs) were measured over 2 years. Analysis was conducted in terms of incremental net monetary benefits (NMBs), using non-parametric bootstrapping and multiple imputation. RESULTS: Over a 2-year time horizon, the mean costs and QALYs per patient in the 10TT group were £1889 (95% CI £1522 to £2566) and 1.51 (95% CI 1.44 to 1.58). The mean costs and QALYs for usual care were £1925 (95% CI £1599 to £2251) and 1.51 (95% CI 1.45 to 1.57), respectively. This generated a mean cost difference of -£36 (95% CI -£512 to £441) and a mean QALY difference of 0.001 (95% CI -0.080 to 0.082). The incremental NMB for 10TT versus usual care was £49 (95% CI -£1709 to £1800) at a maximum willingness to pay for a QALY of £20 000. 10TT had a 52% probability of being cost-effective at this threshold. CONCLUSIONS: Costs and QALYs for 10TT were not significantly different from usual care and therefore 10TT is as cost-effective as usual care. There was no evidence to recommend nor advice against offering 10TT to obese patients in general practices based on cost-effectiveness considerations. TRIAL REGISTRATION NUMBER: ISRCTN16347068; Post-results.

Sensitivity Analysis for Not-at-Random Missing Data in Trial-Based Cost-Effectiveness Analysis: A Tutorial.

Cost-effectiveness analyses (CEA) of randomised controlled trials are a key source of information for health care decision makers. Missing data are, however, a common issue that can seriously undermine their validity. A major concern is that the chance of data being missing may be directly linked to the unobserved value itself [missing not at random (MNAR)]. For example, patients with poorer health may be less likely to complete quality-of-life questionnaires. However, the extent to which this occurs cannot be ascertained from the data at hand. Guidelines recommend conducting sensitivity analyses to assess the robustness of conclusions to plausible MNAR assumptions, but this is rarely done in practice, possibly because of a lack of practical guidance. This tutorial aims to address this by presenting an accessible framework and practical guidance for conducting sensitivity analysis for MNAR data in trial-based CEA. We review some of the methods for conducting sensitivity analysis, but focus on one particularly accessible approach, where the data are multiply-imputed and then modified to reflect plausible MNAR scenarios. We illustrate the implementation of this approach on a weight-loss trial, providing the software code. We then explore further issues around its use in practice.