Lauren Greenberg

Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data

Objectives To assess the overall effect of vitamin D supplementation on risk of acute respiratory tract infection, and to identify factors modifying this effect. Design Systematic review and meta-analysis of individual participant data (IPD) from randomised controlled trials. Data sources Medline, Embase, the Cochrane Central Register of Controlled Trials, Web of Science, ClinicalTrials.gov, and the International Standard Randomised Controlled Trials Number registry from inception to December 2015. Eligibility criteria for study selection Randomised, double blind, placebo controlled trials of supplementation with vitamin D3 or vitamin D2 of any duration were eligible for inclusion if they had been approved by a research ethics committee and if data on incidence of acute respiratory tract infection were collected prospectively and prespecified as an efficacy outcome. Results 25 eligible randomised controlled trials (total 11 321 participants, aged 0 to 95 years) were identified. IPD were obtained for 10 933 (96.6%) participants. Vitamin D supplementation reduced the risk of acute respiratory tract infection among all participants (adjusted odds ratio 0.88, 95% confidence interval 0.81 to 0.96; P for heterogeneity <0.001). In subgroup analysis, protective effects were seen in those receiving daily or weekly vitamin D without additional bolus doses (adjusted odds ratio 0.81, 0.72 to 0.91) but not in those receiving one or more bolus doses (adjusted odds ratio 0.97, 0.86 to 1.10; P for interaction=0.05). Among those receiving daily or weekly vitamin D, protective effects were stronger in those with baseline 25-hydroxyvitamin D levels <25 nmol/L (adjusted odds ratio 0.30, 0.17 to 0.53) than in those with baseline 25-hydroxyvitamin D levels ≥25 nmol/L (adjusted odds ratio 0.75, 0.60 to 0.95; P for interaction=0.006). Vitamin D did not influence the proportion of participants experiencing at least one serious adverse event (adjusted odds ratio 0.98, 0.80 to 1.20, P=0.83). The body of evidence contributing to these analyses was assessed as being of high quality. Conclusions Vitamin D supplementation was safe and it protected against acute respiratory tract infection overall. Patients who were very vitamin D deficient and those not receiving bolus doses experienced the most benefit. Systematic review registration PROSPERO CRD42014013953.

Vitamin D supplementation to prevent asthma exacerbations: a systematic review and meta-analysis of individual participant data

BACKGROUND A previous aggregate data meta-analysis of randomised controlled trials showed that vitamin D supplementation reduces the rate of asthma exacerbations requiring treatment with systemic corticosteroids. Whether this effect is restricted to patients with low baseline vitamin D status is unknown. METHODS For this systematic review and one-step and two-step meta-analysis of individual participant data, we searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, and Web of Science for double-blind, placebo-controlled, randomised controlled trials of vitamin D3 or vitamin D2 supplementation in people with asthma that reported incidence of asthma exacerbation, published between database inception and Oct 26, 2016. We analysed individual participant data requested from the principal investigator for each eligible trial, adjusting for age and sex, and clustering by study. The primary outcome was the incidence of asthma exacerbation requiring treatment with systemic corticosteroids. Mixed-effects regression models were used to obtain the pooled intervention effect with a 95% CI. Subgroup analyses were done to determine whether effects of vitamin D on risk of asthma exacerbation varied according to baseline 25-hydroxyvitamin D (25[OH]D) concentration, age, ethnic or racial origin, body-mass index, vitamin D dosing regimen, use of inhaled corticosteroids, or end-study 25(OH)D levels; post-hoc subgroup analyses were done according to sex and study duration. This study was registered with PROSPERO, number CRD42014013953. FINDINGS Our search identified 483 unique studies, eight of which were eligible randomised controlled trials (total 1078 participants). We sought individual participant data for each and obtained it for seven studies (955 participants). Vitamin D supplementation reduced the rate of asthma exacerbation requiring treatment with systemic corticosteroids among all participants (adjusted incidence rate ratio [aIRR] 0·74, 95% CI 0·56-0·97; p=0·03; 955 participants in seven studies; high-quality evidence). There were no significant differences between vitamin D and placebo in the proportion of participants with at least one exacerbation or time to first exacerbation. Subgroup analyses of the rate of asthma exacerbations treated with systemic corticosteroids revealed that protective effects were seen in participants with baseline 25(OH)D of less than 25 nmol/L (aIRR 0·33, 0·11-0·98; p=0·046; 92 participants in three studies; moderate-quality evidence) but not in participants with higher baseline 25(OH)D levels (aIRR 0·77, 0·58-1·03; p=0·08; 764 participants in six studies; moderate-quality evidence; pinteraction=0·25). p values for interaction for all other subgroup analyses were also higher than 0·05; therefore, we did not show that the effects of this intervention are stronger in any one subgroup than in another. Six studies were assessed as being at low risk of bias, and one was assessed as being at unclear risk of bias. The two-step meta-analysis did not reveal evidence of heterogeneity of effect (I2=0·0, p=0·56). INTERPRETATION Vitamin D supplementation reduced the rate of asthma exacerbations requiring treatment with systemic corticosteroids overall. We did not find definitive evidence that effects of this intervention differed across subgroups of patients. FUNDING Health Technology Assessment Program, National Institute for Health Research (reference number 13/03/25).

Attrition in trials evaluating complex interventions for schizophrenia: Systematic review and meta-analysis

Essential criteria for the methodological quality and validity of randomized controlled trials are the drop-out rates from both the experimental intervention and the study as a whole. This systematic review and meta-analysis assessed these drop-out rates in non-pharmacological schizophrenia trials. A systematic literature search was used to identify relevant trials with ≥100 sample size and to extract the drop-out data. The rates of drop-out from the experimental intervention and study were calculated with meta-analysis of proportions. Meta-regression was applied to explore the association between the study and sample characteristics and the drop-out rates. 43 RCTs were found, with drop-out from intervention ranging from 0% to 63% and study drop-out ranging from 4% to 71%. Meta-analyses of proportions showed an overall drop-out rate of 14% (95% CI: 13-15%) at the experimental intervention level and 20% (95% CI: 17-24%) at the study level. Meta-regression showed that the active intervention drop-out rates were predicted by the number of intervention sessions. In non-pharmacological schizophrenia trials, drop-out rates of less than 20% can be achieved for both the study and the experimental intervention. A high heterogeneity of drop-out rates across studies shows that even lower rates are achievable.

Satisfaction with sex life among patients with schizophrenia.

BACKGROUND Whilst subjective quality of life has been extensively studied in patients with schizophrenia, little is known specifically about their satisfaction with their sex lives. Aim To assess the level of satisfaction with sex lives of patients with schizophrenia and explore patient characteristics associated with lower satisfaction. METHOD Data of five independent samples of patients with schizophrenia or related disorders (ICD-10 F20-29) were analysed. Quality of life including satisfaction with sex life was assessed on the Manchester Short Assessment of Quality of Life. RESULTS Across all patients (N=1404), satisfaction with sex life was significantly lower than satisfaction with any other life domain, and in each sample mean scores were below the middle scale point, indicating explicit dissatisfaction. Lower satisfaction was associated with male gender, being unmarried and more affective symptoms. CONCLUSION Patients with schizophrenia experience their sex life as an area of particular dissatisfaction. Future research should identify context and reasons for this dissatisfaction.

Predictors of length of stay in psychiatric inpatient units: Does their effect vary across countries?

BACKGROUND Previous studies in individual countries have identified inconsistent predictors of length of stay (LoS) in psychiatric inpatient units. This may reflect methodological inconsistencies across studies or true differences of predictors. In this study we assessed predictors of LoS in five European countries and explored whether their effect varies across countries. METHODS Prospective cohort study. All patients admitted over 14 months to 57 psychiatric inpatient units in Belgium, Germany, Italy, Poland and United Kingdom were screened. Putative predictors were collected from medical records and in face-to-face interviews and tested for their association with LoS. RESULTS Average LoS varied from 17.9days in Italy to 55.1days in Belgium. In the overall sample being homeless, receiving benefits, social isolation, diagnosis of psychosis, greater symptom severity, substance use, history of previous admission and being involuntarily admitted predicted longer LoS. Several predictors showed significant interaction effects with countries in predicting LoS. One variable, homelessness, predicted a different LoS even in opposite directions, whilst for other predictors the direction of the association was the same, but the strength of the association with LoS varied across countries. CONCLUSIONS The same patient characteristics have a different impact on LoS in different contexts. Thus, although some predictor variables related to clinical severity and social dysfunction appear of generalisable relevance, national studies on LoS are required to understand the complex influence of different patient characteristics on clinical practice in the given contexts.

Evaluation of community-level interventions to increase early initiation of antenatal care in pregnancy: protocol for the Community REACH study, a cluster randomised controlled trial with integrated process and economic evaluations

BackgroundThe provision of high-quality maternity services is a priority for reducing inequalities in health outcomes for mothers and infants. Best practice includes women having their initial antenatal appointment within the first trimester of pregnancy in order to provide screening and support for healthy lifestyles, well-being and self-care in pregnancy. Previous research has identified inequalities in access to antenatal care, yet there is little evidence on interventions to improve early initiation of antenatal care. The Community REACH trial will assess the effectiveness and cost-effectiveness of engaging communities in the co-production and delivery of an intervention that addresses this issue.Methods/designThe study design is a matched cluster randomised controlled trial with integrated process and economic evaluations. The unit of randomisation is electoral ward. The intervention will be delivered in 10 wards; 10 comparator wards will have normal practice. The primary outcome is the proportion of pregnant women attending their antenatal booking appointment by the 12th completed week of pregnancy. This and a number of secondary outcomes will be assessed for cohorts of women (n = approximately 1450 per arm) who give birth 2–7 and 8–13 months after intervention delivery completion in the included wards, using routinely collected maternity data. Eight hospitals commissioned to provide maternity services in six NHS trusts in north and east London and Essex have been recruited to the study. These trusts will provide anonymised routine data for randomisation and outcomes analysis. The process evaluation will examine intervention implementation, acceptability, reach and possible causal pathways. The economic evaluation will use a cost-consequences analysis and decision model to evaluate the intervention. Targeted community engagement in the research process was a priority.DiscussionCommunity REACH aims to increase early initiation of antenatal care using an intervention that is co-produced and delivered by local communities. This pragmatic cluster randomised controlled trial, with integrated process and economic evaluation, aims to rigorously assess the effectiveness of this public health intervention, which is particularly complex due to the required combination of standardisation with local flexibility. It will also answer questions about scalability and generalisability.Trial registrationISRCTN registry: registration number 63066975. Registered on 18 August 2015.

Pre-specification of statistical analysis approaches in published clinical trial protocols was inadequate

OBJECTIVES Results from randomized trials can depend on the statistical analysis approach used. It is important to prespecify the analysis approach in the trial protocol to avoid selective reporting of analyses based on those which provide the most favourable results. We undertook a review of published trial protocols to assess how often the statistical analysis of the primary outcome was adequately prespecified. METHODS We searched protocols of randomized trials indexed in PubMed in November 2016. We identified whether the following aspects of the statistical analysis approach for the primary outcome were adequately prespecified: (1) analysis population; (2) analysis model; (3) use of covariates; and (4) method of handling missing data. RESULTS We identified 99 eligible protocols. Very few protocols adequately prespecified the analysis population (8/99, 8%), analysis model (27/99, 27%), covariates (40/99, 40%), or approach to handling missing data (10/99, 10%). Most protocols did not adequately predefine any of these four aspects of their statistical analysis approach (39%) or predefined only one aspect (36%). No protocols adequately predefined all four aspects of the analysis. CONCLUSION The statistical analysis approach is rarely prespecified in published trial protocols. This may allow selective reporting of results based on different analyses.

Clinicians have several therapeutic relationships and patients only one: The effect on their assessments of relationships

Little attention has been given to the common assessment problem that clinicians assess outcomes of several patients and may rate them in comparison to one another, whereas patients assess only their own outcomes without any comparison. We explored empirically whether this would lead to a greater variability of clinician ratings as compared to patient ratings.

S102 Vitamin d supplementation to prevent acute respiratory infections: systematic review and meta-analysis of individual participant data

Introduction and objectives Randomised controlled trials of vitamin D to prevent acute respiratory infection have yielded mixed results. We conducted an individual patient data (IPD) meta-analysis to identify factors that may explain this heterogeneity. Methods We performed an IPD meta-analysis of 25 trials of vitamin D supplementation with incidence of acute respiratory infection as a pre-specified outcome (total 11,321 participants, aged 0 to 95 years). We used one-step logistic regression with random effects adjusting for age, sex, study duration and clustering by study. Pre-specified sub-group analyses were done to determine whether effects of vitamin D on risk of acute respiratory infection varied according to baseline 25-hydroxyvitamin D (25[OH]D) concentration or dosing regimen. Results IPD were obtained for 10,933/11,321 (96.6%) participants. Vitamin D supplementation reduced risk of acute respiratory infection among all participants (adjusted Odds Ratio [aOR] 0.88, 95% CI: 0.81 to 0.96, P = 0.003; P for heterogeneity < 0.001). Sub-group analysis revealed a strong protective effect among individuals with baseline 25(OH) D < 25 nmol/L (aOR 0.62, 95% CI: 0.45 to 0.83, P = 0.002), not seen among those with higher levels (aOR 0.91, 95% CI: 0.78 to 1.05; Pinteraction = 0.01). A protective effect was also seen in individuals receiving daily or weekly vitamin D without additional bolus doses (aOR 0.81, 95% CI: 0.72 to 0.91, P < 0.001), but not in those receiving one or more bolus doses (aOR 0.97, 95% CI: 0.86 to 1.10, Pinteraction = 0.05). Vitamin D did not influence the proportion of participants experiencing at least one serious adverse event (aOR 0.98, 95% CI: 0.80 to 1.20, P = 0.83). The body of evidence contributing to these analyses was assessed as being of high quality. Conclusions Vitamin D supplementation was safe, and it protected against acute respiratory infection overall. Very deficient individuals and those not receiving bolus doses experienced the most benefit.