C Metcalfe

Comparison of hypertonic saline and alternate-day or daily recombinant human deoxyribonuclease in children with cystic fibrosis: a randomised trial

BACKGROUNDnDaily recombinant human deoxyribonuclease (rhDNase) is an established but expensive treatment in cystic fibrosis. Alternate-day treatment, if equally effective, would reduce the drug cost. Hypertonic saline improved lung function to the same degree as rhDNase in short-term studies. We compared the effectiveness of daily rhDNase, hypertonic saline, and alternate-day rhDNase in children with cystic fibrosis.nnnMETHODSnIn an open cross-over trial, 48 children were allocated in random order to 12 weeks of once-daily rhDNase (2.5 mg), alternate-day rhDNase (2.5 mg), and twice-daily 5 mL 7% hypertonic saline. The primary outcome was forced expiratory volume in 1 s (FEV(1)). Secondary outcomes were forced vital capacity, number of pulmonary exacerbations, weight gain, quality of life, exercise tolerance, and the total costs of hospital and community care.nnnFINDINGSnMean FEV(1) increased by 16% (SD 25%), 14% (22%), and 3% (21%) with daily rhDNase, alternate-day rhDNase, and hypertonic saline, respectively. There was no difference between daily and alternate-day rhDNase (2% [95% CI -4 to 9], p=0.55). However, daily rhDNase showed a significantly greater increase in FEV(1) than hypertonic saline (8% [2 to 14], p=0.01). The average difference in 12-week cost between daily and alternate-day rhDNase was pound513 (95% CI -546 to 1510) and that between daily rhDNase and hypertonic saline was pound1409 (440 to 2318). None of the secondary clinical outcomes showed significant differences between treatments.nnnINTERPRETATIONnHypertonic saline, delivered by jet nebuliser, is not as effective as daily rhDNase, although there is variation in individual response. There is no evidence of a difference between daily and alternate-day rhDNase.

Are the effects of psychosocial exposures attributable to confounding? Evidence from a prospective observational study on psychological stress and mortality

STUDY OBJECTIVES To examine the association between perceived psychological stress and cause specific mortality in a population where perceived stress was not associated with material disadvantage. DESIGN Prospective observational study with follow up of 21 years and repeat screening of half the cohort five years from baseline. Measures included perceived psychological stress, coronary risk factors, and indices of lifecourse socioeconomic position. SETTING 27 workplaces in Scotland. PARTICIPANTS 5388 men (mean age 48 years) at first screening and 2595 men at second screening who had complete data on all measures. MAIN OUTCOME MEASURES Hazard ratios for all cause mortality and mortality from cardiovascular disease (ICD9 390–459), coronary heart disease (ICD9 410–414), smoking related cancers (ICD9 140, 141, 143–9, 150, 157, 160–163, 188 and 189), other cancers (ICD9 140–208 other than smoking related), stroke (ICD9 430–438), respiratory diseases (ICD9 460–519) and alcohol related causes (ICD9 141, 143–6, 148–9, 150, 155, 161, 291, 303, 571 and 800–998). RESULTS At first screening behavioural risk (higher smoking and alcohol consumption, lower exercise) was positively associated with stress. This relation was less apparent at second screening. Higher stress at first screening showed an apparent protective relation with all cause mortality and with most categories of cause specific mortality. In general, these estimates were attenuated on adjustment for social position. This pattern was also seen in relation to cumulative stress at first and second screening and with stress that increased between first and second screening. The pattern was most striking with regard to smoking related cancers: relative risk high compared with low stress at first screening, age adjusted 0.64 (95% CI 0.42, 0.96), p for trend 0.016, fully adjusted 0.69 (95% CI 0.45, 1.06), p for trend 0.10; high compared with low cumulative stress, age adjusted 0.69 (95% CI 0.44, 1.09), p for trend 0.12, fully adjusted 0.76 (95% CI 0.48, 1.21), p for trend 0.25; increased compared with decreased stress, age adjusted 0.65 (95% CI 0.40, 1.06), p for trend 0.09, fully adjusted 0.65 (95% CI 0.40, 1.06), p for trend 0.08. CONCLUSIONS This implausible protective relation between higher levels of stress, which were associated with increased smoking, and mortality from smoking related cancers, was probably a product of confounding. Plausible reported associations between psychosocial exposures and disease, in populations where such exposures are associated with material disadvantage, may be similarly produced by confounding, and of no causal significance.

A controlled trial of personal construct psychotherapy for deliberate self-harm.

Evidence for the effectiveness of psychological therapies for people who self-harm is limited. Personal construct theory provides a model of self-harm and a framework for therapeutic intervention, which was evaluated in the present study. Sixty-four adults presenting to Accident and Emergency departments following self-harm were allocated to a personal construct psychotherapy or a normal clinical practice condition. They completed various measures at assessment points pre- and post-therapy. Repetition of self-harm was assessed over a 3-year period. Participants in the intervention condition showed significantly greater reduction in suicidal ideation, hopelessness and depression post-treatment than the control group; and significantly more reconstruing at this point and 6-month follow-up. There was some evidence suggestive of a lower frequency of repetition of self-harm in the intervention than in the control group. It is concluded that brief personal construct psychotherapy may be effective for people who self-harm and merits further exploration.

An investigation of the effectiveness of a voluntary sector psychodynamic counselling service

Clients attending a London voluntary sector counselling centre completed assessments pre- and post-psychodynamic counselling and at follow-up. Although there was a very high attrition rate following initial assessment, this did not appear to affect adversely the representativeness of the sample completing the later assessments. Clients were found to improve in terms of psychological well-being, control and various other aspects of their lives, and attributed many of the changes to counselling. Counsellors also rated the counselling as effective with most clients, and particularly those who were inner directed, had expectancies favourable towards psychotherapy, had greater perceived control over their lives, attended more sessions, and with whom an interaction/transference approach was taken. Clients with more severe problems showed less improvement in other areas of their lives. There was no difference in the outcome of clients seen by qualified and trainee counsellors.

OP13 Interventions to ameliorate the impact of unemployment and economic hardship on mental health in the general population: Systematic review

Background Job loss, debt and financial difficulties are associated with increased risk of mental illness and suicide. During economic recessions the incidence of these rises. Interventions targeting people in debt or unemployed might help mitigate these effects. We systematically reviewed randomised controlled trials (RCTs) for evidence of effects on mental health outcomes of interventions for the unemployed, people in debt or on low incomes in the general population. Methods We searched MEDLINE, PsycINFO, EMBASE, CENTRAL, Science, Social Science, and Arts and Humanities Citation Index on Web-of-Science (January 16th 2016) and citations and reference lists of included studies. We included randomised controlled trials (RCTs) of public health or health service interventions designed to mitigate the effect of unemployment, debt or austerity measures in the general population with mental health outcomes. Studies on people with serious mental health problems, ill health or rehabilitation interventions were excluded. We screened abstracts for relevance, assessed eligibility, and extracted data in duplicate. Bias was assessed with the Cochrane risk-of-bias tool. We prepared a structured narrative synthesis. Data were too sparse and interventions too heterogeneous for meta-analysis. Results Database searching identified 2389 records. We read 136 full-text papers and included eleven RCTs (n = 5303 participants) for our review. Seven were published before the year 2000. Five assessed ‘job-club’ interventions, two group cognitive behavioural therapy (CBT) and single RCTs assessed emotional competency training, expressive writing, guided imagery and debt advice. Reports omitted much detail necessary to assess bias but all studies were at high risk-of-bias. ‘Job-club’ interventions (n = 4222) were associated with lower levels of depression than control interventions up to 2 years post-intervention; effects were strongest amongst those identified at baseline at increased risk of depression (improvements of up to 0.2 to 0.3 SD in depression scores). In one RCT (n = 289), compared to social support CBT was associated with reduced GHQ-30 scores at 3 months (ANOVA, difference in means −1.44 F = 3.91 p < 0.05). A second RCT of CBT versus first-aid training (n = 195) showed no effect on the mental health (SF-36 MCS difference in means −2.17 95% CI −7.13 to 2.79). Single RCTs of four other interventions showed no evidence of benefit. Conclusion ‘Job club’ interventions may be effective in reducing the incidence of depression in unemployed people, particularly those at high risk of depression. Evidence for CBT-type interventions is mixed; further trials are needed. The studies are dated and at high risk-of-bias and future studies should follow CONSORT guidelines.

Investigating the effects of lycopene and green tea on the metabolome of men at risk of prostate cancer: The ProDiet randomised controlled trial : Investigating the effects of lycopene and green tea on the metabolome of men at risk of prostate cancer: The ProDiet randomised controlled trial

Lycopene and green tea consumption have been observationally associated with reduced prostate cancer risk, but the underlying mechanisms have not been fully elucidated. We investigated the effect of factorial randomisation to a 6‐month lycopene and green tea dietary advice or supplementation intervention on 159 serum metabolite measures in 128 men with raised PSA levels (but prostate cancer‐free), analysed by intention‐to‐treat. The causal effects of metabolites modified by the intervention on prostate cancer risk were then assessed by Mendelian randomisation, using summary statistics from 44,825 prostate cancer cases and 27,904 controls. The systemic effects of lycopene and green tea supplementation on serum metabolic profile were comparable to the effects of the respective dietary advice interventions (R2 = 0.65 and 0.76 for lycopene and green tea respectively). Metabolites which were altered in response to lycopene supplementation were acetate [β (standard deviation difference vs. placebo): 0.69; 95% CI = 0.24, 1.15; p = 0.003], valine (β: −0.62; −1.03, −0.02; p = 0.004), pyruvate (β: −0.56; −0.95, −0.16; p = 0.006) and docosahexaenoic acid (β: −0.50; −085, −0.14; p = 0.006). Valine and diacylglycerol were lower in the lycopene dietary advice group (β: −0.65; −1.04, −0.26; p = 0.001 and β: −0.59; −1.01, −0.18; p = 0.006). A genetically instrumented SD increase in pyruvate increased the odds of prostate cancer by 1.29 (1.03, 1.62; p = 0.027). An intervention to increase lycopene intake altered the serum metabolome of men at risk of prostate cancer. Lycopene lowered levels of pyruvate, which our Mendelian randomisation analysis suggests may be causally related to reduced prostate cancer risk.

P25 Feasibility cluster randomised controlled trial and process evaluation of an environmental intervention in nurseries and a web-based home intervention to increase physical activity, oral health and healthy eating in children aged 2–4 years: nap sacc uk

Background Systematic reviews have identified the lack of intervention studies to prevent obesity in young children. Most 3u2009year old children in the UK attend formal childcare, and the Government plans to extend free childcare to 30u2009hours per week for 3 and 4u2009year olds; therefore these settings present an opportunity to improve health. The Nutrition and Physical Activity Self Assessment for Childcare (NAP SACC) programme aims to improve child nutrition and physical activity through changes to the nursery environment. Feasibility and acceptability have been demonstrated through Randomised Controlled Trials (RCT) in the USA. This study examined the feasibility and acceptability of adapting the NAP SACC intervention for the UK. Methods A feasibility cluster RCT in 12 nurseries with 2–4u2009year olds in the southwest region of England. Focus groups and interviews with Health Visitors (community children’s nurses), nursery staff and parents informed adaptation of the intervention for the UK. The intervention comprised: two staff workshops on physical activity and nutrition; Health Visitor support to review nursery practices against 80 areas of best practice, set goals and make changes; a digital media-based home component. Measures were assessed at baseline and post-intervention: zBMI, accelerometer-measured physical activity and sedentary time, diet, child quality of life, health care usage, parental and nursery staff mediators and quality of nursery environment. Fidelity and acceptability were assessed through observation and interviews analysed via thematic analysis. Results Formative work resulted in the following adaptations: inclusion of an oral health component; changes to confirm with UK guidance; specialist workshop facilitators; and development of the home component. 168 (37%) eligible children were recruited from 12 nurseries. Interviews were completed with four Health Visitors, 17 nursery staff and 20 parents. The intervention was implemented with high fidelity, with two exceptions: one nursery did not implement the intervention due to staff workload; and the digital home component was used by just 12 (14%) parents. Intervention acceptability was high. A mean of seven staff per nursery attended each workshop. The workshops and Health Visitor contact were highly valued. The mean number of goals set was eight. Nursery changes included: menu modifications, reducing portion sizes and sugary snacks, role modelling physical activity and eating, and active story telling. The trial design and methods were highly acceptable. Descriptive analysis of the outcomes will be available by September 2017. Conclusion NAP SACC UK is feasible and acceptable with the exception of the home component; effectiveness should be tested through a full-scale RCT.

OC-078 Evaluating innovative surgery: a nested ideal phase 2 study within an external randomised pilot (the romio trial)

Introduction There is a need for well designed and conducted pragmatic randomised controlled trials (RCTs) of open and minimally invasive approaches for oesophageal cancer, but totally minimally invasive techniques are still evolving. The NIHR ROMIO pilot RCT was designed to inform a definitive trial. This paper describes how the ROMIO Study informed the main trial design and incorporated a nested IDEAL (Idea, Development, Evaluation, Assessment and Long-term evaluation of innovative surgery) Phase 2a evaluation of totally minimally invasive oesophagectomy (TMIO). Method The pilot ROMIO trial was conducted in two centres. In one centre (with a team of 3 surgeons) patients were randomised to open gastric mobilisation and right thoracotomy (open surgery) or laparoscopic gastric mobilisation and right thoractomy (hybrid surgery) and in the other centre (team of 6 surgeons) patients were randomised into three groups, also including totally TMIO. The surgical protocol for open and hybrid surgery was agreed and monitored during the trial, where as the protocol for TMIO was deliberately flexible to monitor development of the technique and to document changes in the procedure and collect prospective data. Results During 20 months of recruitment, 256 patients were assessed for eligibility, 132 (52%) were found to be eligible and 101 (76.5%) agreed to participate. A high proportion of patients received their randomised allocation (87%). Dressing patients with large bandages, covering all possible incisions, was successful in keeping patients blind whilst pain was assessed during the first week post-surgery (patients were unable to guess the type of surgery they had received). In the TMIO group three-phase surgery was undertaken by three of the six surgeons in one centre. This evolved to two-phase TMIO surgery with continuing modifications to the anastomotic technique. During the study period the national audit data showed that only 14% of oesophagectomies are TMIO. Conclusion Rapid recruitment to the pilot ROMIO trial and the successful refinement of methodology indicated that a definitive two group trial comparing open and hybrid surgery is feasible. Techniques for TMIO are however still evolving and the procedure is not widely undertaken. The main ROMIO trial, therefore, is designed within a continuing IDEAL Phase 2b study to monitor when this complex technique has stabilised and ready for full evaluation within a pragmatic trial design. Disclosure of interest None Declared.

OP89 The Association of Parental Fatal and Non-Fatal Suicidal Behaviour with Offspring Suicidalbehaviourand Depression: A Systematic Review and Meta-Analysis

Background Children whose parents die by, or attempt, suicide are believed to be at greater risk of suicidal behaviours and affective disorders. We systematically reviewed the literature on the association of parental fatal and non-fatal suicidal behaviours with offspring suicidal behaviour and depression and, using meta-analysis, estimated the strength of these associations. We further investigated the role of parental and offspring gender, and offspring age at exposure as potential effect modifiers. Methods We carried out a comprehensive literature search using Medline (1950-April 2011), PsycINFO (1876-April 2011), EMBASE (1980-April 2011) and Web of Science. Twenty eight articles met our inclusion criteria, 14 of which contributed to the meta-analysis. Crude odds ratio (OR) and adjusted odds ratio (AOR) were pooled using fixed-effects models. Results Controlling for relevant confounders, offspring whose parents died by suicide were more likely than offspring of two living parents to die by suicide [AOR 1.94, 95% confidence interval (CI) 1.54–2.45] but there were heterogeneous findings in the two studies investigating the impact of parental suicide on offspring suicide attempt (AOR 1.31, 95% CI 0.73–2.35). Children whose parents attempted suicide were more likely than unexposed children to attempt suicide (AOR 1.95, 95% CI 1.48–2.57). However, compared with offspring of parents who died by other causes, the risk of suicidal behaviour was only slightly elevated for offspring of suicide decedents (suicide: OR 1. 81, 95% CI 1.56–2.10; suicide attempt: OR 1.73, 95% CI 1.63–1.83); no adjusted analyses were available. Limited published research indicated that offspring exposure to parental death by suicide is associated with subsequent increased risk of affective disorders compared to offspring of two living parents. Maternal suicidal behaviour was associated with larger effect estimates compared to paternal suicidal behaviours. There was some evidence that younger age at exposure to parental suicidal behaviours was associated with greater risk than exposure in later childhood/adolescence. There was no evidence that the association differed in sons versus daughters. Conclusion Parental suicidal behaviour is associated with increased risk of offspring suicidal behaviour, above and beyond the risk associated with a loss of a parent to a cause other than suicide. Findings suggest that maternal suicidal behaviour is a more potent risk factor than paternal suicidal behaviour. Limited evidence suggests that children are more vulnerable than adolescents and adults. However, there is no evidence of a stronger association in either male or female offspring.

Clinical versus economic interpretations of RCT results - Mixed messages?

Background For randomised controlled trials (RCT), the sample size needed to detect an important effect on clinical outcome is commonly believed to be insufficient to firmly establish the efficiency of the intervention. Objectives To review cost-utility analyses (CUAs) conducted alongside RCTs to determine: (1) if cost-effectiveness is considered in sample size calculations, (2) the frequency with which economic conclusions conflict with clinical conclusions and (3) whether economic evaluations are underpowered and so more likely to come to indeterminate results. Methods We searched the National Health Service (NHS) Economic Evaluation Database and identified 717 articles. We extracted data from nine high impact/volume journals and from a 50% random sample of the remaining journals that published 3 or more CUAs (n=302). 264 were excluded because they were models (235), had insufficient information (16), failed to measure individual patient data (11) or were not RCTs (2). 38 articles (40 RCTs) were included. Information was collected on study characteristics, primary clinical outcomes, Quality Adjusted Life Years (QALY) and incremental costs. We categorised trials according to the strength of their conclusions on clinical and cost per QALY outcomes. Results Of 24 RCTs analysed to date, only 1/24 (4%) considered economic factors in sample size calculation. 12/24 (50%) studies reported evidence of one intervention being more effective based on the primary clinical outcome (p<0.05). Fewer studies provided evidence of differences between treatments when using the QALY outcome (8/24; 33%) or cost per QALY (6/24; 25%). In 2/24 (8%) studies, conclusions about the ‘optimal’ intervention strategy, based on the primary clinical outcome, were partially reversed once cost-effectiveness data were taken into consideration. We calculated the median power to detect a minimum important difference for 7 studies with sufficient information and found: primary clinical outcome 77.7%, QALY 31.2% and costs 25.9%. Conclusions Based on preliminary analysis, economic factors rarely feature in sample size calculations. There was an occasional discrepancy between cost-effectiveness and clinical conclusions but no complete reversal of interpretation. CUAs were more likely to come to indeterminate conclusions. This suggests that RCTs may often cease recruitment before the efficiency of the intervention can be firmly established and therefore only provide incomplete evidence to policy makers about the cost-effectiveness of healthcare technologies.