Is there a role for n-3 long-chain polyunsaturated fatty acids in the regulation of mood and behaviour? A review of the evidence to date from epidemiological studies, clinical studies and intervention trials

Selected biochemical evidence suggests a potential role for n-3 long-chain PUFA (n-3PUFA) in the regulation of mood and behaviour. The present paper reviews the relevant evidence, to date, from epidemiological studies, clinical studies and intervention trials. Most evidence is available investigating a role for n-3PUFA in depression, depressive illness and suicidal behaviour, but work is also available on anxiety and anxiety-related disorders, fatigue and fatigue-related disorders, aggression, hostility and anti-social behaviour, inattention, impulsivity and attention deficit hyperactivity disorder and schizophrenic disorders. For all these aspects of mood and behaviour, the evidence available is currently limited and highly inconsistent, both in terms of study methodology and study findings. There is a clear need for further work in this area.

Developing a Reporting Guideline for Social and Psychological Intervention Trials

Social and psychological interventions are often complex. Understanding randomized controlled trials (RCTs) of these complex interventions requires a detailed description of the interventions tested and the methods used to evaluate them; however, RCT reports often omit, or inadequately report, this information. Incomplete and inaccurate reporting hinders the optimal use of research, wastes resources, and fails to meet ethical obligations to research participants and consumers. In this article, we explain how reporting guidelines have improved the quality of reports in medicine and describe the ongoing development of a new reporting guideline for RCTs: Consolidated Standards of Reporting Trials-SPI (an extension for social and psychological interventions). We invite readers to participate in the project by visiting our website, in order to help us reach the best-informed consensus on these guidelines (http://tinyurl.com/CONSORT-study).

Scientific standards for human intervention trials evaluating health benefits of foods, and their application to infants, children and adolescents

Associations between the consumption of particular foods and health outcomes may be indicated by observational studies. However, intervention trials that evaluate the health benefits of foods provide the strongest evidence to support dietary recommendations for health. Thus, it is important that these trials are carried out safely, and to high scientific standards. Accepted standards for the reporting of the health benefits of pharmaceutical and other medical interventions have been provided by the Consolidated Standards of Reporting Trials (CONSORT) statement. However, there are no generally accepted standards for trials to evaluate the health benefits of foods. Trials with foods differ from medical trials in issues related to safety, ethics, research governance and practical implementation. Furthermore, these important issues can deter the conduct of both medical and nutrition trials in infants, children and adolescents. This paper provides standards for the planning, design, conduct, statistical analysis and interpretation of human intervention trials to evaluate the health benefits of foods that are based on the CONSORT guidelines, and outlines the key issues that need to be addressed in trials in participants in the paediatric age range.

The effect of increased dietary fruit and vegetable consumption on endothelial activation, inflammation and oxidative stress in hypertensive volunteers

Background and aims

Public health campaigns recommend increased fruit and vegetable (FV) consumption as an effective means of cardiovascular risk reduction. During an 8 week randomised control trial among hypertensive volunteers, we noted significant improvements in endothelium-dependent vasodilatation with increasing FV consumption. Circulating indices of inflammation, endothelial activation and insulin resistance are often employed as alternative surrogates for systemic arterial health. The responses of several such biomarkers to our previously described FV intervention are reported here.
Methods and results

Hypertensive volunteers were recruited from medical outpatient clinics. After a common 4 week run-in period during which FV consumption was limited to 1 portion per day, participants were randomised to 1, 3 or 6 portions daily for 8 weeks. Venous blood samples for biomarker analyses were collected during the pre and post-intervention vascular assessments. A total of 117 volunteers completed the 12 week study. Intervention-related changes in circulating levels of high sensitivity C-reactive protein (hsCRP), soluble intracellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1), von Willebrand factor (vWF) and plasminogen activator inhibitor-1 (PAI-1) did not differ significantly between FV groups. Similarly, there were no significant between group differences of change in homeostasis model assessment (HOMA) scores.
Conclusions

Despite mediating a significant improvement in acetylcholine induced vasodilatation, increased FV consumption did not affect a calculated measure of insulin resistance or concentrations of the circulating biomarkers measured during this study. Functional indices of arterial health such as endothelium-dependent vasomotion are likely to provide more informative cardiovascular end-points during short-term dietary intervention trials.

UK Food Standards Agency Workshop Report: carbohydrate and cardiovascular risk

This report summarises a workshop convened by the UK Food Standards Agency (FSA) on 14 October 2008 to discuss current FSA-funded research on carbohydrates and cardiovascular health. The objective of this workshop was to discuss the results of recent research and to identify any areas which could inform future FSA research calls. This workshop highlighted that the FSA is currently funding some of the largest, well-powered intervention trials investigating the type of fat and carbohydrate, whole grains and fruit and vegetables, on various CVD risk factors. Results of these trials will make a substantive contribution to the evidence on diet and cardiovascular risk.

Micronutrients: dietary intake v. supplement use

Whilst clinical deficiency of micronutrients is uncommon in the developed world, a suboptimal intake of certain micronutrients has been linked with an increased risk of chronic diseases such as CVD and cancer. Attention has therefore focused on increasing micronutrient status in order to theoretically reduce chronic disease risk. Increasing micronutrient status can involve a number of approaches: increasing dietary intake of micronutrient-rich foods; food fortification; use of supplements. Observational cohort studies have demonstrated an association between high intakes of micronutrients such as vitamin E, vitamin C, folic acid and beta-carotene, and lower risk of CHD, stroke and cancer at various sites. However, randomised intervention trials of micronutrient supplements have, to date, largely failed to show an improvement in clinical end points. The discordance between data from cohort studies and the results so far available from clinical trials remains to be explained. One reason may be that the complex mixture of micronutrients found, for example, in a diet high in fruit and vegetables may be more effective than large doses of a small number of micronutrients, and therefore that intervention studies that use single micronutrient supplements are unlikely to produce a lowering of disease risk. Studies concentrating on whole foods (e.g. fruit and vegetables) or diet pattern (e.g. Mediterranean diet pattern) may be more effective in demonstrating an effect on clinical end points. The present review will consider the clinical trial evidence for a beneficial effect of micronutrient supplements on health, and review the alternative approaches to the study of dietary intake of micronutrients.

Effect of increased fruit and vegetable consumption on bone turnover in older adults:a randomised controlled trial

Evidence suggests that increased fruit and vegetable (FV) intake may be associated with improved bone health, but there is limited evidence from intervention trials to support this. This 16-week study showed that increased FV consumption (five or more portions per day) does not have any effect on the markers of bone health in older adults. INTRODUCTION: Observational evidence suggests that increased FV consumption may be associated with improved bone health. However, there is lack of evidence from intervention trials to support this. This study examined the effect of increased FV consumption on bone markers among healthy, free-living older adults. METHODS: A randomised controlled trial was undertaken. Eighty-three participants aged 65-85 years, habitually consuming less than or equal to two portions of FV per day, were randomised to continue their normal diet or to consume five or more portions of FV per day for 16 weeks. FV were delivered to all participants each week, free of charge. Compliance was assessed at baseline and at 6, 12 and 16 weeks by diet histories and biomarkers of micronutrient status. Fasting serum bone markers (osteocalcin (OC) and C-terminal telopeptide of type 1 collagen (CTX)) were measured using enzyme-linked immunosorbent assay. RESULTS: Eighty-two participants completed the intervention. The five portions per day group showed a significantly greater change in daily FV consumption compared to the two portions per day group (p?

Lipoproteins and diabetic microvascular complications

Risk factors for the microvascular complications (nephropathy and retinopathy) of Type 1 and Type 2 diabetes mellitus and the associated accelerated atherosclerosis include: age, diabetes duration, genetic factors, hyperglycaemia, hypertension, smoking, inflammation, glycation and oxidative stress and dyslipoproteinaemia. Hypertriglyceridaemia, low HDL and small dense LDL are common features of Type 2 diabetes and Type 1 diabetes with poor glycaemic control or renal complications. With the expansion of knowledge and of clinical and research laboratory tools, a broader definition of 'lipid' abnormalities in diabetes is appropriate. Dyslipoproteinaemia encompasses alterations in lipid levels, lipoprotein subclass distribution, composition (including modifications such as non-enzymatic glycation and oxidative damage), lipoprotein-related enzymes, and receptor interactions and subsequent cell signaling. Alterations occur in all lipoprotein classes; chylomicrons, VLDL, LDL, HDL, and Lp(a). There is also emerging evidence implicating lipoprotein related genotypes in the development of diabetic nephropathy and retinopathy. Lipoprotein related mechanisms associated with damage to the cardiovascular system may also be relevant to damage to the renal and ocular microvasculature. Adverse tissue effects are mediated by both alterations in lipoprotein function and adverse cellular responses. Recognition and treatment of lipoprotein-related risk factors, supported by an increasing array of assays and therapeutic agents, may facilitate early recognition and treatment of high complication risk diabetic patients. Further clinical and basic research, including intervention trials, is warranted to guide clinical practice. Optimal lipoprotein management, as part of a multi-faceted approach to diabetes care, may reduce the excessive personal and economic burden of microvascular complications and the related accelerated atherosclerosis.

Fruit and vegetable intake and risk of cardiovascular disease

A high intake of fruit and vegetables (FV) has been shown to be associated with reduced risk of a number of chronic diseases, including CVD. This review aims to provide an overview of the evidence that increased FV intake reduces risk of CVD, focusing on studies examining total FV intake. This evidence so far available is largely based on prospective cohort studies, with meta-analyses demonstrating an association between increased FV intake and reduced risk of both CHD and stroke. Controlled intervention trials examining either clinical or cardiovascular risk factor endpoints are scarce. However, such trials have shown that an increase in FV consumption can lower blood pressure and also improve microvascular function, both of which are commensurate with a reduced risk of CVD. The effects of increased FV consumption on plasma lipid levels, risk of diabetes and body weight have yet to be firmly established. In conclusion, evidence that FV consumption reduces the risk of CVD is so far largely confined to observational epidemiology, with further intervention studies required.

Biomarker responses to folic acid intervention in healthy adults: a meta-analysis of randomized controlled trials

BACKGROUND: The task of revising dietary folate recommendations for optimal health is complicated by a lack of data quantifying the biomarker response that reliably reflects a given folate intake.

OBJECTIVE: We conducted a dose-response meta-analysis in healthy adults to quantify the typical response of recognized folate biomarkers to a change in folic acid intake.

DESIGN: Electronic and bibliographic searches identified 19 randomized controlled trials that supplemented with folic acid and measured folate biomarkers before and after the intervention in apparently healthy adults aged ≥18 y. For each biomarker response, the regression coefficient (β) for individual studies and the overall pooled β were calculated by using random-effects meta-analysis.

RESULTS: Folate biomarkers (serum/plasma and red blood cell folate) increased in response to folic acid in a dose-response manner only up to an intake of 400 μg/d. Calculation of the overall pooled β for studies in the range of 50 to 400 μg/d indicated that a doubling of folic acid intake resulted in an increase in serum/plasma folate by 63% (71% for microbiological assay; 61% for nonmicrobiological assay) and red blood cell folate by 31% (irrespective of whether microbiological or other assay was used). Studies that used the microbiological assay indicated lower heterogeneity compared with studies using nonmicrobiological assays for determining serum/plasma (I(2) = 13.5% compared with I(2) = 77.2%) and red blood cell (I(2) = 45.9% compared with I(2) = 70.2%) folate.

CONCLUSIONS: Studies administering >400 μg folic acid/d show no dose-response relation and thus will not yield meaningful results for consideration when generating dietary folate recommendations. The calculated folate biomarker response to a given folic acid intake may be more robust with the use of a microbiological assay rather than alternative methods for blood folate measurement.

The contribution of qualitative research in designing a complex intervention for secondary prevention of coronary heart disease in two different healthcare systems

Background: Developing complex interventions for testing in randomised controlled trials is of increasing importance in healthcare planning. There is a need for careful design of interventions for secondary prevention of coronary heart disease (CHD). It has been suggested that integrating qualitative research in the development of a complex intervention may contribute to optimising its design but there is limited evidence of this in practice. This study aims to examine the contribution of qualitative research in developing a complex intervention to improve the provision and uptake of secondary prevention of CHD within primary care in two different healthcare systems.

Methods: In four general practices, one rural and one urban, in Northern Ireland and the Republic of Ireland, patients with CHD were purposively selected. Four focus groups with patients (N = 23) and four with staff (N = 29) informed the development of the intervention by exploring how it could be tailored and integrated with current secondary prevention activities for CHD in the two healthcare settings. Following an exploratory trial the acceptability and feasibility of the intervention were discussed in four focus groups (17 patients) and 10 interviews (staff). The data were analysed using thematic analysis.

Results: Integrating qualitative research into the development of the intervention provided depth of information about the varying impact, between the two healthcare systems, of different funding and administrative arrangements, on their provision of secondary prevention and identified similar barriers of time constraints, training needs and poor patient motivation. The findings also highlighted the importance to patients of stress management, the need for which had been underestimated by the researchers. The qualitative evaluation provided depth of detail not found in evaluation questionnaires. It highlighted how the intervention needed to be more practical by minimising administration, integrating role plays into behaviour change training, providing more practical information about stress management and removing self-monitoring of lifestyle change.

Conclusion: Qualitative research is integral to developing the design detail of a complex intervention and tailoring its components to address individuals' needs in different healthcare systems. The findings highlight how qualitative research may be a valuable component of the preparation for complex interventions and their evaluation.

Development of a Complex Intervention for Secondary Prevention of Coronary Heart Disease in Primary Care Using the UK Medical Research Council Framework

Objective: To apply the UK Medical Research Council (MRC) framework for development and evaluation of trials of complex interventions to a primary healthcare intervention to promote secondary prevention of coronary heart disease. Study Design: Case report of intervention development. Methods: First, literature relating to secondary prevention and lifestyle change was reviewed. Second, a preliminary intervention was modeled, based on literature findings and focus group interviews with patients (n = 23) and staff (n = 29) from 4 general practices. Participants’ experiences of and attitudes toward key intervention components were explored. Third, the preliminary intervention was pilot-tested in 4 general practices. After delivery of the pilot intervention, practitioners evaluated the training sessions, and qualitative data relating to experiences of the intervention were collected using semistructured interviews with staff (n = 10) and patient focus groups (n = 17). Results: Literature review identified 3 intervention components: a structured recall system, practitioner training, and patient information. Initial qualitative data identified variations in recall system design, training requirements (medication prescribing, facilitating behavior change), and information appropriate to the prospective study participants. Identifying detailed structures within intervention components clarified how the intervention could be tailored to individual practice, practitioner, and patient needs while preserving the theoretical functions of the components. Findings from the pilot phase informed further modeling of the intervention, reducing administrative time, increasing practical content of training, and omitting unhelpful patient information. Conclusion: Application of the MRC framework helped to determine the feasibility and development of a complex intervention for primary care research.

Monitoring treatment fidelity in a randomised controlled trial of a complex intervention.

Aim. This paper is a report of a study to describe how treatment fidelity is being enhanced and monitored, using a model from the National Institutes of Health Behavior Change Consortium. Background. The objective of treatment fidelity is to minimize errors in interpreting research trial outcomes, and to ascribe those outcomes directly to the intervention at hand. Treatment fidelity procedures are included in trials of complex interventions to account for inferences made from study outcomes. Monitoring treatment fidelity can help improve study design, maximize reliability of results, increase statistical power, determine whether theory-based interventions are responsible for observed changes, and inform the research dissemination process. Methods. Treatment fidelity recommendations from the Behavior Change Consortium were applied to the SPHERE study (Secondary Prevention of Heart DiseasE in GeneRal PracticE), a randomized controlled trial of a complex intervention. Procedures to enhance and monitor intervention implementation included standardizing training sessions, observing intervention consultations, structuring patient recall systems, and using written practice and patient care plans. The research nurse plays an important role in monitoring intervention implementation. Findings. Several methods of applying treatment fidelity procedures to monitoring interventions are possible. The procedure used may be determined by availability of appropriate personnel, fiscal constraints, or time limits. Complex interventions are not straightforward and necessitate a monitoring process at trial stage. Conclusion. The Behavior Change Consortium’s model of treatment fidelity is useful for structuring a system to monitor the implementation of a complex intervention, and helps to increase the reliability and validity of evaluation findings.

Identifying strategies to maximise recruitment and retention of practices and patients in a multicentre randomised controlled trial of an intervention to optimise secondary prevention for coronary heart disease in primary care.

Background Recruitment and retention of patients and healthcare providers in randomised controlled trials (RCTs) is important in order to determine the effectiveness of interventions. However, failure to achieve recruitment targets is common and reasons why a particular recruitment strategy works for one study and not another remain unclear. We sought to describe a strategy used in a multicentre RCT in primary care, to report researchers’ and participants’ experiences of its implementation and to inform future strategies to maximise recruitment and retention. Methods In total 48 general practices and 903 patients were recruited from three different areas of Ireland to a RCT of an intervention designed to optimise secondary prevention of coronary heart disease. The recruitment process involved telephoning practices, posting information, visiting practices, identifying potential participants, posting invitations and obtaining consent. Retention involved patients attending reviews and responding to questionnaires and practices facilitating data collection. Results We achieved high retention rates for practices (100%) and for patients (85%) over an 18-month intervention period. Pilot work, knowledge of the setting, awareness of change in staff and organisation amongst participant sites, rapid responses to queries and acknowledgement of practitioners’ contributions were identified as being important. Minor variations in protocol and research support helped to meet varied, complex and changing individual needs of practitioners and patients and encouraged retention in the trial. A collaborative relationship between researcher and practice staff which required time to develop was perceived as vital for both recruitment and retention. Conclusions Recruiting and retaining the numbers of practices and patients estimated as required to provide findings with adequate power contributes to increased confidence in the validity and generalisability of RCT results. A continuous dynamic process of monitoring progress within trials and tailoring strategies to particular circumstances, whilst not compromising trial protocols, should allow maximal recruitment and retention.