Breastfeeding and breastmilk substitute use and feeding motivations among mothers in Bandung City, Indonesia.

Suboptimal breastfeeding is common in Indonesia, with only half of infants 0-5 months of age exclusively breastfed and feeding of breastmilk substitutes (BMS) highly prevalent among infants and toddlers. Various factors influence these feeding practices, including social norms, limited health system support and BMS manufacturer marketing practices. This cross-sectional survey aimed to identify the prevalence of breastfeeding and BMS feeding among children aged 0-35 months, explore socio-demographic characteristics and motivating factors associated with these feeding behaviours and identify the prevalence of mothers' exposure to BMS promotions. Indonesian mothers of children <3 years of age (n = 595) were interviewed in Bandung City health facilities using structured questionnaires. Although all children were ever breastfed, half of children across all age groups received BMS in the previous day. Maternal employment outside the home and insufficient breastmilk production were associated with BMS use. The most important motivational factors for feeding BMS were perceived benefits for growth, intelligence and immunity. Despite Indonesian legislation restricting some BMS marketing, 93% of mothers reported observing a BMS promotion outside the health system, with television, social media and newspapers as the most common sources. Half of mothers (43%) reported observing a BMS promotion within the health system, and half (46%) reported receiving recommendations from health workers to use BMS. Such high prevalence of BMS marketing may be influencing caregivers' feeding choices; stronger national legislation and implementation of laws are needed to ensure mothers' ability to make feeding choices free from manufacturer influence.

COVID-19 and maternal and child food and nutrition insecurity: a complex syndemic.

Globally, the COVID-19 pandemic has already led to major increases in unemployment and is expected to lead to unprecedented increases in poverty and food and nutrition insecurity, as well as poor health outcomes. Families where young children, youth, pregnant and lactating women live need to be protected against the ongoing protracted pandemic and the aftershocks that are very likely to follow for years to come. The future wellbeing of the vast majority of the world now depends on reconfiguring the current ineffective food, nutrition, health, and social protection systems to ensure food and nutrition security for all. Because food, nutrition, health, and socio-economic outcomes are intimately inter-linked, it is essential that we find out how to effectively address the need to reconfigure and to provide better intersecoral coordination among global and local food, health care, and social protection systems taking equity and sutainability principles into account. Implementation science research informed by complex adaptive sytems frameworks will be needed to fill in the major knowledge gaps. Not doing so will not only put the development of individuals at further risk, but also negatively impact on the development potential of entire nations and ultimately our planet.

Embedding supportive parenting resources into maternity and early years care pathways: a mixed methods evaluation.

BACKGROUND: During pregnancy and postnatally, women seek information from a variety of sources. The potential to incorporate educational pregnancy and parenting resources into conventional health services is underexplored. In 2014-2016, UK-based charity Best Beginnings used an embedding model to embed three of their resources - the Baby Buddy app, Baby Express magazine, and 'From Bump to Breastfeeding' DVD - into maternity and early years care pathways at three sites in the north of England. A mixed-methods evaluation comprising an impact evaluation and a process evaluation was undertaken. Here we report findings from the process evaluation that aimed to understand the embedding process, explore maternity and early years' professionals' views and use of the resources, explore women's engagement with and views of the resources, and identify barriers and facilitators to the embedding process. METHODS: We carried out semi-structured interviews with stakeholders (professionals involved in embedding) and observations of embedding activities to understand how embedding worked. Surveys of postnatal women were conducted over a two-month period both prior to, and after, the resources had been embedded, to ascertain engagement with and views of the resources. A survey of professionals was carried out post-embedding to understand how, where and when the resources were used in practice, and professionals' views. Descriptive and thematic analyses were undertaken. RESULTS: Thirty stakeholders took part in interviews. Surveys were completed by 146 professionals, and by 161 and 192 women in the pre and post-embedding phases respectively. Themes derived from analysis of qualitative data were 'Implementation of the embedding model', 'Promotion and distribution of, and engagement with, the resources', 'Fit with care pathways', and 'Perceptions of the resources'. While survey responses indicated that embedding of the resources into practice was not yet complete, those who had used the resources believed that they had helped increase knowledge, build confidence and support relationship-building. CONCLUSIONS: Incorporating supportive parenting resources into maternity and early years' care pathways requires a planned embedding approach, committed champions, and senior management support. Findings indicate largely positive views of women and professionals, and suggest the resources can be a beneficial aid for families.

Women's experiences of pharmacological and non-pharmacological pain relief methods for labour and childbirth: a qualitative systematic review.

BACKGROUND: Many women use pharmacological or non-pharmacological pain relief during childbirth. Evidence from Cochrane reviews shows that effective pain relief is not always associated with high maternal satisfaction scores. However, understanding women's views is important for good quality maternity care provision. We undertook a qualitative evidence synthesis of women's views and experiences of pharmacological (epidural, opioid analgesia) and non-pharmacological (relaxation, massage techniques) pain relief options, to understand what affects women's decisions and choices and to inform guidelines, policy, and practice. METHODS: We searched seven electronic databases (MEDLINE, CINAHL, PsycINFO, AMED, EMBASE, Global Index Medicus, AJOL), tracked citations and checked references. We used thematic and meta-ethnographic techniques for analysis purposes, and GRADE-CERQual tool to assess confidence in review findings. We developed review findings for each method. We then re-analysed the review findings thematically to highlight similarities and differences in women's accounts of different pain relief methods. RESULTS: From 11,782 hits, we screened full 58 papers. Twenty-four studies provided findings for the synthesis: epidural (n = 12), opioids (n = 3), relaxation (n = 8) and massage (n = 4) - all conducted in upper-middle and high-income countries (HMICs). Re-analysis of the review findings produced five key themes. 'Desires for pain relief' illuminates different reasons for using pharmacological or non-pharmacological pain relief. 'Impact on pain' describes varying levels of effectiveness of the methods used. 'Influence and experience of support' highlights women's positive or negative experiences of support from professionals and/or birth companions. 'Influence on focus and capabilities' illustrates that all pain relief methods can facilitate maternal control, but some found non-pharmacological techniques less effective than anticipated, and others reported complications associated with medication use. Finally, 'impact on wellbeing and health' reports that whilst some women were satisfied with their pain relief method, medication was associated with negative self-reprisals, whereas women taught relaxation techniques often continued to use these methods with beneficial outcomes. CONCLUSION: Women report mixed experiences of different pain relief methods. Pharmacological methods can reduce pain but have negative side-effects. Non-pharmacological methods may not reduce labour pain but can facilitate bonding with professionals and birth supporters. Women need information on risks and benefits of all available pain relief methods.

A realist qualitative study to explore how low-income pregnant women use Healthy Start food vouchers.

Healthy Start is the UK government's food voucher programme for low-income pregnant women and young children. It was introduced in 2006, but the impact of the programme on nutritional outcomes remains understudied. This study sought to explore potential outcomes of the Healthy Start programme (including intended and unintended outcomes) and develop explanations for how and why these outcomes might occur. A realist review preceded this study, in which programme theories were developed and tested using existing evidence. This qualitative study aimed to further refine and consolidate the programme theories from the realist review while remaining open to new and emerging theories (or hypotheses) about how low-income pregnant women use Healthy Start vouchers. Semistructured interviews were conducted with 11 low-income women from North West England, who received Healthy Start vouchers during pregnancy. A realist logic of analysis was applied to generate clear and transparent linkages between outcomes and explanations. The findings suggested that some women used the vouchers to improve their diets during pregnancy (intended outcome), whereas some women were diverted towards alternative or unintended outcomes. Women's circumstances, values, beliefs, and motivations influenced how they perceived and responded to the vouchers. This paper presents four evidence-based programme theories to explain four contrasting (and potentially overlapping) outcomes: dietary improvements (theory refined from review), shared benefits (new theory), financial assistance (theory refined from review), and stockpiling formula (new theory). It considers how the Healthy Start programme could be improved, to increase the possibilities for low-income women to experience the intended outcome of dietary improvements.

Report of the International Society for Zinc Biology 5th Meeting, in Collaboration with Zinc-Net (COST Action TD1304)-UCLan Campus, Pyla, Cyprus.

From 18 to 22 June 2017, the fifth biennial meeting of the International Society for Zinc Biology was held in conjunction with the final dissemination meeting of the Network for the Biology of Zinc (Zinc-Net) at the University of Central Lancashire, Cyprus campus. The meeting attracted over 160 participants, had 17 scientific symposia, 4 plenary speakers and 2 poster discussion sessions. In this report, we give an overview of the key themes of the meeting and some of the highlights from the scientific programme.

The role of nutrition in integrated early child development in the 21st century: contribution from the Maternal and Child Nutrition journal.

Even though it is widely recognized that early childhood development (ECD) is one of the most important predictors of future social capital and national productivity, the recently published ECD Lancet Series reports that about 250 million children under 5 years are at risk of not reaching their developmental potential, mainly as a result of poverty and social injustice. So why is this and what will it take to reverse this situation? The purpose of this special issue is to highlight important contributions from previously published articles in Maternal & Child Nutrition to the field of nutrition and ECD. The collection of papers presented in this special issue collectively indicates that although nutrition-specific interventions are essential for child development, they are not sufficient by themselves for children to reach their full developmental potential. This is because ECD is influenced by many other factors besides nutrition, including hand washing/sanitation, parenting skills, psychosocial stimulation, and social protection. Future research should focus on mixed-methods implementation science seeking to understand how best to translate evidence-based integrated ECD packages into effective intersectoral policies and programs on a large scale. In addition to health and nutrition, these programs need to consider and include responsive parenting (including responsive feeding), learning stimulation, education, and social protection. Future studies should also address if and how childhood obesity affects human physical, socioemotional, and cognitive development.

Integrating a sense of coherence into the neonatal environment.

BACKGROUND: Family centred care (FCC) is currently a valued philosophy within neonatal care; an approach that places the parents at the heart of all decision-making and engagement in the care of their infant. However, to date, there is a lack of clarity regarding the definition of FCC and limited evidence of FCCs effectiveness in relation to parental, infant or staff outcomes. DISCUSSION: In this paper we present a new perspective to neonatal care based on Aaron Antonovksy's Sense of Coherence (SOC) theory of well-being and positive health. Whilst the SOC was originally conceptualised as a psychological-based construct, the SOCs three underpinning concepts of comprehensibility, manageability and meaningfulness provide a theoretical lens through which to consider and reflect upon meaningful care provision in this particular care environment. By drawing on available FCC research, we consider how the SOC concepts considered from both a parental and professional perspective need to be addressed. The debate offered in this paper is not presented to reduce the importance or significance of FCC within neonatal care, but, rather, how consideration of the SOC offers the basis through which meaningful and effective FCC may be delivered. Practice based implications contextualised within the SOC constructs are also detailed. SUMMARY: Consideration of the SOC constructs from both a parental and professional perspective need to be addressed in FCC provision. Service delivery and care practices need to be comprehensible, meaningful and manageable in order to achieve and promote positive well-being and health for all concerned.

Effect of zinc intake on serum/plasma zinc status in infants: a meta-analysis.

A systematic review and meta-analysis of available randomised controlled trials (RCTs) was conducted to evaluate the effect of zinc (Zn) intake on serum/plasma Zn status in infants. Out of 5500 studies identified through electronic searches and reference lists, 13 RCTs were selected after applying the exclusion/inclusion criteria. The influence of Zn intake on serum/plasma Zn concentration was considered in the overall meta-analysis. Other variables were also taken into account as possible effect modifiers: doses of Zn intake, intervention duration, nutritional status and risk of bias. The pooled ß of status was 0.09 [confidence interval (CI) 0.05 to 0.12]. However, a substantial heterogeneity was present in the analyses (I(2) = 98%; P = 0.00001). When we performed a meta-regression, the effect of Zn intake on serum/plasma Zn status changed depending on the duration of the intervention, the dose of supplementation and the nutritional situation (P ANCOVA = 0.054; <0.001 and <0.007, respectively). After stratifying the sample according to the effect modifiers, the results by duration of intervention showed a positive effect when Zn intake was provided during medium and long periods of time (4-20 weeks and >20 weeks). A positive effect was also seen when doses ranged from 8.1 to 12 mg day(-1). In all cases, the pooled ß showed high evidence of heterogeneity. Zn supplementation increases serum/plasma Zn status in infants, although high evidence of heterogeneity was found. Further standardised research is urgently needed to reach evidence-based conclusions to clarify the role of Zn supplementation upon infant serum/plasma Zn status, particularly in Europe.

Participatory action research to co-design a culturally appropriate COVID-19 risk communication and community engagement strategy in rural Pakistan.

Background: Community engagement has shown to be fundamental component of the response to previous disease outbreaks. This study aimed co-design and implement a culturally appropriate COVID-19 risk communication and community engagement strategy with a resource-poor rural community in Northwest Pakistan. Methods: Participatory Action Research (PAR) was conducted from January 2021 to March 2022. Five PAR meetings took place with community members (n = 30) to: (1) explore how the COVID-19 pandemic impacted on the community; (2) identify challenges to limit the spread of the virus; (3) identify and implement solutions to these challenges; and (4) highlight the enablers, challenges and knowledge of the cultural context needed to optimize safety during emergencies. Focus group discussions (N = 6) with community members not involved in the PAR meetings (N = 50) and children of the community (N = 26) were conducted following the PAR meetings. Thematic analysis of the PAR and focus group data was conducted. Results: Delivery of messages on how to keep families safe, provision of personal protective equipment and improved water systems were part of the strategies taken by the community to create awareness and reduce the spread of COVID-19. Nine themes were identified: Attitudes to the pandemic: From skepticism to acceptance, Changing attitudes about vaccination: rumors and trust, COVID-19 and Faith, Social impact of the pandemic, Access to water, Resource mobilization: personal protective equipment, Spaces where collaborative effort can bring to solutions, Agents of change, and Empowerment of women. Discussion: The participatory approach of this research allowed understanding of the challenges faced by the community to engage in behavior change strategies to reduce the spread of COVID-19 and enabled the community to find sustainable solutions. Engagement with the community empowered men and women to be agents of change and promoted necessary precautionary actions to reduce the risk of infection within their community. Conclusion: Participatory approach highlighted the importance of engaging with and integrating to local culture and values to overcome challenges such as gender imbalance and distrust. Findings of this study are relevant to others working in diverse cultural settings in similar crises events regardless of particular cultural variations.

Farmers' and millers' experiences and attitudes towards the production and processing of zinc biofortified wheat in Pakistan: a mixed methods study.

Background: Zinc biofortified wheat may be a sustainable strategy to increase zinc intake in areas where fortification and dietary diversification are not feasible or are limited by household purchasing power. This convergent mixed methods study aimed to explore the farmers' and millers' experiences and attitudes towards the production and processing of zinc biofortified wheat in Pakistan. Methods: A telephone survey was conducted with farmers (n = 418) who were provided with Zincol-2016 biofortified wheat seed for the 2019-2020 growing season, as part of a wheat grain micronutrient mapping study across Punjab Province. The survey explored the farmers' experiences of growing Zincol-2016 and whether they opted to grow it again in the subsequent season. Semi-structured focus group discussions were undertaken in a separate group of farmers in Khyber Pakhtunkhwa (KP) province (n = 12) who grew Zincol-2016 for the BiZiFED2 RCT. Millers were also interviewed in KP, both those who had processed Zincol-2016 for the trial (n = 12) and those who had no experience of processing biofortified wheat (n = 12). Survey data were analyzed using descriptive statistics and transcripts of focus groups were analyzed using thematic analysis. Results: Nearly half of farmers who responded to the survey (47%) re-cultivated Zincol-2016 in the following season. The drivers for Zincol-2016 re-cultivation were seed availability (100%), grain yield and growth resistance (98%), quality of the flour from the previous harvest (97%) and nutritional benefit (94.5%). Discussions with farmers suggested that the main motivators for potential scale-up of biofortified wheat were the perceived quality of the grain, wheat, and flour. Millers saw it as an opportunity to expand their business. Farmers and millers valued the health benefits of the wheat. Challenges for scale-up include the need of additional support to produce it, unfamiliarity with the biofortification process, production costs, and external threats to the supply chain. Conclusion: Farmers and millers showed a strong implicit preference for Zincol-2016 over alternative varieties. Crop performance and product yield were the most cited motivators for growing Zincol-2016. Farmers and millers are willing to produce and process biofortified wheat if financial and educational support is provided.

Closeness and separation in neonatal intensive care.

UNLABELLED: In this paper, we highlight the need for acknowledging the importance and impact of both physical and emotional closeness between the preterm infant and parent in the neonatal intensive care unit. Physical closeness refers to being spatially close and emotional closeness to parental feelings of being emotionally connected to the infant (experiencing feelings of love, warmth and affection). Through consideration of the literature in this area, we outline some of the reasons why physical closeness and emotional closeness are crucial to the physical, emotional and social well-being of both the infant and the parent. These include positive effects on infant brain development, parent psychological well-being and on the parent-infant relationship. The influence of the neonatal unit environment and culture on physical and emotional closeness is also discussed. CONCLUSIONS: Culturally sensitive care practices, procedures and the physical environment need to be considered to facilitate parent-infant closeness, such as through early and prolonged skin-to-skin contact, family-centred care, increased visiting hours, family rooms and optimization of the space on the units. Further research is required to explore factors that facilitate both physical and emotional closeness to ensure that parent-infant closeness is a priority within neonatal care.

Community Perceptions of Zinc Biofortified Flour during an Intervention Study in Pakistan.

Zinc-biofortified flour may be a cost-effective approach to improve zinc status of populations in low-resource settings. The success of biofortification programmes is subject to acceptability and uptake by consumers. This study explored community leaders' and community members' (n = 72) experiences and attitudes towards the flour provided during a cluster randomised controlled trial of zinc biofortified wheat in rural Pakistan (BiZiFED2). Focus group discussions (n = 12) were conducted and thematic analysis applied using an inductive, semantic, contextualist approach. Five themes were identified: (1) Contribution to food security; (2) Better sensory and baking properties than local flour; (3) Perceived health benefits; (4) Willingness to pay for the flour; and (5) Importance of trusted promoters/suppliers. Although the participants were blind to whether they had received control or biofortified flour, referred to collectively as "study flour", the results indicated that the study flour performed well in terms of its taste and bread making qualities, with no adverse reports from participants in either arm of the BIZIFED2 RCT. Participants suggested that they would buy the biofortified wheat if this was available at a fair price due to perceived health benefits, reporting positive sensory characteristics and cooking attributes when compared to the flour available in the local markets. Overall, there was a positive reception of the programme and flour among the participants, and members of the community hoped for its continuation and expansion.

The nutritional requirements of infants. Towards EU alignment of reference values: the EURRECA network.

This paper presents a review of the current knowledge regarding the macro- and micronutrient requirements of infants and discusses issues related to these requirements during the first year of life. The paper also reviews the current reference values used in European countries and the methodological approaches used to derive them by a sample of seven European and international authoritative committees from which background scientific reports are available. Throughout the paper, the main issues contributing to disparities in micronutrient reference values for infants are highlighted. The identification of these issues in relation to the specific physiological aspects of infants is important for informing future initiatives aimed at providing standardized approaches to overcome variability of micronutrient reference values across Europe for this age group.

Impact of parenting resources on breastfeeding, parenting confidence and relationships.

OBJECTIVE: Pregnancy and the postnatal period offers an opportunity to optimise maternal health. A UK-based charity has developed parenting resources - Baby Buddy smartphone app, Baby Express magazine, and 'From Bump to Breastfeeding' DVD - designed to complement health service care to promote maternal wellbeing, breastfeeding and positive parenting. We evaluated the embedding of these resources into maternity and early years care pathways at three sites in the north of England. Here we present results relating to the impact of the resources on breastfeeding, women's parenting confidence, and mother-infant bonding. DESIGN AND SETTING: We conducted a mixed-methods study comprising qualitative interviews and women and care provider surveys at three sites. Women's questionnaires were issued to two cohorts of postnatal women pre and post embedding of the resources. This questionnaire included validated scales (Iowa Infant Feeding Attitude Scale, Breastfeeding Self-Efficacy, Parenting Sense of Competency, Mother to Baby Bonding Scale), and bespoke questions to elicit women's views of the resources and infant feeding data. A survey of professionals in the post-embedding phase explored how the resources were used in practice. Interviews with stakeholders explored views of the resources and embedding process. We conducted descriptive and inferential statistics of quantitative data, and thematic analysis of qualitative data. FINDINGS: There were 30 stakeholder interviews, 146 professionals completed a survey, and 161 and 192 women completed a survey before and after embedding, respectively. Receipt and use of the resources was relatively low, however, overall views of the resources were positive. There was no significant change in outcomes relating to infant feeding or parenting confidence, before and after embedding. After embedding, scores on the Mother to Baby Bonding Scale were significantly more positive when compared to pre-embedding scores. KEY CONCLUSIONS: While there were issues with the receipt and use of the resources, the resources were well received by women and professionals. While the resources did not appear to have influenced parents' confidence and self-efficacy, there may be a positive impact on mother-infant bonding. Further research is needed to understand whether more focussed integration of the resources into care pathways over a longer term can increase user engagement, and the impact of such on key parenting outcomes.

Biofortification of wheat with zinc for eliminating deficiency in Pakistan: study protocol for a cluster-randomised, double-blind, controlled effectiveness study (BIZIFED2).

INTRODUCTION: Micronutrient deficiencies, commonly referred to as 'hidden hunger', affect more than two billion people worldwide, with zinc and iron-deficiency frequently reported. The aim of this study is to examine the impact of consuming zinc biofortified flour (Zincol-2016) on biochemical and functional measures of status in adolescent girls and children living in a low-resource setting in Pakistan. METHODS AND ANALYSIS: We are conducting a pragmatic, cluster-randomised, double-blind, controlled trial. A total of 482 households have been recruited from two catchment areas approximately 30-40 km distance from Peshawar. Household inclusion criteria are the presence of both an adolescent girl, aged 10-16 years, and a child aged 1-5 years. The study duration is 12 months, divided into two 6-month phases. During phase 1, all households will be provided with locally procured flour from standard varieties of wheat. During phase 2, clusters will be paired, and randomised to either the control or intervention arm of the study. The intervention arm will be provided with zinc biofortified wheat flour, with a target zinc concentration of 40 mg/kg. The control arm will be provided with locally procured wheat flour from standard varieties with an expected zinc concentration of 20 mg/kg. The primary outcome measure is plasma zinc concentration. Secondary outcomes include anthropometric measurements, biomarkers of iron and zinc status, and the presence and duration of respiratory tract infections and diarrhoea. ETHICS AND DISSEMINATION: Ethical approval was granted from the University of Central Lancashire STEMH Ethics Committee (reference number: STEMH 1014) and Khyber Medical University Ethics Committee (DIR/KMU-EB/BZ/000683). The final study methods will be published in peer-reviewed journals, alongside the study outcomes. In addition, findings will be disseminated to the scientific community via conference presentations and abstracts and communicated to the study participants through the village elders at an appropriate community forum. TRIAL REGISTRATION NUMBER: ISRCTN17107812; Pre-results.

Qualitative exploration of women's experiences of intramuscular pethidine or remifentanil patient-controlled analgesia for labour pain.

OBJECTIVES: To explore women's experiences of remifentanil or pethidine for labour pain and infant feeding behaviours at 6weeks post partum. DESIGN: Qualitative postnatal sub-study to the randomised controlled trial of remifentanil intravenous patient controlled analgesia (PCA) versus intramuscular pethidine for pain relief in labour (RESPITE). Semistructured telephone interviews were conducted at 6 weeks post partum, and thematic analysis was undertaken. SETTING: Women recruited to the RESPITE trial from seven UK hospitals. PARTICIPANTS: Eighty women consented and 49 (30 remifentanil group and 19 pethidine group) completed the interview. RESULTS: Eight themes emerged which encompassed women's antenatal plans for pain management (Birth Expectations) through to their future preferences for pain relief (Reflections for Future Choices). Many women who used remifentanil felt it provided effective pain relief (Effectiveness of Pain Relief), whereas women in the pethidine group expressed more mixed views. Both groups described side effects, with women using pethidine frequently reporting nausea (Negative Physiological Responses) and women using remifentanil describing more cognitive effects (Cognitive Effects). Some women who used remifentanil reported restricted movements due to technical aspects of drug administration and fear of analgesia running out (Issues with Drug Administration). Women described how remifentanil enabled them to maintain their ability to stay focused during the birth (Enabling a Sense of Control). There was little difference in reported breastfeeding initiation and continuation between pethidine and remifentanil groups (Impact on Infant Behaviour and Breastfeeding). CONCLUSIONS: Qualitative insights from a follow-up study to a trial which explored experiences of intravenous remifentanil PCA with intramuscular pethidine injection found that remifentanil appeared to provide effective pain relief while allowing women to remain alert and focused during labour, although as with pethidine, some side effects were noted. Overall, there was little difference in reported breastfeeding initiation and duration between the two groups. TRIAL REGISTRATION NUMBER: ISRCTN29654603.