A Canadian Critical Care Trials Group project in collaboration with the international forum for acute care trialists - Collaborative H1N1 Adjuvant Treatment pilot trial (CHAT): study protocol and design of a randomized controlled trial

Background

The Vaccine Assessment using Linked Data (VALiD) trial compared opt-in and opt-out parental consent for a population-based childhood vaccine safety surveillance program using data linkage. A subsequent telephone interview of all households enrolled in the trial elicited parental intent regarding the return or non-return of reply forms for opt-in and opt-out consent. This paper describes the rationale for the trial and provides an overview of the design and methods.

Methods/Design

Single-centre, single-blind, randomised controlled trial (RCT) stratified by firstborn status. Mothers who gave birth at one tertiary South Australian hospital were randomised at six weeks post-partum to receive an opt-in or opt-out reply form, along with information explaining data linkage. The primary outcome at 10 weeks post-partum was parental participation in each arm, as indicated by the respective return or non-return of a reply form (or via telephone or email response). A subsequent telephone interview at 10 weeks post-partum elicited parental intent regarding the return or non-return of the reply form, and attitudes and knowledge about data linkage, vaccine safety, consent preferences and vaccination practices. Enrolment began in July 2009 and 1,129 households were recruited in a three-month period. Analysis has not yet been undertaken. The participation rate and selection bias for each method of consent will be compared when the data are analysed.

Discussion

The VALiD RCT represents the first trial of opt-in versus opt-out consent for a data linkage study that assesses consent preferences and intent compared with actual opting in or opting out behaviour, and socioeconomic factors. The limitations to generalisability are discussed.

Trial registration

Australian New Zealand Clinical Trials Registry ACTRN12610000332022     

Tissue distribution of DNA-Hsp65/TDM-loaded PLGA microspheres and uptake by phagocytic cells

Background

Mucopolysaccharidosis type IIIA (MPS IIIA) is the most common of the mucopolysaccharidoses. The disease is caused by a deficiency of the lysosomal enzyme sulphamidase and results in the storage of the glycosaminoglycan (GAG), heparan sulphate. MPS IIIA is characterised by widespread storage and urinary excretion of heparan sulphate, and a progressive and eventually profound neurological course. Gene therapy is one of the few avenues of treatment that hold promise of a sustainable treatment for this disorder.

Methods

The murine sulphamidase gene cDNA was cloned into a lentiviral vector and high-titre virus produced. Human MPS IIIA fibroblast cultures were transduced with the sulphamidase vector and analysed using molecular, enzymatic and metabolic assays. High-titre virus was intravenously injected into six 5-week old MPS IIIA mice. Three of these mice were pre-treated with hyperosmotic mannitol. The weight of animals was monitored and GAG content in urine samples was analysed by polyacrylamide gel electrophoresis.

Results

Transduction of cultured MPS IIIA fibroblasts with the sulphamidase gene corrected both the enzymatic and metabolic defects. Sulphamidase secreted by gene-corrected cells was able to cross correct untransduced MPS IIIA cells. Urinary GAG was found to be greatly reduced in samples from mice receiving the vector compared to untreated MPS IIIA controls. In addition, the weight of treated mice became progressively normalised over the 6-months post-treatment.

Conclusion

Lentiviral vectors appear promising vehicles for the development of gene therapy for MPS IIIA.     

The influence of litter quality on the relationship between vegetation and below-ground compartments: a Procrustean approach

Aims

We used a Procrustean superimposition approach associated with regression analysis to test hypotheses regarding the relationship between plant communities and distinct below-ground compartments—soil chemistry (SC) and soil microbial activity (SMA). Additionally, we evaluated litter chemical quality as an interface between the above and below-ground compartments.

Methods

Plant community, and soil chemical and biochemical data from three post-mining degraded sites under reclamation and from one nearby forest site in the Brazilian Amazon Basin were analyzed.

Results

All studied sites presented distinct plant community, litter quality, SC and SMA. Plant community consistently affected the below-ground variation in both SC and SMA compartments. The influence of litter quality was greater in the plant community versus SMA relationship than in the plant community versus SC. Nevertheless, the SC affected significantly the SMA, but without influence of litter quality.

Conclusions

Differently from previous studies, our findings suggest that plant community and soil chemistry can affect the soil microbial activity independently. Specifically for our study area, these results point to a rupture of the ‘in nested’ structure of the causal relationship between changes in vegetation, changes in the chemical litter quality, changes in the SC and the response of SMA.     

A trial on unruptured intracranial aneurysms (the TEAM trial): results, lessons from a failure and the necessity for clinical care trials

Background

There is a large treatment gap with few community services for people with schizophrenia in low income countries largely due to the shortage of specialist mental healthcare human resources. Community based rehabilitation (CBR), involving lay health workers, has been shown to be feasible, acceptable and more effective than routine care for people with schizophrenia in observational studies. The aim of this study is to evaluate whether a lay health worker led, Collaborative Community Based Care (CCBC) intervention, combined with usual Facility Based Care (FBC), is superior to FBC alone in improving outcomes for people with schizophrenia and their caregivers in India.

Methods/Design

This trial is a multi-site, parallel group randomised controlled trial design in India. The trial will be conducted concurrently at three sites in India where persons with schizophrenia will be screened for eligibility and recruited after providing informed consent. Trial participants will be randomly allocated in a 2:1 ratio to the CCBC+FBC and FBC arms respectively using an allocation sequence pre-prepared through the use of permuted blocks, stratified within site. The structured CCBC intervention will be delivered by trained lay community health workers (CHWs) working together with the treating Psychiatrist. We aim to recruit 282 persons with schizophrenia. The primary outcomes are reduction in severity of symptoms of schizophrenia and disability at 12 months. The study will be conducted according to good ethical practice, data analysis and reporting guidelines.

Discussion

If the additional CCBC intervention delivered by front line CHWs is demonstrated to be effective and cost-effective in comparison to usually available care, this intervention can be scaled up to expand coverage and improve outcomes for persons with schizophrenia and their caregivers in low income countries.

Trial registration

The trial is registered with the International Society for the Registration of Clinical Trials and the allocated unique ID number is ISRCTN 56877013.     

Ethical frameworks for obtaining informed consent in tumour profiling: an evidence-based case for Singapore

Background

Genomic profiling of malignant tumours has assisted clinicians in providing targeted therapies for many serious cancer-related illnesses. Although the characterisation of somatic mutations is the primary aim of tumour profiling for treatment, germline mutations may also be detected given the heterogenous origin of mutations observed in tumours. Guidance documents address the return of germline findings that have health implications for patients and their genetic relations. However, the implications of discovering a potential but unconfirmed germline finding from tumour profiling are yet to be fully explored. Moreover, as tumour profiling is increasingly applied in oncology, robust ethical frameworks are required to encourage large-scale data sharing and data aggregation linking molecular data to clinical outcomes, to further understand the role of genetics in oncogenesis and to develop improved cancer therapies.

Results

This paper reports on the results of empirical research that is broadly aimed at developing an ethical framework for obtaining informed consent to return results from tumour profiling tests and to share the biomolecular data sourced from tumour tissues of cancer patients. Specifically, qualitative data were gathered from 36 semi-structured interviews with cancer patients and oncology clinicians at a cancer treatment centre in Singapore. The interview data indicated that patients had a limited comprehension of cancer genetics and implications of tumour testing. Furthermore, oncology clinicians stated that they lacked the time to provide in depth explanations of the tumour profile tests. However, it was accepted from both patients and oncologist that the return potential germline variants and the sharing of de-identified tumour profiling data nationally and internationally should be discussed and provided as an option during the consent process.

Conclusions

Findings provide support for the return of tumour profiling results provided that they are accompanied with an adequate explanation from qualified personnel. They also support the use of broad consent regiments within an ethical framework that promotes trust and benefit sharing with stakeholders and provides accountability and transparency in the storage and sharing of biomolecular data for research.

     

Participant informed consent in cluster randomized trials: review

Background

The Nuremberg code defines the general ethical framework of medical research with participant consent as its cornerstone. In cluster randomized trials (CRT), obtaining participant informed consent raises logistic and methodologic concerns. First, with randomization of large clusters such as geographical areas, obtaining individual informed consent may be impossible. Second, participants in randomized clusters cannot avoid certain interventions, which implies that participant informed consent refers only to data collection, not administration of an intervention. Third, complete participant information may be a source of selection bias, which then raises methodological concerns. We assessed whether participant informed consent was required in such trials, which type of consent was required, and whether the trial was at risk of selection bias because of the very nature of participant information.

Methods and Findings

We systematically reviewed all reports of CRT published in MEDLINE in 2008 and surveyed corresponding authors regarding the nature of the informed consent and the process of participant inclusion. We identified 173 reports and obtained an answer from 113 authors (65.3%). In total, 23.7% of the reports lacked information on ethics committee approval or participant consent, 53.1% of authors declared that participant consent was for data collection only and 58.5% that the group allocation was not specified for participants. The process of recruitment (chronology of participant recruitment with regard to cluster randomization) was rarely reported, and we estimated that only 56.6% of the trials were free of potential selection bias.

Conclusions

For CRTs, the reporting of ethics committee approval and participant informed consent is less than optimal. Reports should describe whether participants consented for administration of an intervention and/or data collection. Finally, the process of participant recruitment should be fully described (namely, whether participants were informed of the allocation group before being recruited) for a better appraisal of the risk of selection bias.     

Trends in publications regarding evidence-practice gaps: A literature review

Background

Well-designed trials of strategies to improve adherence to clinical practice guidelines are needed to close persistent evidence-practice gaps. We studied how the number of these trials is changing with time, and to what extent physicians are participating in such trials.

Methods

This is a literature-based study of trends in evidence-practice gap publications over 10 years and participation of clinicians in intervention trials to narrow evidence-practice gaps. We chose nine evidence-based guidelines and identified relevant publications in the PubMed database from January 1998 to December 2007. We coded these publications by study type (intervention versus non-intervention studies). We further subdivided intervention studies into those for clinicians and those for patients. Data were analyzed to determine if observed trends were statistically significant.

Results

We identified 1,151 publications that discussed evidence-practice gaps in nine topic areas. There were 169 intervention studies that were designed to improve adherence to well-established clinical guidelines, averaging 1.9 studies per year per topic area. Twenty-eight publications (34%; 95% CI: 24% - 45%) reported interventions intended for clinicians or health systems that met Effective Practice and Organization of Care (EPOC) criteria for adequate design. The median consent rate of physicians asked to participate in these well-designed studies was 60% (95% CI, 25% to 69%).

Conclusions

We evaluated research publications for nine evidence-practice gaps, and identified small numbers of well-designed intervention trials and low rates of physician participation in these trials.     

Hereditary sensory neuropathy type I

Background

Mucopolysaccharidosis type I (MPS I) is a rare lysosomal storage disease subdivided into three phenotypes of increasing severity: Scheie, Hurler-Scheie and Hurler. To gauge the effectiveness of treatments and to determine the load likely to fall on health-care systems, it is necessary to understand the prevalence and natural progression of the disease especially with regard to life-expectancy. In general such data on the natural history of lysosomal storage diseases is sparse.

Methods

Analysis of prevalence and patient survival in MPS I disease using a unique longitudinal data set initiated and maintained over a period of more than 20 years by the Society for Mucopolysaccharide Diseases (UK).

Results

The birth prevalence of MPS I in England and Wales over the period 1981 to 2003 was 1.07/100,000 births and within ± 5% of estimates reported in several studies that examined reasonably large populations. The median survival for MPS I patients (including all phenotypes irrespective of various treatments) was found by Kaplan-Meier analysis to be 11.6 years. This result was driven by the relatively poor survival of patients with the Hurler phenotype who, irrespective of any treatments received, had a median survival of 8.7 years; when censoring for receipt of bone marrow transplant (BMT) was implemented median survival of Hurler patients was diminished to 6.8 years. The difference between these survival curves was statistically significant by log rank test and can be attributed to beneficial effects of BMT and or selection of patients with superior prognosis for intervention with BMT. Survival curves for Hurler patients who received and did not receive BMT were very different. Probability of survival at 2 year after BMT was ~68% and was similar to this after 5 years (66%) and ten years (64%); the mean age of Hurler patients at receipt of BMT was 1.33 years (range 0.1 to 3 years). Follow up was insufficient to determine median survival of the milder phenotypes however, unsurprisingly, this was clearly superior to that for Hurler patients.

Conclusion

The birth prevalence of MPS I in England and Wales is 1.07/100,000 and the median survival for MPS I patients is 11.6 years.     

Gastric type I carcinoid: a pilot study with human G17DT immunogen vaccination

Context

Gastric type I carcinoid is a rare neoplasm, deriving from enterochromaffin-like cells (ECL), mainly affecting women with autoimmune gastritis. The approach to treatment, either endoscopic, medical or surgical, is not well defined, particularly in multifocal tumours or carcinoids with rapid growth/frequent recurrence.

Objective

To determine whether an anti-G17 vaccination might interfere on the natural history of gastric type I carcinoid.

Setting

Padua teaching Hospital, outpatient clinic.

Design and patients

Three patients with type I gastric carcinoid in autoimmune gastritis were administered, after informed consent and ethic committee approval, with a vaccine against gastrin 17 (G17), a synthetic peptide that stimulates specific and high-affinity anti-G17 antibodies, and followed up endoscopically and clinically for a mean of 36?months.

Main outcome measures

Gastric histology and specifically carcinoid growth/recurrence and trend in time in gastrin, G17, pepsinogens, chromogranin A and clinical parameters.

Results

Following vaccination, carcinoid regression was observed in 2/3 patients and, in one of the patients, even the disappearance of ECL hyperplasia, with a reduced ECL cells stimulation, confirmed by a significant reduction in chromogranin A levels. Regression was observed in the two patients that showed a more clear local response to the vaccine. Increased autoantibody titre was observed, but no appearance of new autoimmune diseases.

Conclusions

Anti-G17 vaccination induced regression of type I gastric carcinoid and could be considered for the treatment of this tumour, when endoscopic removal is not indicated.     

Optimising informed consent for participants in a randomised controlled trial in rural Uganda: a comparative prospective cohort mixed-methods study

Background

Poor participant understanding of research information can be a problem in community interventional studies with rural African women, whose levels of illiteracy are high. This study aimed to improve the informed consent process for women living in rural eastern Uganda. We assessed the impact of alternative consent models on participants’ understanding of clinical trial information and their contribution to the informed consent process in rural Uganda.

Methods

The study applied a parallel mixed-methods design for a prospective comparative cohort, nested within a pilot study on the community distribution of an alcohol-based hand rub to prevent neonatal sepsis (BabyGel pilot trial). Women of at least 34 weeks’ pregnancy, suitable for inclusion in the BabyGel pilot trial, were recruited into this study from their homes in 13 villages in Mbale District. As part of the informed consent process, information about the trial was presented using one of three consent methods: standard researcher-read information, a slide show using illustrated text on a flip chart or a video showing the patient information being read as if by a newsreader in either English or the local language. In addition, all women received the patient information sheet in their preferred language. Each information-giving method was used in recruitment for 1 week. Two days after recruitment, women’s understanding of the clinical trial was evaluated using the modified Quality of Informed Consent (QuIC) tool. They were also shown the other two methods and their preference assessed using a 5-point Likert scale. Semi-structured interviews were administered to each participant. The interviews were audio-recorded, transcribed and translated verbatim, and thematically analysed.

Results

A total of 30 pregnant women in their homes participated in this study. Their recall of the trial information within the planned 48 h was assessed for the majority (90%, 27/30). For all three consent models, women demonstrated a high understanding of the study. There was no statistically significant difference between the slide-show message (mean 4.7; standard deviation, SD 0.47; range 4–5), video message (mean 4.9; SD 0.33; range 4–5) and standard method (mean 4.5; SD 0.53; range 4–5; all one-way ANOVA, p =?0.190). The slide-show message resulted in the most objective understanding of question items with the highest average QuIC score of 100 points. For women who had been recruited using any of the three models, the slide show was the most popular method, with a mean score for all items of not less than 4.2 (mean 4.8; SD 0.6; range 4–5). Most women (63%, 19/30) preferred the slide-show message, compared with 17% (5/30) and 20% (6/30) for the standard and video messages, respectively. The reasons given included the benefits of having pictures to aid understanding and the logical progression of the information.

Conclusion

Our results from this small study suggest that slide-show messages may be an effective and popular alternative way of presenting trial information to women in rural Uganda, many of whom have little or no literacy.

Trial registration

ISRCTN, ISRCTN67852437. Registered on 18 March 2018.

     

The Definition of Placebo in the Informed Consent Forms of Clinical Trials

Aim

Lack of knowledge concerning the nature of placebo and why it is necessary may influence the participation of patients in clinical trials. The objective of the present study is to review how placebo is described in written information for participants in clinical trials to be evaluated by a Human Research Ethics Committee.

Methods

All research protocols submitted for evaluation in a Spanish hospital during 2007–2013 were reviewed. The main characteristics of the studies using a placebo were collected. Three authors read each of them to determine how the term “placebo” was explained and if there was any comment on its efficacy and safety.

Results

Two thousand seven-hundred and forty research protocols were evaluated, of which three hundred and fifty-nine used a placebo. Pharmaceutical companies sponsored most placebo-controlled clinical trials (91.9%), and phase III studies were the commonest (59.9%). Oncology (15.0%), cardiology (14.2%), and neurology (13.1%) made the greatest contributions. A review of the informed consent forms showed that placebo was described in a similar manner in most studies: the explanation was limited to between four and eight words. Very few gave information about the risks of its use or adverse reactions from its administration. None of the studies provided details about the placebo effect. And 23 lacked any information about placebo at all.

Conclusions

Explanations about placebo in informed consent forms is often scarce, and information about the placebo effect and associated risks are absent. This situation may influence a full understanding of placebo by participants in clinical trials and might reduce their informed decision to participate.     

Evaluating the Consent Preferences of UK Research Volunteers for Genetic and Clinical Studies

Objectives

To establish the views of research volunteers on the consent process; to explore their views on the consent process in different research scenarios; to inform debate on emerging models of consent for participation in research.

Design, Setting and Participants

2,308 adult volunteers from the TwinsUK Registry (www.twinsuk.ac.uk) completed an online survey about their views on the consent process for use of their DNA and medical information in research. Their views on the re-consenting process in different scenarios were assessed.

Results

The majority of volunteers preferred to be informed of the identity of the main researcher of a study in which they are participating, which is contrary to current practice. Over 80% were willing to complete the consent process online instead of face to face. On the whole, respondents did not view their DNA differently from their medical information with regard to the consent process. Research participants were more willing to give broad consent to cover future research if their DNA was to be used by the original researcher than by another researcher, even if the disease under investigation varied, in contrast to the traditional ‘gold standard’ whereby specific consent is required for all new research projects.

Discussion

In some scenarios, research participants reported that they would be comfortable with not signing a new consent form for future research uses of their data and DNA, and are comfortable with secure, online consent processes rather than traditional face-to-face consent processes. Our findings indicate that the perceived relationship between research participants and researchers plays an important role in shaping preferences regarding the consent process and suggest that this relationship is not captured by traditional consent processes. We argue that the development of new formats of consent should be informed by empirical research on volunteers’ perceptions and preferences regarding the consent process.     

Could the Decision of Trial Participation Precede the Informed Consent Process? Evidence From Burkina Faso

Background

Over the last years, the number of clinical trials carried out in low-income countries with poor medical infrastructure and limited access to health care has increased. In these settings, the decision of participating in a clinical study may be influenced by factors related to participants’ vulnerability that limit the efficacy of the informed consent.

Methods

A mixed methods social science study, based on the triangulation of qualitative and quantitative data, was carried out in a socio-economically disadvantaged and semi-urban area of Bobo Dioulasso, Burkina Faso. The study aimed at assessing the relevance of the informed consent procedure on the decision-making process of the parents and/or guardians of potential participants in a pediatric malaria trial.

Results

For most parents (70.4%), the decision of participating had already been taken before undergoing the informed consent process and was based on the information conveyed through the community. Access to free and good quality health care often inspired this decision. In addition, the parents’ willingness to have their child included in the trial made them develop active strategies to achieve this purpose.

Discussion

In a context of socio-economic vulnerability and poor access to free health care, the process of informed consent does not always accomplish its goal of informing people and enabling them to make a free and informed decision. This information role is somehow anticipated by the community and trial participation becomes a strategic action to secure otherwise unavailable health resources leading community members to decide on participation even prior to the informed consent process.     

GRACE and TIMI risk scores but not stress imaging predict long-term cardiovascular follow-up in patients with chest pain after a rule-out protocol

Objective

To determine the long-term prognostic value of stress imaging and clinical risk scoring for cardiovascular mortality in chest pain patients after ruling out acute coronary syndrome (ACS).

Methods

A standard rule-out protocol was performed in emergency room patients with a normal or non-diagnostic admission electrocardiogram (ECG) within 6 h of chest pain onset. ACS patients were identified by troponin T, recurrent angina and serial ECG. Dobutamine stress echocardiography (DSE) was performed after ACS was ruled out. Myocardial perfusion scintigraphy (MPS) was performed within 6 months in an outpatient setting according to the physician’s discretion.

Results

524 patients were included. GRACE and TIMI risk scores were 75 (57–96) and 1 (0–2) in the rule-out ACS group, and 89 (74–107) and 2 (1–3) in the ACS group, respectively (median, interquartile range). Follow-up (median 9.4 (8.9–10.0) years) was complete in 96%. 350 of 379 rule-out ACS patients had an interpretable DSE and 52 patients underwent an MPS. 21 of the rule-out ACS patients (6%) died of a cardiovascular cause compared with 24 (17%) ACS patients (p?<?0.001). For rule-out ACS patients, C-statistics were 0.829 and 0.803 for the GRACE and TIMI scores. In these patients, DSE and MPS outcome did not predict long-term cardiovascular mortality. In multivariate analysis, known chronic heart failure, ACE inhibitor use, and GRACE score were independent predictors of cardiovascular mortality.

Conclusions

TIMI and GRACE score but not DSE and MPS are accurate predictors of long-term cardiovascular mortality, even in chest pain patients with a normal or non-diagnostic electrocardiogram undergoing a rule-out protocol.     

Random Amplified Polymorphic DNA (RAPD) for differentiation between Thai and Myanmar strains of Wuchereria bancrofti

Background

Information on the physical and psychosocial disability of lymphatic filariasis in Sri Lanka is scarce. Therefore this study was carried out to describe the physical disability and psychosocial impact associated with chronic lymphoedema in patients attending filariasis clinics in the Colombo district, Sri Lanka.

Methods

Four hundred and thirteen patients with lymphoedema of limbs attending filariasis clinics in Werahera and Dehiwala in the Colombo district were enrolled in the study after obtaining informed written consent. Data were collected using a pre-tested, interviewer-administered questionnaire and analyzed using SPSS.

Results

Majority (95%) of patients had lower limbs affected and there was a significant association with difficulty in walking (p = 0.023). The swollen limb affected the work of 87 (52 %) of employed patients and 26 persons reported loss of job. Approximately 25 % and 6 % reported having problems interacting with the community and family, respectively and 8.7 % felt that they were rejected by society. The swollen limb was perceived as a major problem by 36.8 % of patients. Of the married persons, 5.7 % and 6.2 % reported sexual and marital problems respectively, due to their swollen limb/s. Of those who had marital problems, 77.3% reported sexual problems as well (p < 0.001).

Conclusion

Lymphoedema significantly affects physical, psychological and social functioning in affected individuals. Morbidity control, in addition to control of physical disability, should target the psychosocial consequences.     

The effect of long-term homocysteine-lowering on carotid intima-media thickness and flow-mediated vasodilation in stroke patients: a randomized controlled trial and meta-analysis

Background

Experimental and epidemiological evidence suggests that homocysteine (tHcy) may be a causal risk factor for atherosclerosis. B-vitamin supplements reduce tHcy and improve endothelial function in short term trials, but the long-term effects of the treatment on vascular structure and function are unknown.

Methods

We conducted a sub-study of VITATOPS, a randomised, double-blind, placebo-controlled intervention trial designed to test the efficacy of long term B-vitamin supplementation (folic acid 2 mg, vitamin B₆ 25 mg and vitamin B₁₂ 0.5 mg) in the prevention of vascular events in patients with a history of stroke. We measured carotid intima-medial thickness (CIMT) and flow-mediated dilation (FMD) at least two years after randomisation in 162 VITATOPS participants. We also conducted a systematic review and meta-analysis of studies designed to test the effect of B-vitamin treatment on CIMT and FMD.

Results

After a mean treatment period of 3.9 ± 0.9 years, the vitamin-treated group had a significantly lower mean plasma homocysteine concentration than the placebo-treated group (7.9 μmol/L, 95% CI 7.5 to 8.4 versus 11.8 μmol/L, 95% CI 10.9 to 12.8, p < 0.001). Post-treatment CIMT (0.84 ± 0.17 mm vitamins versus 0.83 ± 0.18 mm placebo, p = 0.74) and FMD (median of 4.0%, IQR 0.9 to 7.2 vitamins versus 3.0%, IQR 0.6 to 6.6 placebo, p = 0.48) did not differ significantly between groups. A meta-analysis of published randomised data, including those from the current study, suggested that B-vitamin supplements should reduce CIMT (-0.10 mm, 95% CI -0.20 to -0.01 mm) and increase FMD (1.4%, 95% CI 0.7 to 2.1%). However, the improvement in endothelial function associated with homocysteine-lowering treatment was significant in short-term studies but not in longer trials.

Conclusion

Although short-term treatment with B-vitamins is associated with increased FMD, long-term homocysteine-lowering did not significantly improve FMD or CIMT in people with a history of stroke.

Trial Registration

Clinical Trial Registration URL: http://www.actr.org.au/ Trial Registration number: 12605000005651     

Initial breastfeeding attitudes and practices of women born in Turkey, Vietnam and Australia after giving birth in Australia

Background

Many studies of the impact of breastfeeding on child or maternal health have relied on data reported retrospectively. The goal of this study was to assess recall accuracy among breastfeeding mothers of retrospectively collected data on age of weaning, reasons for cessation, breast pain, lactation mastitis, and pumping.

Methods

Women in Michigan and Nebraska, U.S.A. were interviewed by telephone every 3 weeks during the first 3 months after the birth of their child, and mailed a questionnaire at 6 months. A subset was interviewed again by telephone approximately 1–3.5 years after the birth. The results for the three recall periods, collected 1994–1998, were compared using correlation, linear and Cox regression analysis, and sensitivity and specificity estimates.

Results

The 184 participants were aged 18–42, mostly white (95%) and 63% had an older child. The age of weaning tended to be overestimated in interviews 1–3.5 years after birth compared to those within 3 weeks of the event, by approximately one month for 1–3.5 year recall and two weeks for 6-month recall (p < 0.001 in both cases). Recall accuracy of reasons for weaning varied greatly by reason, with mastitis and return to work having the most recall validity. The sensitivity of 1–3.5 year recall of mastitis was 80%, but was only 54% for nipple cracks or sores.

Conclusion

Breastfeeding duration among short-term breastfeeders tended to be somewhat overestimated when measured at 1–3.5 years post-partum. Reporting of other breastfeeding characteristics had variable reliability. Studies employing retrospective breastfeeding data should consider the possibility of such errors.     

Cluster-randomised controlled trial of community mobilisation in Mumbai slums to improve care during pregnancy, delivery, postpartum and for the newborn

Background

Chronic back pain is a major public health problem and the primary reason patients seek acupuncture treatment. Therefore, an objective assessment of acupuncture efficacy is critical for making informed decisions about its appropriate role for patients with this common condition. This study addresses methodological shortcomings that have plagued previous studies evaluating acupuncture for chronic low back pain.

Methods and Design

A total of 640 participants (160 in each of four arms) between the ages of 18 and 70 years of age who have low back pain lasting at least 3 months will be recruited from integrated health care delivery systems in Seattle and Oakland. They will be randomized to one of two forms of Traditional Chinese Medical (TCM) acupuncture needling (individualized or standardized), a "control" group (simulated acupuncture), or to continued usual medical care. Ten treatments will be provided over 7 weeks. Study participants and the "Diagnostician" acupuncturists who evaluate participants and propose individualized treatments will be masked to the acupuncture treatment actually assigned each participant. The "Therapist" acupuncturists providing the treatments will not be masked but will have limited verbal interaction with participants. The primary outcomes, standard measures of dysfunction and bothersomeness of low back pain, will be assessed at baseline, and after 8, 26, and 52 weeks by telephone interviewers masked to treatment assignment. General health status, satisfaction with back care, days of back-related disability, and use and costs of healthcare services for back pain will also be measured. The primary analysis comparing outcomes by randomized treatment assignment will be analysis of covariance adjusted for baseline value. For both primary outcome measures, this trial will have 99% power to detect the presence of a minimal clinically significant difference among all four treatment groups and over 80% power for most pairwise comparisons. Secondary analyses will compare the proportions of participants in each group that improve by a clinically meaningful amount.

Conclusion

Results of this trial will help clarify the value of acupuncture needling as a treatment for chronic low back pain.

Trial registration

Clinical Trials.gov NCT00065585.     

Reversibility of stress-echo induced ST-segment depression by long-term oral n-3 PUFA supplementation in subjects with chest pain syndrome, normal wall motion at stress-echo and normal coronary angiogram

Background

Normal coronary arteries may coexist with abnormal coronary and systemic endothelial function in patients with chest pain. Recent work by the renowned Pisa echo-group elegantly suggests that isolated ST-segment depression during stress-echo (SE) can be used as a marker of coronary endothelial dysfunction, in the absence of stress-inducible wall motion abnormalities and in the absence of angiographically-significant coronary artery disease (CAD). The long chain n-3 polyunsaturated fatty acids (PUFAs) have been reported to possess several properties that may positively influence vascular function. The present study's hypothesis is that a 4 month-course of oral supplementation with n-3 PUFAs can reverse endothelial dysfunction.

Methods

Subjects were selected on the basis of the following criteria: 1) reported chest pain syndrome, 2) significant ST-segment depression during an otherwise normal SE, 3) absence of angiographically-significant CAD. Subjects underwent a 4-month course of oral supplementation with commercially available n-3 PUFA, 1 g once a day. Normalization of endothelial dysfunction was defined, at the end of the supplementation period, by the absence of significant ST-segment depression during repeat SE. We tested the aforementioned hypothesis in a very small series of consecutive subjects, with the intent to produce a hypothesis-generating study.

Results

Seven out of the total nine subjects enrolled (77.8%) had normal ST-segment during repeat SE performed after the 4 month course of therapy.

Conclusions

A striking rate of reversion of SE-induced ST-segment depression after oral n-3 PUFAs suggests reversion of coronary endothelial dysfunction; nonetheless these data need to be validated in larger, placebo-controlled studies.