Following the introduction of a computerised diabetes register in part of the northeast of England, care initially improved but then plateaued. We therefore enhanced the existing diabetes register to address these problems. The aim of the trial was to evaluate the effectiveness and efficiency of an area wide 'extended,' computerised diabetes register incorporating a full structured recall and management system, including individualised patient management prompts to primary care clinicians based on locally-adapted, evidence-based guidelines.The study design was a pragmatic, cluster randomised controlled trial, with the general practice as the unit of randomisation. Set in 58 general practices in three Primary Care Trusts in the northeast of England, the study outcomes were the clinical process and outcome variables held on the diabetes register, patient-reported outcomes, and service and patient costs. The effect of the intervention was estimated using generalised linear models with an appropriate error structure. To allow for the clustering of patients within practices, population averaged models were estimated using generalized estimating equations.Patients in intervention practices were more likely to have at least one diabetes appointment recorded , to have a recording of a foot check , have a recording of receiving dietary advice , and have a recording of blood pressure (BP) . There was no difference in mean HbA1c or BP levels, but the mean cholesterol level in patients from intervention practices was significantly lower . There were no differences in patient-reported outcomes or in patient-reported use of drugs, or uptake of health services. The average cost per patient was not significantly different between the intervention and control groups. Costs incurred in administering the system at the register and in general practice were in addition to these.This study has shown benefits from an area-wide, computerised diabetes register incorporating a full structured recall and individualised patient management system. However, these benefits were achieved at a cost. In future, these costs may fall as electronic data exchange becomes a reliable reality. Trial registration: International Standard Randomised Controlled Trial Number (ISRCTN) Register, ISRCTN32042030. However, they also identified important methodological concerns, with larger studies and randomised studies showing smaller benefits than smaller or non-randomised ones, which strongly suggest the presence of publication bias. Studies in the highest quartile of sample size reported a median reduction in serum HbA1c of only 0.10%.There is broad, international agreement over what constitutes high-quality health care for people with diabetes ,2. In thWithin their taxonomy of interventions the categories of "provider reminders" and "audit and feedback" most closely approximate to the intervention in this study. Across 14 trials examining one or both of these interventions, they found median improvements in provider adherence of between 4% and 8%, and improvements in HbA1c of around 0.1%. They alFollowing the introduction of a computerised diabetes management system in three (then) Primary Care Group areas, in the northeast of England, care initially improved but then plateaued, a phenomenon also reported by others ,7. At thThis study aimed to evaluate, within a pragmatic, cluster randomised controlled trial design, the effectiveness and efficiency of an area-wide, 'extended' computerised diabetes register incorporating a full-structured recall and management system, actively involving patients, and including individualised patient-management prompts to primary care clinicians based on locally-adapted, evidence-based guidelines.The study methods described here are reported in detail elsewhere .The study general practices were those in three Primary Care Trusts (PCTs) served by two district hospital-based diabetes registers, both using the same register software. When the study was designed, it was based in three PCTs  served by a single register. However, the withdrawal of one of these PCTs necessitated the recruitment of a replacement PCT served by a second register. Several factors led to the withdrawal of this PCT. Despite our having appropriate administrative approval, when the trial began it became apparent that the administrative authority did not have the cooperation necessary for all of the GPs to participate in the trial. Consequently we had to enrol individual practices directly (rather than via the PCT), which resulted in fewer practices enrolling and our being at risk of not achieving our required sample size. We recruited a further PCT to address this problem, however, the original PCT then suspended involvement with the diabetes register and their practices had to be excluded from the study. This was a deviation from the published protocol.Study patients were those people with type 2 diabetes appearing on the registers, aged over 35 years and receiving diabetes care exclusively from study general practices or shared between study general practices (GPs) and hospital. At the time of the study, approximately 20% of patients received both GP and specialist care, though there was no formal shared-care scheme in operation in the PCTs studied.The study was a pragmatic two-arm cluster randomised controlled trial with the general practice as the unit of randomisation. Randomisation was performed using electronically-generated random numbers by the study statistician and was stratified by PCT and practice size.The study outcomes were: the clinical process and outcome variables held on the diabetes registers; patient reported outcomes  for measures of process calculated from local data was 0.14, whether a blood pressure measurement or an HbA1c measurement has been recorded in a 12-month period. Therefore, to detect a difference of 15% (42.5% v 57.5%) in a binary variable with 80% power, assuming a significance level of 5%, required 60 practices each contributing 30 patients  – and thst April 2002 to 30th June 2003). All data were extracted from the registers at the end of the intervention period. Prescription data were similarly collected, but, because of problems reliably determining the date of initiation of prescriptions, we collected drug data back to the point at which a study patient first appeared on the register. We gathered data on patient reported outcomes by postal questionnaire at the end of the intervention period. Questions on the costs incurred by patients were developed by the study health economist and were included in the questionnaire. These questions included the self-reported use of medication. Non-responders to the initial posting received a reminder letter after two weeks; non-responders to this received a second reminder letter and a copy of the questionnaire after a further two weeks.We collected process data for the 12 months preceding the start of the intervention and for the 15 months of the intervention period  and link function . To allow for the clustering of patients within practices, population averaged models were estimated using generalized estimating equations (GEEs). Baseline variables (pre-intervention data) were included in the model as a covariate.Examination of the drug therapy data suggested that the variable that was recorded most reliably on the register was the date that the medication was started. In general, patients who started on a particular medication prior to the intervention period also were taking that medication during the intervention period. For each type of medication, the total number of patients prescribed that medication in each practice was determined. This variable was analysed using negative binomial regression with the total number of relevant patients in the practice included as an exposure variable; the number of patients prescribed that medication prior to the intervention was included as a covariate.Questionnaire data were only available following the intervention. Patient-reported outcome measures were analysed using population averaged models as described for the process data above, except that, as we had no pre-intervention measure, no adjustment for differences at baseline was possible, thus no baseline covariate was included in the model. Patient reported medication data were analysed for the register medication data, except that, again, there were no baseline data to include as a covariate.In addition to the above analyses that were pre-specified, because of large systematic differences between the two registers that became apparent once the data had been collected, a further model was fitted which included a register effect. This was not pre-specified, but the differences were so large it was felt that it would be inappropriate to ignore them during the main analysis. All analyses were undertaken using Stata version 8.The economic evaluation adopted a 'cost consequences' approach . All cosThe development and implementation of the intervention have been described in detail elsewhere . In summIn the enhanced structured and recall management system, a 'circle of information exchange' was established between the participating general practices and the database. The central database system identified when patients were due for review and generated a letter to the patients asking them to make an appointment for a review consultation. The rules for generation of review letters were adapted for each PCT area. In one PCT, the system acted as a prompting system for annual review, and patients were identified 11 months after their last diabetes appointment. In the other two PCTs, patients who had missed annual reviews were identified by searching for patients who had not had a diabetes appointment for 14 months or more. At the same time, the central database generated a letter to the practice stating that the patient should be making a review appointment in the near future. The letter to the practice included a 'structured management sheet' (to be held in the patient's record) to capture an agreed minimum data set that would be collected during the consultation. This management sheet also contained relevant prompts tailored to a patient's known clinical or biochemical values, derived from locally adapted, national evidence-based guidelines [see Additional file When the patient was seen in the practice, the primary care professional (often the practice nurse) completed the management sheet and returned a copy for entry into the central register within a designated period of time. This circle of information was broken if the patient did not visit the general practice as planned or the general practice did not return the management sheet to the central register. If this happened, the central register would print reminder letters and further structured management sheets at the next routine database search by the diabetes register facilitator, which occurred at least weekly.In addition to this cycle based on annual reviews, routine ongoing structured management sheets were produced every time a patient in an intervention practice was identified by the diabetes register facilitator on the register database. For example, when data were inputted on the database for any reason, the system would print a structured management sheet updated for any new data and relevant management prompts, and this would be sent to the relevant practice.The trial intervention ran for 15 months, commencing on 1 April 2002 and ending on 30 June 2003. The letters to patients inviting them for annual review commenced in October 2002 – delayed to overcome concerns about the accuracy of patient details on the database up to this point. The enhanced system also was capable of producing patient letters to accompany routine ongoing structured management sheets for practices, but because of difficulties operating this element of the software it was not possible to run this feature during the lifetime of the trial. This was a deviation from the published protocol.The study was approved by the South Tyneside, Southwest Durham, Hartlepool, and North Tees Local Research Ethics Committees (LRECs).Figure only and register effect only are presented alongside this analysis in Additional file The findings from analysis of the process of care clinical variables and drug data from the register-derived dataset are shown in Table We surveyed a random sample of 3056 patients, receiving usable responses from 1433. With 241 exclusions, this gave an overall response rate of 51%  , and improvement in one measure of clinical control (serum cholesterol). These benefits incurred costs.Although we showed significant improvements in the recording of drugs in the database, there were problems with the dating of the drug data. The patient reported data on drug use showed no significant differences in usage between the two groups. Given this discrepancy and the potential for inaccuracy in both data sets, the impact of the intervention on prescribing has to be regarded as unclear.In our study which utilised provider reminders and audit and feedback within an information system, we found changes in provider adherence that were considerably larger than those identified in the review by Shojania et al., and four of our nine were statistically significant improvements . HoweverThere is some suggestion of under-recording of data on the registers, with an apparently low proportion of people on aspirin and insulin . This is almost certainly due to a combination of factors of which a degree of under-recording is only one. Low aspirin prescription rates could be due to patients buying aspirin directly from pharmacies rather than receiving it via prescription (common in the UK). This is supported by the figures for self-reported aspirin use being higher than those on the registers. Excluded from the study were people being treated for their diabetes solely by hospital, who are more likely to be treated on insulin and less likely to be on diet alone. However, while we have the same rates for patients treated with diet alone from the register and from self-report, self-report of insulin use was considerably higher than on the registers. This suggests that insulin use was under-recorded on the registers, but equally so for both intervention and control groups.Unlike the studies in the review, we found no significant effect on levels of HbA1c. This may reflect the overall levels of control in our study population with baseline HbA1c of 7.7, and both groups improving to 7.3. The studies in the review were conducted in more poorly controlled populations, with median baseline HbA1c values of over 8 (and in one case over 10). Our findings also may reflect the relatively short period for which the intervention ran as fully intended. While the intervention was in place for the planned 15 months, the full intervention ran for only 9 months, and the intended patient intervention was never fully operational.We did, however, show a modest and statistically significant lowering of serum cholesterol of 0.15 mmol/l in the intervention group compared to the control group. As the impact of the intervention on medication, including lipid-lowering therapy, was unclear from the register-derived data and negative from the patient-reported data, it is possible that this effect may be due to the increased delivery of dietary advice – one of the four areas of improvement in provider adherence to recommended care.We showed no significant difference in patient-reported outcomes between intervention and control groups. The observed clustering in the outcome scores was smaller than that assumed in the sample size calculation, and, as we achieved the desired sample size, the lack of significant changes in patient outcomes is unlikely to be due to a lack of power. However, we do have to consider the possibility of non-response bias for all the self-reported data with a response rate of 51%, even though there was no difference between intervention and control group response rates, or on sociodemographic variables.It is very unusual for implementation trials to include a rigorous economic evaluation . Given tThis study has shown benefits from an area-wide, computerised diabetes register incorporating a full structured recall and individualised patient management system. However, these benefits were achieved at a cost. In future, these costs may fall as electronic data exchange becomes a reliable reality. However, as performance steadily rises it will become ever more difficult to demonstrate smaller and smaller incremental improvements. Considering our findings alongside those of Shojania's review, such developments should only be evaluated in large-scale, randomised controlled trials incorporating a full economic evaluation.DM was senior partner of Westman Medical Software, who developed the software. The company was taken over by ProWellness UK Ltd, who continue to maintain the software used in this study. The remaining authors declare that they have no competing interests.The study was conceived by ME, GH and JG. It was designed by ME, GH, PW, JG, NS, AV, DM and LW. It was run by PW, CS, GH, AV and ME. DM developed and modified the software. Senior clinicians and diabetes register staff in the two sites ran and maintained the intervention. NS supervised the analysis. AV conducted the economic evaluation. All authors commented on successive drafts of the paper. ME is the guarantor of the paper.Example of a structured management sheet. The file provides an anonymised example of a structured management sheet from the enhanced diabetes register.Click here for fileTable Click here for file


Earlier studies have shown that people with low level of education have increased rates of mental health problems. The aim of the present study is to investigate the association between level of education and psychological distress, and to explore to which extent the association is mediated by sense of mastery, and social variables like social support, negative life events, household income, employment and marital status.The data for the study were obtained from the Level of Living Survey conducted by Statistics Norway in 2002. Data on psychological distress and psychosocial variables were gathered by a self-administered questionnaire, whereas socio-demographic data were based on register statistics. Psychological distress was measured by Hopkins Symptom Checklist 25 items.There was a significant association between low level of education and psychological distress in both genders, the association being strongest in women aged 55–67 years. Low level of education was also significantly associated with low sense of mastery, low social support, many negative life events (only in men), low household income and unemployment,. Sense of mastery emerged as a strong mediating variable between level of education and psychological distress, whereas the other variables played a minor role when adjusting for sense of mastery.Low sense of mastery seems to account for much of the association between low educational level and psychological distress, and should be an important target in mental health promotion for groups with low level of education. Mental health problems have become a major public health concern, epidemiological studies showing that up to one-fifth or one-quarter of the general population suffer from some sort of mental disorder at a given time -3. For tFor the purpose of monitoring mental health in the population, the EU has recently recommended a set of indicators . The setThere are various mechanisms which might explain the association between poor mental health and low education. Selection could be one of them, suggesting that children and adolescents with poor mental health, or with increased vulnerability because of individual and/or environmental factors, will be less able to complete higher education. Low education may also contribute to poor mental health through poor economy and problems on the labour market. Lastly, low educational level could be associated with a low sense of mastery, which could be a stressor in itself, or indirectly influence mental health through other psychosocial variables, like social support .Higher rates of psychological distress in people with little education have been reported in several studies ,7. ThereThe aim of the present study was to explore to which extent sense of mastery mediates the effect of education on mental health, when adjusting for the effect of socio-demographic factors, social support and negative life eventsThe data in the present study were obtained from the Health and Level of Living Survey conducted by Statistics Norway in 2002, covering 10, 000 individuals above the age of 15 years. The data on mental health and psychosocial variables were obtained by postal questionnaire, after an initial interview by home visit or telephone. Data on education, income and marital status were based on register statistics from Statistics Norway. The response rate was 70.4%. Non-response analysis showed that the non-responders differed only slightly from the total sample with respect to gender, age and place of living in Norway. Only those in the age group 25–67 years were included in present the study, and the final sample with data on education counted 4446 persons. Missing data on other social and psychosocial variables were substituted by means.Mental health was measured by the HSCL-25  which coSense of mastery is measured by a 5-item version of a 7-items scale developed by Pearlin et al  comprisiThere is really no way I can solve some of the problems I haveSometimes I feel that I'm pushed around in lifeI have little control over the things that happen to meI often feel helpless in dealing with the problems of lifeThere is little I can do to change many of the important things in my lifeThe responses , were numbered from 1 to 5, and summarised into the score of sense of mastery. The Cronbach's alpha for the scale in the sample was 0.86.The correlation between sense of mastery and psychological distress was high (Pearson correlation 0.6), and one may ask to which extent the two concepts are overlapping. To investigate this, principal component analysis  was carried out. The result is shown in Table headache, which loaded 0.4 on the HSCL-25 component. Explained variance by the first component was 39.6% and by the second component 6.5%. Three and four component extractions resulted in a split of the first component in respectively two and three components, first anxiety/depression and somatization, and then anxiety, somatization and depression, which are known as subcomponents of HSCL-25. The second component, sense of mastery, remained unchanged under three and four component extraction. From this we conclude that sense of mastery is a factor different from HSCL-25 and its subcomponents. Also a scatter plot  and between 0.5 and 0.7 (HSCL-25), with the exception of one item, t Figure  supporteWhereas those with strong sense of mastery were likely to have low psychological distress, low sense of mastery only to a limited extent predicted high psychological distress.The Oslo social support scale ,19 was uNegative life events were measured by a 12 item scale concerning major negative life events during the last 12 months .Education was split in three groups according to years of education: 7–10 years (low), 11–14 years (moderate) and 15 years or more (high). Net household income was defined as the sum of net income in the household divided by the square root of household members, and split in eight ordinal categories. Marital status was dichotomized into "married/cohabitant" and "others", and employment status was dichotomized into "usually in paid work" and "others". "Usually in paid work" was defined as having at least one hour of paid work during the last week (including work in family enterprise or farm), or having been temporarily away from paid work last week. Hence, "others" is a complex group, including unemployed, people on disability pension, home-makers and students.For a mediator to be demonstrated, besides an association between the initial and the outcome condition, the possible mediator has to be associated with both conditions. In this case, level of education has to be associated with psychological distress, and sense of mastery and the other possible mediators to both these variables. To investigate this, and to explore the mediating effects, the following analyses have been carried out:The association between education and psychological distress was tested by linear regression analysis, across gender and age groups. Possible interactions were looked into by multivariate linear regression analyses.The associations between level of education and sense of mastery, social support, negative life events, household income and paid work were tested by Pearson correlation, and between level of education and marital status by chi square statistics.The associations between sense of mastery, the other independent variables and psychological distress were tested by multivariate linear regression analyses across gender, first adjusting for age and then for all independent variables.In the final analysis, the mediating effects of sense of mastery and other variables on the association between level of education and psychological distress were tested by a number of multiple regression analyses, adjusting for various independent factors.There was a significant association between level of education and psychological distress across age groups and gender, with the exception of the eldest age group in men Table .A test did not yield a statistically significant trend, and only the eldest women differed significantly from the rest, showing the highest association between level of education and psychological distress.The associations between level of education and psychosocial and socio-demographic variables showed an approximately linear trend, with the exception of marital status. The associations in terms of correlations are shown in Table Educational level was positively correlated with sense of mastery, social support, household income and having paid work, and negatively correlated with negative life events (significant only in men). With respect to marital status, men with high or low level of education were more often married than those with moderate level of education (66% in the two first groups against 60% in the last (P = 0.031)). Different from this, women with lowest level of education were more often married than those with moderate or high level of education (67% in the first group against 63% and 58% in the two last groups (P = 0.032)).We also studied if the differences in correlation coefficients between men and women were associated with different regression slopes. A statistically significant difference was only found for social support and paid work, indicating that these variables were higher associated with level of education in women than in men.The associations between the psychosocial and socio-demographic variables and psychological distress are shown in Table When only adjusting for age, all variables were significantly associated with psychological distress in both genders. Interaction analysis showed that the association between household income and psychological distress was significantly higher in men than in women. For the other variables there were no significant gender differences. The associations remained statistically significant in the fully adjusted model, with the exceptions of marital status in men and household income in women. The strongest association was between sense of mastery and psychological distress, and this association was only slightly reduced when adjusting for the other variables. The associations between psychological distress and the other variables were, however, strongly reduced when adjusting for sense of mastery. This pattern was more or less the same when splitting in four age groups , the association between education and psychological distress was strongly reduced in both genders, but it was still significant. Sense of mastery accounted for 58% of the association between educational level and mental health problems in men, and 44% in women. Further adjustment for marital status (model 3) had no effect on the association between level of education and psychological distress in any gender, whereas social support (model 4) had a slight effect in both genders. Negative life events (model 5) had no effect on the association between level of education and psychological distress in any gender, whereas household income and not having paid work had a slight effect (models 6 and 7). When introducing the independent variables one by one in the sequence shown in Table In the full model (model 7) the association between level of education and psychological distress is eliminated in men, and strongly reduced in women. Sense of mastery emerges as the most important variable in both genders, with negative life events as next. It is interesting that marital status in men is not longer associated with psychological distress when adjusting for social support, negative life events and household income, which is not the case in women. Interaction analysis shows a significant gender difference only for negative life events, indicating that such events are closer related to psychological distress in women than in men.There was a significant association between level of education and psychological distress in both genders, those with low education reporting most symptoms of distress. This association was especially strong in women in the age group 55–67 years.Sense of mastery accounted for about half of the association between level of education and psychological distress, whereas the other variables contributed less to explain the association.It is a strength of the study that it is based on a an extensive nation wide sample, matching well the population with respect to age, gender and place of living in Norway, and with register based data on socio-demographic variables . The response rate, 70%, is somewhat low, and this may to some extent have influenced the results. Even if there may be some under-representation of people with mental and social problems, which is likely to be the case in such studies, this should not to any substantial degree invalidate the internal comparison of groups, which is the focus of the present study.As a measure of income, one may question the use of net income, as it is known that many of real high income earners have a low net income. This might reduce the association between household income and psychological distress in the study, but it is difficult to say how it would effect the association between sense of mastery and psychological distress. Anyhow, it is not likely that this will substantially influence the main results of the study.In the context of the present study, it is a weakness that we are dealing with cross-sectional data, which makes it difficult to draw conclusions about causality.The finding that the association between level of education and psychological distress is strongest in women above the age of 55 years, is somewhat surprising. A possible explanation could be that women in this age group, when their eventual children are grown up, and their role in the family context is less central, will have problems when entering the labour marked if they are lacking in education. In men the problems with lacking education is likely to be stronger in the younger age groups, when problems on the labour market is difficult to combine with the establishment of a family.The finding that sense of mastery emerged as an important mediating factor between education and psychological distress is in accordance with other studies suggesting that lack of control plays an important role in explaining the association between social inequality and mental health -23. It lOne possibility is that the association between sense of mastery and level of education is explained by psychological selection: Because of lower coping skills, which might be explained by genetic and/or early environmental factors, those with low sense of mastery are less likely to succeed in the school system, and end up with little formal education .Another possibility is that low sense of mastery is a reflection of the life situation of people with low education and low social status. Without education the possibility to control one's life situation is reduced, not least with respect to options on the labour marked. Hence environmental factors may influence the sense of mastery . ObviousWhy is sense of mastery associated with psychological distress? One possibility is that low sense of mastery in itself is a stressor ,25. AnotBecause of the strong association between sense of mastery and psychological distress, the possibility of overlapping concepts has been raised. The principal component analysis, suggesting that we are dealing with two separate factors, weakens this hypothesis. Also a scatter-plot points in the direction of two different factors.Low level of education is an important risk factor for mental health, and should be kept in mind in psychiatric prevention and mental health promotion. It is likely to be a mental health gain in reducing school dropouts among young people, and in providing support and guidance for those who have educational problems. It is also important to provide education for elder people who enter the labour marked at a later stage in life, most of them women. Since low sense of mastery seems to contribute strongly to the increased rate of mental health problems in those with little education, education should have a strong element of empowerment. School should not only be a place for teaching of theoretical and practical skills, but should also contribute to psychological growth, with the strengthening of coping and mastery as important elements. Education should also be flexible in relation to each pupil's abilities and psychological resources, and practical as well as theoretical assets should be taken into consideration.The study illustrates how a national health monitoring system may be used in exploring risk factors for mental health, thereby giving ideas for mental health promotion. Repeated surveys every third year, which is the plan in Norway, will strongly strengthen the potentials of this type of health monitoring. At present a reform in the Norwegian school system is launched, aiming at reducing the problems with school drop outs, and with stronger emphasize on practical education and individualized and supportive career planning. It will be interesting to see in the years to come, by repeated surveys, if this affects the relationship between level of education and mental health, and if it contributes to stronger sense of mastery and better mental health of the population.The author(s) declare that they have no competing interests.OSD has conceived the study, done the statistical analysis and written the manuscript.AM and PHZ have assisted in the statistical analysis and RJ has prepared the data file. All co-authors have contributed to the design of the study, drafted the manuscript and given their final approval of the version to be published.The pre-publication history for this paper can be accessed here:Associations between psychosocial, socio-demographic variables and psychological distress. Age group 25–34 yearsClick here for fileAssociations between psychosocial, socio-demographic variables and psychological distress. Age group 35–44 yearsClick here for fileAssociations between psychosocial, socio-demographic variables and psychological distress. Age group 45–54 yearsClick here for fileAssociations between psychosocial, socio-demographic variables and psychological distress. Age group 55–67 yearsClick here for file


Relative to research on effects of environmental exposures on exacerbation of existing asthma, little research on incident asthma and environmental exposures has been conducted. However, this research is needed to better devise strategies for the prevention of asthma. The U.S. Environmental Protection Agency (EPA) and National Institute of Environmental Health Sciences held a conference in October 2004 to collaboratively discuss a future research agenda in this area. The first three articles in this mini-monograph summarize the discussion on potential putative environmental exposure; they include an overview of asthma and conclusions of the workshop participants with respect to public health actions that could currently be applied to the problem and research needs to better understand and control the induction and incidence of asthma, the potential role of indoor/outdoor air pollutants in the induction of asthma), and biologics in the induction of asthma. Susceptibility is a key concept in the U.S. EPA “Asthma Research Strategy” document and is associated with the U.S. EPA framework of protecting vulnerable populations from potentially harmful environmental exposures. Genetics, age, and lifestyle  are major susceptibility factors in the induction of asthma and can interact with environmental exposures either synergistically or antagonistically. Therefore, in this fourth and last article we consider a number of “susceptibility factors” that potentially influence the asthmatic response to environmental exposures and propose a framework for developing research hypotheses regarding the effects of environmental exposures on asthma incidence and induction. From an epidemiologic framework, we have included variables that are sometimes considered confounders or effect modifiers, such as smoking or obesity  is the product of the incidence (I) of the disease times the duration (D): P = I × D. Compared with prevalence, much less is known about factors associated with incident asthma. Thus, we include in this article factors associated with prevalent asthma, acknowledging that factors that influence the prevalence of the disease may not necessarily affect the incidence of the disease in the same way and that additional factors may affect the remission of the disease.Most epidemiologic research on asthma and environmental risk factors has focused on prevalence because prevalent asthma is easier to measure than incident asthma. Prevalence  workshop “Environmental Influences on the Induction and Incidence of Asthma” held 19–20 October 2004, are considered in this article by experts in their fields: genetics, “window of exposure” , occupational asthma (OA), and lifestyle factors . We define susceptibility as the degree to which a person or a population is sensitive to either adverse or protective exposures in developing asthma . SmokingStudies of family history and genetic studies of familial aggregation and segregation of asthma have convincingly shown that the disease has a strong genetic component. Many investigators have sought to identify the specific genes and polymorphisms that determine hereditary susceptibility to the disease . A recenVarious technical reasons may explain these disappointing results. Type I and type II errors, for example, can result in spurious results or in results that cannot be replicated  SimilariAlthough most of the literature on these issues has acknowledged these technical problems, analyses of the published results of population studies suggest that the discrepancies among results cannot be attributed only to deficiencies in study design or in the statistical analysis of the data. It is now clear that asthma is a heterogeneous condition , that diTLR2; GenBank accession no. U88878; http://www.ncbi.nlm.gov) appear to modulate the protective effect of the farm environment: only carriers of certain TLR2 polymorphisms are protected by this environment  that are known to be present in the farm animal environment, it is suspected (but not yet demonstrated) that these polymorphisms in TLR2 may increase or decrease the reactivity of the individual to these products. Note that toll-like receptor 4  is the principal receptor for bacterial endotoxin, a glycolipid of the outer cell wall of gram-negative bacteria, whereas TLR2 is part of the signaling complex responding to cell membranes of gram-positive and -negative bacteria, mycoplasma, mycobacteria, parasites, and yeast . This gene encodes a receptor required for activation of TLR4 by endotoxin. Thus, the identity of polymorphic genes modulating development of allergic sensitization may vary depending on specific environmental exposures. These findings further suggest that the development of specific T helper (TH) 2-type immunity  is strongly influenced by the state of activation of the innate immune system, the maturation state of the developing innate immune system at the time of microbial exposure, and the responsiveness of the latter to ligands that are generally derived from exogenous microbial products but may include endogenous compounds.Recently, for example, researchers in Germany, Austria, and Switzerland have shown that, in rural areas of those countries, children raised in the farm animal environment are much less likely to have asthma and allergic sensitization than are those raised in the same rural areas but away from such farms . Furtherironment . Becausend yeast . Similarnd yeast  for the Genetic polymorphisms that influence susceptibility to the development of asthma exist, regardless of the environment in which the individual is raised or lives, and similarly, environmental exposures, may influence to some degree the susceptibility to allergic airways disease in the absence of genetic predisposition . Howeverin utero environment is the first environment to which an individual is exposed. Exposures in utero occurring during the critical periods for organogenesis have the potential to produce long-lasting effects. Postnatal organ function can be profoundly affected by in utero exposures  to mitogenic stimuli decreases with birth order. A plausible explanation for this phenomenon is an increasing response of the maternal immune system to “paternal” human leukocyte antigens in fetal cells. Such a response is likely to be of the TH1 type and is likely to counterbalance the TH2 skewed fetal and neonatal responses. Pregnancy complications ]. In addition to being essential for continued pregnancy, these cytokines may influence the developing fetal immune system and be responsible for the TH2 bias seen in stimulated CBMCs in vitro. Infants born to smoking mothers have lower levels of cytokines (both TH1 and TH2) in their cord blood, demonstrating that placental trophoblasts are vulnerable to in utero exposures -6, IL-10] and “anti-Txposures , which cin utero is controversial. It is not certain whether allergens cross the placenta in vivo; although this has been demonstrated using perfused placental models in vitro, the relevance of these findings is unclear. The results of strict dietary allergen-avoidance strategies during pregnancy  have been disappointing and may even increase the severity of clinical atopy when exposure occurs postnatally , increased collagen deposition in airway and alveolar walls, abnormal lung function at birth, and suppressed ventilatory responses to postnatal hypoxia  are also important. The data on the effects of other environmental agents are still equivocal. CBMC studies need to be interpreted cautiously, and evidence for in utero priming remains dubious. In summary, The following paragraphs include descriptions of prevalent rather than incident asthma because little is known about incident childhood asthma. Asthma is the most common chronic childhood disease . In addiEstimates of the effects of recall bias can be made from prospective epidemiologic studies. From 30 to 50% of children will forget that they had the diagnosis of asthma or wheeze symptoms 3 years earlier . A majorThere are several factors that are predictive of asthma in childhood. Parental history is an index of genetic susceptibility to asthma: 80% of children with two asthmatic parents develop the disease compared with 40% of children with one asthmatic parent and 10% of children with no asthmatic parents . Sex is Relatively little is known about the important predictors of asthma in young adulthood. Recently Work place exposures are responsible for 15–25% of asthma in adults . Hence, OA has been successfully prevented in several settings . An imprHowever, cohort studies that objectively assess exposure–response relationships for causative agents are available for only a minority of agents. Furthermore, studies have generally focused on inhalation exposure and have not attempted to address the roles of other potential routes of exposure such as skin, upper respiratory tract, and mucus membranes in development of sensitization and disease . In someOn a national level the overall prevalence of self-reported asthma in the United States increased from 3.2 to 4.6% in people 65 or more years of age between 1980 and 1996 . As the Exposures associated with asthma in older adults include indoor and outdoor air pollution, occupational exposures, and active and passive smoking. Allergen sensitization has been associated with asthma in older adults . Older aThe Centers for Disease Control and Prevention has yet to conduct longitudinal studies of asthma incidence. Although the increased prevalence suggests that the incidence has also risen, based on currently available data, it is hard to know how much of the asthma seen in older adults is newly developed disease and how much is persistence or recurrence or exacerbation of disease developed earlier in life.Up to half of older adults with asthma are current or former smokers . SmokersAsthma in older women living in Northern California was associated with occupations in art, decorating, photography, technology, health professions, food preparation, cleaning, social work, and service work , as wellIf the asthma phenotype is more heterogeneous in older adults compared with children, the strategies needed to prevent new-onset cases, as well as exacerbation of existing asthma, in this population may be different from those needed to protect children. To develop effective strategies, we need studies that specifically target older adults.Obesity is a large and rapidly growing public health problem both in the United States and worldwide. From 1976 through 1994, the prevalence of overweight children and adolescents in the United States almost doubled . NumerouObesity may be particularly important for severe asthma because a large epidemiologic survey indicates that > 75% of subjects visiting emergency departments for asthma are obese or overweight . These aIt is important that we understand the mechanistic basis for the relationship between obesity and asthma, both because the prevalence of obesity is extremely high among inner-city children , who havLongitudinal studies controlling for other confounding variables, including exercise, indicate that obesity antedates asthma and that the relative risk of incident asthma increases with increasing obesity . FurtherOb/ob mice, which are genetically deficient in the satiety hormone leptin ; db/db mice, which lack the leptin receptor isoform 1 gene ; and Cpefat mice, which are genetically deficient in an enzyme involved in cleavage of neuropeptides involved in satiety, are all obese. Each of these mouse strains demonstrates innate airway hyperresponsiveness that is not the result of differences in absolute lung volume or tidal volume. It has been hypothesized that this airway hyperresponsiveness may be related to chronic low-grade systemic inflammation, a characteristic of both human and murine obesity  found a 15-fold variation in prevalence of asthma symptoms among countries. Economically developed countries tended to have the higher prevalence (with English-speaking countries having the highest) . Asthma Other epidemiologic evidence found to support the hygiene hypothesis include a higher prevalence of eczema, skin prick positivity, and allergen specific IgE in children brought up in smaller and more affluent families and in first-born children . Early eH1 response pathways instead of the TH2 path-ways and thereby protects against the development of asthma and allergy. Other supportive evidence on factors that may program the initial susceptibility to asthma and allergy include studies of parasitic infections , respiratory syntactical virus (RSV) infection, obesity, pesticide exposures , OA Ell, and livH2 sensitization to common environmental antigens without causing harm to susceptible individuals.The challenge for the future is to identify the factors that confer the protection proposed by the hygiene hypothesis and to find strategies to modify the environment to reduce the incidence of asthma and TMuch of the ongoing asthma research is based on “high-risk” cohorts that maximize inclusion of children with a family history of asthma and recruit primarily children with allergic asthma. The knowledge gained from these studies, although important and useful for high-risk children, does not represent the entire population. There seems to be an assumption that the only good knowledge left to be gained epidemiologically will come from future and existing cohort studies. Yet, case–control studies and cross-sectional studies are still quite useful and much less costly, take much less time, and can be used for hypothesis generation. The studies by Braunfahrlander, von Mutius, and colleagues, described previously, are a case in point. An astute observation that farm children have a lower prevalence of asthma than non-farm children has spawned an entire field of research into endotoxin and toll-like receptors.There is a dearth of research into factors associated with asthma and allergy remission. Remission studies can be highly informative about the natural history of the disease. In one of the few reports in this area, Animal models have been developed primarily for the study of allergic sensitization rather than asthma. Perhaps toxicologists and immunologists can also broaden their efforts to improve animal models of asthma development. Collaborative research among epidemiologists, toxicologists, immunologists, allergists, occupational hygienists, and pulmonologists will help us reach our goal of developing strategies to prevent asthma in future generations.There is substantial evidence that genetics, obesity, and the window of exposure  are major susceptibility factors in the pathogenesis of asthmatic disease. Future research on the incidence and induction of asthma should take susceptibility factors into account. New research findings should then be used to generate public health interventions aimed at preventing a further rise in asthma and ultimately to reverse the existing trend.


Labels with special instructions regarding how a prescription medication should be taken or its possible side effects are often applied to pill bottles. The goal of this study was to determine whether the addition of illustrations to these labels affects patient comprehension.Study participants (N = 130) were enrolled by approaching patients at three family practice clinics in Toronto, Canada. Participants were asked to interpret two sets of medication instruction labels, the first with text only and the second with the same text accompanied by illustrations. Two investigators coded participants' responses as incorrect, partially correct, or completely correct. Health literacy levels of participants were measured using a validated instrument, the REALM test.All participants gave a completely correct interpretation for three out of five instruction labels, regardless of whether illustrations were present or not. For the two most complex labels, only 34–55% of interpretations of the text-only version were completely correct. The addition of illustrations was associated with improved performance in 5–7% of subjects and worsened performance in 7–9% of subjects.The commonly-used illustrations on the medication labels used in this study were of little or no use in improving patients' comprehension of the accompanying written instructions. Health literacy is the ability to read, comprehend, and act on health-related materials such as consent forms, prescription drug labels, and medical instructions . ApproxiPharmaceutical labels must provide critical instructional information to people with different experiences and education levels. Patients are faced with the responsibility of converting declarative information into procedural application, resulting in a substantial risk of errors . PictoriSpecial instructions regarding how a prescription medication should be taken or its possible side effects are often applied to medication bottles in the form of auxiliary labels. These labels typically include small illustrations that are intended to enhance comprehension. We conducted this study to determine whether the addition of illustrations to prescription medication instruction labels affects patients' comprehension of the accompanying written information.This study was conducted at three family practice clinics affiliated with an urban academic teaching hospital in Toronto, Ontario. These clinics provide primary care to a large patient population living in the central area of the city. From January to September 2001, consecutive patients presenting to the clinic during regular office hours on selected weekdays were approached and asked to participate in a study of comprehension of prescription labels. Days on which patients were enrolled were selected on the basis of availability of a member of the research team. A total of 130 participants were enrolled. Patients were excluded if they were too ill to participate or were unable to communicate in English. Patients who participated in the study gave written informed consent and received a $5 payment. The St. Michael's Hospital Research Ethics Board approved this study.One of the investigators (CQNT) conducted face-to-face interviews with participants that obtained information on demographic characteristics, native language, and education. Participants were then presented with five instruction labels regarding how certain prescription medications should be taken or their potential side effects Figure . PharmacParticipants were first shown five labels with text only  test. The REALM test is a previously validated instrument that uses an objective scoring system to assign a grade-range estimate of literacy  [Two researchers independently coded participants' interpretations of medication labels as incorrect, partially correct, or completely correct. Disagreements in coding were resolved by consensus after further discussion. Labels A, C, and D were deemed to each convey a single main informational component, and interpretations of these labels were coded as either incorrect or completely correct. Labels B and E were deemed to each convey three main informational components. For example, for label B the informational components were: (1) possibility of drowsiness, (2) alcohol may worsen effect, and (3) caution if driving or handling machinery. If none of these components could be identified in the participant's verbatim response, their answer was coded as incorrect. If one or two of these components was found, the response was coded as partially correct. If all three components were found, the response was coded as completely correct. This method of coding, although not previously validated, offered useful detail regarding the completeness of the participants' comprehension. At the time of coding, investigators were blinded to participants' literacy level. The effect of the addition of illustrations on participants' performance was classified as improved, worse, or unchanged, based on the categorization of their first and second responses as incorrect, partially correct, or completely correct. When improvement or worsening was noted, responses were examined to characterize the nature of the change.The sign test was used to assess whether there was significant improvement or worsening in the interpretation of the label with the addition of the illustration. Chi-square analyses were used to assess whether the effect of the addition of illustrations on participants' performance on label interpretation  was significantly associated (p < 0.05) with sex, age , native language (English or other language), or grade-range estimate of health literacy (assessed using the REALM). All significance tests were two-sided. Statistical analyses were performed using SPSS 10.0 .The power of this study was dependent on both the number of individuals whose performance on label interpretation changed with the addition of illustrations, and the anticipated magnitude of this effect. Assuming that about 25% of subjects or 30 individuals would demonstrate a change in performance, this study would have had 80% power to detect a ratio of 3:1 or greater in terms of the proportion of individuals with improved performance vs. worse performance.Characteristics of participants are shown in Table The addition of visual illustrations in labels B and E resulted in some changes in interpretations Table . With eaSex, age group, being a native English speaker, and health literacy level were not significant predictors of improved or worsened comprehension when illustrations were added. It is important to note, however, that this study was not powered to detect such differences among subgroups of participants.We found that the illustrations selected for examination in this study provided little or no benefit in improving patients' comprehension of labels informing them how medications should be taken or their potential side effects. Participants in this study had perfect comprehension of three relatively simple labels when they were presented without visual illustrations, leaving no opportunity for the addition of illustrations to have any positive effect. In the case of two more complex labels that a number of patients had difficulty fully understanding, the addition of illustrations had positive and negative effects on comprehension in approximately equal numbers of patients.Our finding of mixed effects of illustrations may be explained by a number of factors. The illustrations on the labels we presented may have been ambiguous and failed to clearly convey a specific message, or at worst they may have been misleading. For example, the illustration showing the outline of a stomach could not be understood without some knowledge of human anatomy. Even if it were understood, such an illustration conveyed only one component of a more complex message. Furthermore, the illustrations may have captured the patient's attention, distracting him or her from the full message contained in the accompanying writing. This phenomenon might occur regardless of a patient's level of health literacy.This study has several limitations. We only examined patients in urban family practice units associated with an academic teaching hospital. Because the vast majority of our study sample had an adequate or high literacy level, our data do not support any conclusions regarding the effect of medication label illustrations in patients with low literacy. In addition, our relatively small sample size and the large proportion of subjects whose performance was unchanged with the addition of illustrations raises the possibility of type 2 error, that is, a failure to detect true differences due to inadequate power. We used a selected set of medication labels to provide a range of complexity in terms of both text and illustrations; because our choice of labels was non-random, our results may not accurately represent all of the illustrations in use or their effect on comprehension. The size and readability of the images we used may have affected our results. The use of enlarged versions of the labels may have enhanced their readability, and participants did not undergo formal screening for visual acuity. Some degree of sequencing bias may have occurred, since the labels were presented in the same order for all subjects. Finally, we did not obtain qualitative data through detailed interviews that might have allowed us to clarify how participants perceived the meaning of the illustrations and how the participants related the illustrations to the text.Pictorial illustrations can improve comprehension of medication labels if the illustrations and text are well-matched to each other and are appropriate to the educational and cultural background of the user ,7. HowevThus, while illustrations can be effective in improving patients' understanding of how their medications should be taken or their potential side effects, physicians should not assume that this is always the case. At least some of the images currently in use on prescription medication labels do not appear to be helpful, and the effectiveness of such illustrations should be further evaluated. Given their potential to confuse or distract patients, an alternative would be to replace illustrations with a common symbol, such as a large exclamation mark, to reinforce the importance of the accompanying text. Additional research is needed to better understand the cognitive processes that affect comprehension when written and pictorial pharmaceutical instructions are combined, and to develop more effective communication strategies to improve patients' understanding of the proper use of their medications .The author(s) declare that they have no competing interests.SWH participated in the design of the study, data analysis, and drafting of the manuscript. CQNT participated in the design of the study, data collection, data analysis, and drafting of the manuscript. NK participated in the design of the study, data collection, data analysis, and revision of the manuscript.The pre-publication history for this paper can be accessed here:


The evidence base for improving reproductive health continues to grow. However, concerns remain that the translation of this evidence into appropriate policies is partial and slow. Little is known about the factors affecting the use of evidence by policy makers and clinicians, particularly in developing countries. The objective of this study was to examine the factors that might affect the translation of randomised controlled trial (RCT) findings into policies and practice in developing countries.The recent publication of an important RCT on the use of magnesium sulphate to treat pre-eclampsia provided an opportunity to explore how research findings might be translated into policy. A range of research methods, including a survey, group interview and observations with RCT collaborators and a survey of WHO drug information officers, regulatory officials and obstetricians in 12 countries, were undertaken to identify barriers and facilitators to knowledge translation.It proved difficult to obtain reliable data regarding the availability and use of commonly used drugs in many countries. The perceived barriers to implementing RCT findings regarding the use of magnesium sulphate for pre-eclampsia include drug licensing and availability; inadequate and poorly implemented clinical guidelines; and lack of political support for policy change. However, there were significant regional and national differences in the importance of specific barriers.The policy changes needed to ensure widespread availability and use of magnesium sulphate are variable and complex. Difficulties in obtaining information on availability and use are combined with the wide range of barriers across settings, including a lack of support from policy makers. This makes it difficult to envisage any single intervention strategy that might be used to promote the uptake of research findings on magnesium sulphate into policy across the study settings. The publication of important trials may therefore not have the impacts on health care that researchers hope for. Translating research evidence into policy is crucial to improving the evidence base of health care as well as to improving health care outcomes. Indeed, the recent Ministerial Summit on Health Research in Mexico City noted that, "Research has a crucial but under-recognised part to play in strengthening health systems, improving the equitable distribution of high quality health services, and advancing human development." . Other hA number of models have been suggested to explain the role of research in policy making -13. In sIn this paper, we report the findings of a study that examined, firstly, the factors perceived as limiting the use of the results of a recently published trial of magnesium sulphate for the treatment of pre-eclampsia and, secondly, the extent to which it might be possible to make generalisable inferences regarding barriers to and facilitators of evidence-based pharmaceutical policies for maternal and child health.Eclampsia is an important contributor to maternal morbidity and mortality in low-income countries . EclampsA case study approach, that involves examining a naturally occurring case or cases, was used to explore the research questions . The selData were collected in two phases using a range of complementary qualitative and quantitative methods. Firstly, we conducted observations, a semi-structured group interview and a survey of members of the Magpie Trial Collaborative Group – a research team representing 33 countries and involved in the Magpie Trial. Secondly, we conducted a survey of drug information officers in twelve developing countries. The details of these methods are described below.A meeting of the Magpie Trial collaborators in March 2002 to discuss the trial findings prior to publication provided an opportunity to explore the perceptions of this group, with a strong interest in developing the evidence based for obstetric care, regarding the barriers and facilitators to implementing the findings of their study. Limited time was available during this meeting for data collection. However, we saw this opportunity as important since most of the trial collaborating centres were represented. Several data collection methods were used, as described below.Small group and plenary discussions on the dissemination and implementation of the trial results were observed during the Magpie Trial meeting. The collaborators planned these independently of our study. The groups were organised by geographical regions: Africa, Asia, Latin America, and a fourth group that included European, North American and Australian collaborators. Notes of the discussions were made.A brief semi-structured group discussion was conducted with six collaborators from Brazil, Egypt, Pakistan and Uganda, purposively selected to represent a variety of developing countries. This focused on the implications of the possible Magpie Trial results and strategies for dissemination and implementation. Detailed notes of the interview were taken and the data from the interview and the observations were coded and subjected to thematic analysis. The issues that emerged were used to help interpret the survey results.A questionnaire was designed to explore barriers and facilitators to the uptake of the Magpie Trial findings into national, regional and hospital level policies in the respondent's country. A mix of open- and closed-ended questions addressed current policies regarding magnesium sulphate, specific barriers and facilitators and necessary changes in policies. It also attempted to identify key policy makers. The questionnaire was distributed after presentation of the Magpie Trial results. Spanish speaking participants were given the option of answering the open-ended questions in Spanish. These responses were later translated into English. MA and SI independently coded and qualitatively analysed the responses to the open ended questions. Other data were entered into an Excel database for analysis.Following analysis of Phase 1 data, a pilot survey of national drug information officers in twelve low and lower-middle income countries  was conducted. The survey had the following objectives: to explore the generalisability of the perceptions of the Magpie Trial Collaborative Group; to collect data for countries that had not participated in the Magpie Trial ; to overcome some of the limitations of the information collected from the collaborators; to explore the feasibility of a survey approach for collecting data from a larger sample of countries; and to assess the reliability of the information gathered. The countries were purposively selected to represent geographic, cultural and political variety.Drug information officers were identified through the World Health Organisation (WHO) Department of Essential Drugs and Medicines. We attempted to validate the information provided by drug information officers through surveying obstetricians in each country. These were identified by personal contacts. The questionnaire for drug information officers focused on the registration, supply and distribution of magnesium sulphate. Information was also sought on five other drugs: folic acid to prevent anaemia and the risk of fetal malformation, ergometrin to decrease post partum haemorrhage, oxytocin to induce labour, hydralazine to treat hypertension during pregnancy, and nevirapine to prevent mother-to-child transmission of HIV . The firThe group interview and observations identified a number of issues seen by Magpie collaborators as barriers to translating the Magpie Trial results into appropriate policies and practice. In presenting these, we have utilised the policy analysis framework of actors, context, content and process as an organising scheme . With reA number of actors were identified as important to the research translation process. The collaborators suggested that few clinicians or policy makers in their settings were aware of the concept of evidence-based medicine, would read the Magpie Trial report or be able to interpret the findings. Even if clinicians were aware of the Magpie Trial results, few had opportunities to influence relevant policies. Collaborators from West Africa felt that there was a need, through medical associations, to involve politicians at the national level in discussing the trial findings. Such policy makers were seen to be distant from poor and under-resourced areas of the country, further exacerbating barriers to the development and application of appropriate policies for these areas. Collaborators from high income countries also thought that professional organisations would be important in drawing out the implications of the trial findings and making clear recommendations.The collaborators held differing views about the importance of support from WHO and the United Nations Children's Fund (UNICEF) in influencing policies and practice. For example, collaborators from Nigeria considered it important to get support from the WHO region as this office had close relations with policy makers and politicians. One collaborator in the Asian group argued that if WHO provided magnesium sulphate to health facilities at no cost for one year, this would create pressure on governments and pharmaceutical companies to continue supplying it thereafter. In at least one of the countries represented in the discussion, UNICEF was attempting to implement protocols for emergency obstetrical care and was therefore seen as having as import role in policy making. The influence of international agencies, such as WHO and UNICEF, on the mass media was also highlighted.A range of problems with the process of developing and implementating clinical guidelines for the treatment of hypertensive disorders of pregnancy was raised. Some countries had no national guidelines and institutions were not under any obligation to follow recommended procedures. Consequently, each hospital followed its own policies. Elsewhere national guidelines existed, but magnesium sulphate was used routinely only for eclampsia and not for pre-eclampsia. Furthermore, even where magnesium sulphate was widely available, appropriate hospital facilities, such as intensive care units, were seen as necessary to implementing the Magpie Trial results due to the perceived need for close monitoring of patients. Several participants suggested that an active guideline implementation process was required at each hospital. For example, in South Africa, where national policy recommended the use magnesium sulphate for eclampsia, the main problem was considered to be training for health professionals. Training was also seen as important in the Asian countries. However, it was acknowledged that this would require substantial resources.The content and focus of the policy implementation process was also seen as important and to require tailoring to specific settings. In Latin America one of the important issues identified was the very frequent use, rather than the underuse, of magnesium sulphate. Here, it was suggested, training and implementation needed to focus on raising awareness of the lack of evidence to support giving magnesium sulphate to women with relatively mild disease. A lack of accountability of obstetricians was also considered to be a key problem in several settings. It was suggested that legislation was needed to specify standards of, and responsibilities for care.A number of dissemination and implementation strategies for translating the Magpie Trial findings were suggested. The African group considered it important for the researchers themselves to publish articles in a variety of national and regional medical journals to gain support for developing and implementing appropriate guidelines. Some participants felt that the mass media could play a role in advocating for the registration of magnesium sulphate, but there were perceived problems with the quality of health care reporting and a need for health care professionals to work closely with journalists. It was also noted that many journalists were based in well resourced central urban areas and did not reflect the views of more poorly resourced peripheral regions.In summary, significant regional and national differences in the policy making context were identified, including the importance of clinical guidelines and availability of and access to magnesium sulphate. The role and influence of different policy actors, including international agencies and the media, was also seen to vary between settings, as did the barriers to the process of developing and implementing evidence based policies.A response rate of 81% (89/110 participants) was achieved. Some questions were not answered by some respondents and other responses were illegible. Table Table Table Representatives from 7/13 low and lower-middle income countries and 2/8 high-income countries reported that magnesium sulphate was not licensed for the treatment of pre-eclampsia (not shown in tables). This barrier was not raised by respondents in upper-middle income countries. However, there were frequently conflicting responses to this question by respondents from same country. Reasons why magnesium sulphate was not licensed included failure to submit an application for licensing and "red tape". In each of 4/13 low and lower-middle income countries, one or more respondents said that magnesium sulphate was not available. Distribution of magnesium sulphate was reported to be a problem by at least one respondent from 8/13 low and lower-middle income countries and 1/3 upper-middle income countries.Respondents indicated that there were no national clinical practice guidelines for pre-eclampsia in 8/13 low and lower-middle income countries and 2/8 high-income countries. Local  guidelines were available in most settings (82% of respondents). However, only half of respondents considered the recommendations in local guidelines to be appropriate in light of the Magpie Trial results.Contextual health system factors were identified by respondents as important in determining the uptake of the trial findings into policy. At least one respondent in 13/16 low and middle income countries noted that fewer than 60% of pregnant women had access to services where pre-eclampsia was likely to be appropriately diagnosed. Furthermore, fewer than 40% of pregnant woman had access to professionals who could administer magnesium sulphate, according to at least one respondent in 10/13 low and lower-middle income countries. The costs of magnesium sulphate and hospital care were thought likely to hinder the dissemination and implementation of the Magpie Trial results in six of these countries. However, there were frequently different responses to this question from representatives of the same country. At least one respondent from ten of the thirteen low and lower-middle income countries thought that costs were not a barrier.Most of the respondents from low and lower-middle income countries considered it important to change policies in their countries to improve the availability  and distribution of magnesium sulphate (median importance score = 5.0). Improving access to hospitals offering treatment with magnesium sulphate and to professionals trained to manage pre-eclampsia were also seen as important (median importance scores = 5.0 and 5.0 respectively). Respondents from upper-middle income countries saw changes in policies to improve the availability of the drug as less important (median score = 2.5). The other three issues  were seen as important by these respondents . For high income countries, however, all four of these issues were perceived to be less crucial . Changes in clinical practice guidelines were seen as necessary in low and high-income countries (median importance 5.0 and 4.8 respectively), but less so in upper-middle income countries (median importance 3.5). Changes in policies regarding payment for magnesium sulphate and hospital costs were considered more important in low and lower-middle income countries (median importance 5.0 and 5.0 respectively) than in upper-middle income countries (median importance 2.0 and 4.0) and high-income countries (median importance 1.0 and 1.0). Responsibility for payment for magnesium sulphate and hospital care for pre-eclampsia varied across and within countries and included governments, patients and private insurance.A range of professional and organisational actors was seen to be influential in changing relevant policies related to the use of magnesium sulphate Table . A majorFollowing repeated efforts, responses were obtained from national drug information officers or drug regulatory officials for only nine of the twelve countries. Their responses regarding the licensing, supply and distribution of magnesium sulphate are shown in Table Obstetricians in five of these nine countries  suggested that magnesium sulphate was widely available and widely used for both eclampsia and pre-eclampsia Table . HoweverNo problems were reported by drug information officers regarding the registration, supply or distribution of folic acid in any of the nine countries, with the exception of Bolivia. The same was true for ergometrin, with the exception of Cambodia, where frequent shortages were reported due to its short shelf life. No problems were reported for oxytocin Table . This coFor hydralazine, drug information officers in three countries reported that it was not licensed and in five countries that there were problems with its supply. Problems with the registration, supply and distribution of nevirapine were reported in four of the nine countries, with Rwanda the only country not reporting a problem with the supply or distribution of this drug. Nevirapine is an expensive drug compared to magnesium sulphate and indications for its use vary across countries.Given the difficulties in accessing appropriate respondents for this study, and respondents' limited knowledge of the information required by the questionnaire, we decided that a larger survey of drug information officers in low and lower-middle income countries would not likely provide reliable and useful information.This multi-country study used a range of methods to explore the wide variety of factors that hinder and facilitate the translation of research findings, in this case from the Magpie Trial, into policies and practice across a range of settings. It highlights two important issues: firstly, the barriers to translating the findings of studies such as the Magpie Trial into policy are complex, multifactoral and context specific, as has been suggested elsewhere ,11. For Another complex issue is that of interaction with and support from policy makers – the barrier most frequently cited by respondents. Although we had not anticipated this barrier, and had not asked about it in the closed-ended questions, this finding mirrors that of a recent systematic review of the use of research in health policy-making in which 'absence of personal contact' between researchers and policy makers was identified as the most common problem . AlthougThe second key finding is the difficulties experienced in obtaining detailed information on drug availability and use at country level. The pilot survey focused on low and lower-middle income countries, where there appeared to be both the greatest need and the largest problems. Information was sought from the WHO's network of designated national drug information officers because we believed they would be able to reliably answer questions about the licensing, supply and distribution of magnesium sulphate. However, it was frequently difficult to contact these officers. When they could be reached, they had reliable but limited information about licensing, importation and local production, but no information on actual use. Beyond this there were little, if any, reliable data from WHO or other sources regarding the availability of magnesium sulphate or other drugs at country level. This suggests that a large investment of resources would be required both to ascertain the magnitude and precise nature of problems regarding the distribution and use of magnesium sulphate internationally and to explore how best to address these. The difficulties in obtaining information, combined with the wide and differing range of barriers between settings, makes it difficult to design any single, widely generalisable intervention package that might be used to promote the uptake of the Magpie Trial findings into policy and practice across the study settings. This is also likely to be the case for other drug and maternal and child health interventions that research has shown to be effective and that researchers and others wish to translate into policy and practice.This study has several limitations. Firstly, the findings from the Magpie Trial Collaborative Group reflect the nature of that group, comprised primarily of self-selected obstetricians with a professional interest in pre-eclampsia. However, there were several reasons why this study was initiated with this Group, despite these limitations. It was their concerns about failures to translate results from their earlier trial  into praThis study attempted a broad overview of research translation across a range of countries. This approach had the advantage of allowing us to identify commonalities and differences between countries, thereby improving the generalisability of the findings, but also limited the depth of enquiry in any one setting. Although we have taken the approach of grouping country findings using the World Bank classification of level of income, we acknowledge that this approach might mask differences both within these groups and at sub-national levels. Further in-depth studies, currently in progress, are exploring the use of research evidence in policy making in several of the countries included in the Magpie Trial . These studies are exploring the viewpoints of a wider group of policy actors, including senior policy makers within ministries and departments of health and representatives of international organisations.Despite robust evidence from a landmark trial and systematic review of the effectiveness of magnesium sulphate for the treatment of pre-eclampsia, the drug is still not available in some countries and its availability varies in many others. Licensing, importation and production are probably not the most important barriers in most settings to translating this research evidence into practice. Rather, a complex and multifaceted group of issues, differing across contexts, inhibits the uptake into policy of research findings on health issues such as the treatment of eclampsia and pre-eclampsia . The chaFirstly, there is a need to identify credible national advocates or "knowledge brokers",6. The MOur findings highlight the importance placed by respondents on interactions between policy makers, researchers and other stakeholders in facilitating the uptake of research findings into policies. Other studies examining the process of transferring research findings to key policy actors have also suggested that this process should be interactive in order to maximise its effectiveness . These iAt the implementation level, training health care professionals in developing countries to provide appropriate care presents challenges that are similar to those encountered in high-income countries -38. ThesMore broadly, it would seem sensible to organise a wide programme of support rather than multiple one-off efforts for essential medicines in maternal and child health. Such a programme could provide an ongoing framework and support for ensuring that important research findings, such as those of the Magpie Trial, are translated into appropriate policies and practice.MA has previously carried out short-term pharmacoeconomic projects for the National Insurance Service and the Norwegian Medicines Agency. In 1997–99 he worked for a private company, Brevreklame, doing market research for pharmaceutical firms in Norway. LD was the clinical coordinator of the Collaborative Eclampsia and Magpie trials.MA, SI, MT, SL and ADO planned the group interview, observation and survey of the Magpie Collaborative Group with advice from LD. MA, SI, MT and SL undertook the interview, observations and survey. MA and SI coded and analysed the results of the survey. MA, EJP, ATD and ADO planned the survey of drug information officers with advice from SL, LD and MZ. EJP and ATD undertook the pilot survey. MA and SI prepared the first draft of the report. All of the authors commented on successive drafts.The pre-publication history for this paper can be accessed here: