Physical exercise improves multiple aspects of hippocampal function. In line with the notion that neuronal activity is key to promoting neuronal functions, previous literature has consistently demonstrated that acute bouts of exercise evoke neuronal activation in the hippocampus. Repeated activating stimuli lead to an accumulation of the transcription factor ΔFosB, which mediates long-term neural plasticity. In this study, we tested the hypothesis that long-term voluntary wheel running induces ΔFosB expression in the hippocampus, and examined any potential region-specific effects within the hippocampal subfields along the dorso–ventral axis. Male C57BL/6 mice were housed with or without a running wheel for 4 weeks. Long-term wheel running significantly increased FosB/ΔFosB immunoreactivity in all hippocampal regions measured . Results confirmed that wheel running induced region-specific expression of FosB/ΔFosB immunoreactivity in the cortex, suggesting that the uniform increase in FosB/ΔFosB within the hippocampus is not a non-specific consequence of running. Western blot data indicated that the increased hippocampal FosB/ΔFosB immunoreactivity was primarily due to increased ΔFosB. These results suggest that long-term physical exercise is a potent trigger for ΔFosB induction throughout the entire hippocampus, which would explain why exercise can improve both dorsal and ventral hippocampus-dependent functions. Interestingly, we found that FosB/ΔFosB expression in the DG was positively correlated with the number of doublecortin-immunoreactive  neurons. Although the mechanisms by which ΔFosB mediates exercise-induced neurogenesis are still uncertain, these data imply that exercise-induced neurogenesis is at least activity dependent. Taken together, our current results suggest that ΔFosB is a new molecular target involved in regulating exercise-induced hippocampal plasticity. Exercise confers diverse benefits on molecular, structural, and functional aspects of the hippocampus in rodents ,2, some fosB gene show impaired hippocampal neurogenesis and increased depression-like behavior [The transcription factor ΔFosB, a truncated splice isoform of full-length FosB, is induced by various types of repeated stimuli in specific brain regions, where it gradually accumulates because of its unique stability  -12. A grbehavior ,21. Indebehavior -25. If oThe hippocampus has anatomical and functional gradient along its longitudinal  axis . The dorfosB gene products induced in the hippocampus. We also examined the cortex for region-specific FosB/ΔFosB induction to rule out the possibility that long-term exercise non-specifically increased FosB/ΔFosB immunoreactivity in the brain. Finally, the correlative association between FosB/ΔFosB expression and neurogenesis was investigated as the first step in seeking the functional implications of exercise-induced ΔFosB induction in regulating hippocampal plasticity.The primary hypothesis of this study was that long-term voluntary wheel running would induce ΔFosB expression in the mouse hippocampus. This hypothesis was investigated by FosB/ΔFosB immunohistochemistry in the dorsal and ventral hippocampal subfields, DG, CA1, and CA3, with extra emphasis on identifying region-specific induction. Results were confirmed by western blotting, which was used to identify the isoform of ad libitum. All experimental procedures were approved by the Animal Experimental Ethics Committee of the Tokyo Metropolitan University.Twenty male C57BL/6 mice (8 weeks of age) were purchased from a commercial breeder . Ten mice were used for Experiment 1, and the other ten for Experiment 2. Mice were housed under controlled conditions of temperature (22–24°C) and light , and were provided food and water In each experiment, upon arrival, mice were randomly assigned to either a control group  or a running group . During the first week, all mice were housed in standard plastic cages in groups (5 mice/cage) for initial acclimatization. Then, Runner mice were transferred into a cage equipped with a running wheel . Because social isolation is known to suppress exercise-induced neurogenesis in the hippocampus , Runner The morning (0900–1100) after the last day of the running period, the mice were deeply anesthetized with pentobarbital sodium and transcardially perfused with cold saline. The brain was quickly removed and post-fixed in 4% paraformaldehyde in 0.1 M phosphate buffered saline  overnight. The brain was then cryoprotected in 30% sucrose in PBS and frozen until further processing. Coronal brain sections (40 μm) of a hemisphere were obtained using a freezing microtome and collected in PBS with 0.01% sodium azide.2O2 in PBS, free-floating sections were preincubated with blocking solution containing 10% normal horse serum in PBS for 2 h. Following rinses in PBS, sections were incubated with rabbit polyclonal pan-FosB antibody  diluted in PBS with 0.5% Triton X-100 and 0.5% BSA (PBST-BSA) for 24 h at 4°C. Another series of sections were incubated with goat polyclonal anti-DCX antibody  in PBST-BSA for 48 h at 4 °C. The sections were further incubated with an appropriate biotinylated secondary antibody  in PBST-BSA for 2 h at room temperature. The sections were then treated with avidin-biotin-peroxidase complex  for 90 min following manufacturer’s instructions. The antigens were finally visualized with 0.02% 3,3-diaminobenzidine (DAB) in 0.1 M Tris-HCl (pH 7.6) containing 0.01% H2O2. For FosB/ΔFosB immunostaining, the reaction was intensified with nickel ammonium sulfate. For DCX staining, cell nuclei were counterstained with Nissl staining. Sections were mounted onto gelatin-coated slides and coverslips were placed.A one-in-six series of sections was randomly selected for FosB/ΔFosB immunostaining. An adjacent series was used for labeling doublecortin (DCX), a marker of immature neurons validated for assessing neurogenesis ,41. AfteThe pan-FosB antibody used in this study was raised against an internal region shared by FosB and ΔFosB N-terminal region, so that cannot discriminate between the two isoforms. Therefore, the immunostained structures were described as FosB/ΔFosB immunoreactive (FosB/ΔFosB-ir) nuclei. For an unbiased blind quantification, slides were coded prior to analysis. The mouse brain atlas  was usedDigital images (2070 × 1548 pixels) of each ROI were taken using an optical microscope  equipped with a CCD camera  and imaging software .The objective lens magnification was 10× for hippocampal ROIs and 4× for cortical ROIs. In order to identify moderate-to-strong FosB/ΔFosB immunoreactivity , using s2).To validate this image thresholding analysis, 20 regions were randomly selected from different brain areas with different region sizes. In addition of the image thresholding quantification, the number of FosB/ΔFosB-ir nuclei within the selected regions was manually counted and the density of FosB/ΔFosB-ir nuclei was obtained by dividing the number of FosB/ΔFosB-ir nuclei by the measured area  An image of the GCL was projected on a computer display using imaging software and a 40× objective lens (2). On the live image, a line segment (150 ± 0.1 μm) was drawn along the middle of the GCL  (3). ChaAn additional cohort of mice was treated as above in Experiment 1. After 4 weeks of running intervention, the mice were transcardially perfused with cold saline under deep anesthesia. The hippocampus was quickly dissected out and frozen with liquid nitrogen, and stored at -80°C. The hippocampi of each mouse were homogenized in RIPA buffer  containing protease inhibitors . The lysates were centrifuged for 15 min at 5000 rpm at 4°C and supernatants were collected. Protein concentrations were measured with a BCA Protein Assay kit .Equal amounts of protein (30 μg/lane) were electrophoresed on a 10% polyacrylamide gel, then transferred to a PVDF membrane . Nonspecific binding was blocked by preincubating the membrane for 1 h in TBST  containing 3% BSA. The membrane was incubated with the pan-FosB antibody (1:1000) that used above for immunohistochemistry, dissolved in TBST containing 3% BSA. Following washes with TBST, the membrane was incubated with HRP-conjugated anti-rabbit IgG antibody  for 1 h at room temperature. After washes with TBST, protein bands were visualized by incubation with Enhanced Chemiluminescence  and captured using an Image Quant LAS 4000 mini . The membrane was then reprobed with anti-glyceraldehyde-3-phosphate dehydrogenase (GAPDH) antibody  as a loading control. The optical density of the protein bands was quantified using Image-J and normalized to the level of GAPDH.P < 0.05.Changes in mouse body weight were analyzed by two-way repeated-measures ANOVA (group × time). An unpaired t-test was used to determine statistical differences between groups (Control vs. Runner). Pearson’s correlation analysis was used to validate the FosB/ΔFosB immunoreactivity analysis , and to examine the association between the level of FosB/ΔFosB expression and the number of DCX crossings in the DG. Data were presented as mean ± SEM. The threshold for statistical significance was set at F = 13.6, P < 0.001) and main effect of group F = 6.07, P < 0.05), indicating a significantly lower body weight in Runner mice. The running distance per cage is shown in Changes in body weight of both Control and Runner mice in Experiments 1 and 2 are pooled and shown in P < 00001, There was a significant correlation between FosB/ΔFosB-ir area obtained by image thresholding and density of FosB/ΔFosB-ir nuclei obtained by manual counting  and the ventral hippocampal subfields  and the somatosensory barrel cortex (P < 0.05), but not in the visual cortex (P = 0.662) or the olfactory bulb (P = 0.523). In the auditory cortex, FosB/ΔFosB-ir area tended toward an increase in Runner mice (P = 0.105).Representative images of FosB/ΔFosB immunostaining in the cortical ROIs are shown in P < 0.01) and dDGip . In addition, a significant correlations was also identified when the dorsal DG  and the ventral DG  were analyzed separately.A correlation analysis was performed between the FosB/ΔFosB-ir area and the number of DCX crossings . BecausefosB gene products induced in the hippocampus in response to long-term running, the hippocampi from an additional cohort of mice were subjected to western blotting with using the same pan-FosB antibody. Multiple bands of 35–37 kDa, representing modified isoforms of ΔFosB [P < 0.01). On the other hand, the 48 kDa FosB isoform was undetectable in either group. Another band faintly visible above 25 kDa likely represents the Δ2ΔFosB isoform (27 kDa). There were two other bands, at above 50 kDa and 37 kDa, which were most likely because of non-specific binding. When quantified, no differences were found in these non-ΔFosB bands between groups (data not shown).Finally, to identify the isoform of of ΔFosB , were sifosB gene product accumulating in response to long-term running. These results clearly support the hypothesis that long-term regular exercise is a potent trigger for ΔFosB induction throughout the hippocampus, and that its induction might be a novel molecular mechanism by which exercise affects various types of dorsal and/or ventral hippocampus-dependent functions.In summary, the present study first performed an immunohistochemical analysis to examining 1) whether long-term voluntary wheel running induces FosB/ΔFosB expression in the hippocampus; and 2) whether a region-specific response exists along its dorso–ventral axis. Four weeks of voluntary wheel running induced a significant increase in FosB/ΔFosB immunoreactivity in all of the hippocampal regions analyzed . We confirmed that the 35–37kDa ΔFosB isoform was the major An image thresholding technique, widely used in immunohistochemical studies for counting the number of target cells and for evaluating cell morphology, was adopted in this study for region-specific quantification of FosB/ΔFosB immunoreactivity ,45,46. AIn particular, in the DG of Runner mice , FosB/ΔFThe hippocampus has anatomical and functional gradients along its longitudinal axis , so for The primary pan-FosB antibody used in this study is known to recognize all isoforms of FosB proteins. Upon western blotting analysis, we found that the only isoforms that increased in the hippocampus after long-term running were the modified isoforms of ΔFosB (35–37 kDa), the only stable isoforms among Fos family proteins . This fiLess is known about region-specific effects of exercise on molecular and structural aspects of the hippocampus. However, numerous behavioral studies indicate a great potential for exercise-induced improvements in both the dorsal and ventral hippocampal functions. Exercise has been demonstrated to improve spatial learning and memory -38 and sA functional dissociation of neurogenesis between the dorsal and ventral hippocampus has been also receiving increasing attention . In thisfosB-null mice, which lack FosB, ΔFosB, and Δ2ΔFosB , exhibited deficits in basal hippocampal neurogenesis, including decreased proliferation of neuronal progenitor cells, increased ectopic migration of newborn neurons, and abnormal DG structures [fosB(d/d) mice, which lack FosB, but not ΔFosB/Δ2ΔFosB. Interestingly, in fosB-null mice, expression of some neurogenesis-related genes, including Vgf (VGF nerve growth factor inducible) and Gal  were downregulated [Finally, as the first step in recognizing the functional implications of exercise-induced ΔFosB induction in the hippocampus, we examined the relationship of FosB/ΔFosB immunoreactivity to DCX-ir crossings in both the dorsal and ventral DG and found a significant, positive correlation between the two variables. Although the exact mechanisms by which ΔFosB regulates exercise-induced neurogenesis remain uncertain, a recent study demonstrated that ructures . Howeveregulated . Since Vegulated .Additionally, it should be noted that the region where ΔFosB is induced by running spatially overlaps with the region where neurogenic activity is high. This finding suggests that exercise-induced neurogenesis is at the minimum activity-dependent. Neuronal activation is key to maintaining and improving central nervous system function , throughThe present study only assessed exercise-induced neurogenesis and its association with FosB/ΔFosB expression in the DG. However, FosB/ΔFosB immunoreactivity was also induced in the CA1 and CA3 subfields. While further studies are required to gain more understanding of the functional roles of exercise-induced ΔFosB expression within these subfields, previous literature offers a promising possibility. Guan et al. (2011) demonstrated that specific ablation of the cyclin-dependent kinase 5 (Cdk5) in the CA1 or CA3 pyramidal neurons impaired memory consolidation or retrieval, respectively . InteresWhile acute bouts of exercise were known to induce the expression of immediate early gene proteins in the hippocampus, the present study provides the first evidence that long-term regular exercise significantly induces ΔFosB expression in the entire hippocampus. This uniform induction of ΔFosB supports the current understanding that exercise is an effective non-pharmacological intervention able to improve multiple hippocampal functions. Together with the significant correlation between FosB/ΔFosB expression and neurogenesis, these data are provocative and indicate a need for further studies delineating the role of ΔFosB in mediating the effects of exercise on hippocampal function, including neurogenesis.


Bridging the Evidence Gap in Obesity Prevention — A Framework to Inform Decision Making (2), in the view of 2 of the IOM study committee members (Appendix) and a colleague who is involved in evaluation of Kaiser Permanente’s Community Health Initiatives." In addition, the Acknowledgment was omitted. It should have appeared as follows: Because of an editing error, we inadvertently omitted text from the article "The L.E.A.D. Framework: Using Tools From Evidence-Based Public Health to Address Evidence Needs for Obesity Prevention." The last sentence of the first paragraph should have read, "This essay highlights the findings and implications of a prior IOM report, http://www.cdc.gov/pcd/issues/2012/12_0157.htm. We regret any confusion or inconvenience this error may have caused. Kaiser Permanente, the Robert Wood Johnson Foundation, and the US Centers for Disease Control and Prevention were the sponsors of the report. Drs Kumanyika and Brownson were members of the IOM study committee. Dr Cheadle is involved in the evaluation of Kaiser Permanente’s Community Health Initiatives. Views expressed in this commentary that are not directly identified as content in the report should be attributed to the authors and may not represent the views of the Institute of Medicine. The authors have no conflicts of interest to declare and did not receive financial support for preparing this essay. This correction was made to our website on July 16, 2012, and appears online at


Diabetes during pregnancy can lead to severe risks for both mother and fetus when it is not managed properly. The use of rigorously developed guidelines with a robust implementation process can have a positive influence on the management of diabetes during pregnancy. This study aims to compare recommendations and assess the quality of clinical guidelines on gestational diabetes mellitus (GDM) and pre-existing diabetes mellitus during pregnancy.Guidelines were selected by searching PubMed, the Guideline Clearing House and Google. All guidelines developed since 2000 on diabetes during pregnancy in English or Dutch were considered. Recommendations of the guidelines were compared. Furthermore, the quality was assessed by two authors independently, using the AGREE instrument.Eight guidelines were included. According to the AGREE instrument, the quality of most guidelines was low. The domains editorial independence, stakeholder involvement and rigour of development had the lowest scores. Recommendations were mainly comparable on glycemic control, preconceptional counseling and prenatal care and labour. Differences between recommendations were found for screening on GDM and induction of labour.The quality of most guidelines concerning the management of diabetes during pregnancy needs to be improved. A more systematic approach in the development of these guidelines, more attention for updating procedures and piloting of the guidelines and involvement of target users and patients is recommended. Diabetes during pregnancy can lead to serious risks for both mother and fetus. The manGDM develops often towards the end of the second trimester. MaternaIn the Netherlands, the prevalence of GDM is estimated between 1-15%, depending on the study population[DM1 and DM 2 affect 1% of pregnancies, but this is probably an underestimation. Due to The possible complications due to diabetes during pregnancy are severe. The mother has an increased risk of pre-eclampsia, infections, ketoacidosis, hypoglycemia and micro-vascular diseases such as retinopathy, nephropathy and neuropathy. In addiThere is strong evidence that proper management of GDM and pre-existing DM during pregnancy leads to better health outcomes for both mother and child,11. To eSo far, the quality of guidelines concerning diabetes in pregnancy has not been established. Therefore, the aim of this study was to assess the quality of guidelines on diabetes during pregnancy by an internationally acknowledged instrument. In addition, the recommendations for the management of diabetes during pregnancy were compared.diabetes, gestational diabetes and pregnancy and limited by ‘clinical guidelines’. Because guidelines are often not published in medical journals, the search was extended to the Internet by screening the Guideline Clearing House and Google. When searching these databases, the following terms were used: clinical guidelines, diabetes, gestational diabetes and pregnancy. The authors checked the links in Google until saturation was reached.To identify relevant clinical guidelines, the database of PubMed (Medline) was searched up to October 2011 using the following terms: To be included in this study, guidelines had to meet the following criteria:1) the patient group consisted of pregnant women with GDM or pre-existing DM, 2) the guideline addressed the management of GDM or pre-existing DM during pregnancy, 3) full text was available on the internet, 4) the guideline concerned Western populations and 5) the guideline was available in the English or Dutch language.Guidelines were excluded if they focused on the management of diabetes mellitus in general and did not include pregnant subjects. Furthermore, reports that provided reviews on guidelines but did not contain specific recommendations were excluded, as well as guidelines that were developed before 2000 or that had not been updated in the last 10 years.Two reviewers independently assessed the quality of the guidelines by using the English version of the AGREE instrument. The AGRvs. 3 or 4) of the two reviewers were resolved in a consensus meeting. Finally, domain scores were calculated by dividing the differences between the obtained score and the minimum possible score by the difference between the maximum possible score and the minimum possible score. In line with similar studies, we defined scores of 50% or less as low quality[Each item was assessed on a 4-point scale: 1 = strongly disagree; 2 = disagree; 3 = agree and 4 = strongly agree. The additional information in the AGREE guide was used in order to clarify and correctly interpret each item. Differences between the scores on positive and negative assessment [1) ts (ACOG)American Diabetes Association (ADA), GDM[and pre-existing DM[2) ADA), GDMand pre-eisting DMAustralasian Diabetes in Pregnancy Society (ADIPS), GDM[and pre-existing DM[3) IPS), GDMand pre-eisting DMBritish Columbia Reproductive Care Program (BCRCP) [4)  (BCRCP) ,27Colorado Clinical Guidelines Collaborative (CCGC)[5) ve (CCGC)Dutch Society of Obstetrics and Gynaecology (DSOG)[6) gy (DSOG)International Diabetes Federation (IDF) [7) on (IDF) National Institute for Clinical Excellence (NICE) [8) e (NICE) There was a high level of agreement between the two independent reviewers. In general, the quality of most guidelines was questionable when using the AGREE instrument. The domains with the highest scores were applicability, clarity and presentation and scope and purpose. The domains editorial independence, stakeholder involvement and rigour of development had the lowest scores. The domain scores of each guideline are shown in Table The majority of the guidelines described their scope and purpose quite specific. Four guidelines adequately described both objectives and patient groups,17,29-31Regarding stakeholder involvement, seven guidelines scored below 50%. Patients’ view and preferences were often not included in the development of the guideline. Moreover, the guidelines had not been piloted among target users, with the exception of the NICE guideline.Seven guidelines had a low score on rigour of development. This was mainly because most guidelines did not describe explicitly how they had identified, selected and summarized the available evidence. Also information on updating was not reported adequately in most guidelines; only the NICE guideline providedIn contrast, except for the guideline from the BCRCP,27, all Regarding clarity and presentation, seven guidelines scored over 50%. Key recommendations were easily identifiable and different options for management were given. It should be noted that only the CCGC guideline and NICEOn applicability, five guidelines scored over 50%. All guidelines presented key review criteria for monitoring and/or audit purposes. Considerations on costs or additional resources were described by four guidelines,25,30,31Regarding editorial independence, all eight guidelines scored at or below 50%. Five guidelines did not report anything on both independency of funding body and conflicts of interest-25,28,29The recommendations in the guidelines can be divided into four domains, namely screening for GDM, glycemic control, prenatal care and labour and preconception counselling for women with DM1 or 2. The similarities and differences between the different guidelines on each domain will be discussed.The first domain is screening for GDM. The recommendations in this domain were inconsistent. Three guidelines recommended that all pregnant women should be screened,25,28,30Not all guidelines were explicit about what screening criteria to use and at what time the screening should take place. Regarding the screening criteria, two guidelines stated that the Coustan & Carpenter criteria should be used-28 and oThe second domain is glycemic control. All guidelines made similar recommendations such as, among others;Use a multidisciplinary approach that is adjusted to the individual.Primary strategy is focused on nutrition and physical activity.When glucose levels remain too high, medication therapy should be started.Insulin is the primary choice; the use of hypoglycaemic agents is discouraged.Blood glucose should be self-monitored regularly and the importance of maintaining normal glucose levels should be emphasized.The third domain is prenatal care and labour. Two recommendations were similar for most guidelines, namely; 1) extra fetal surveillance is not necessary unless there are complications and 2) during labour, it is important to maintain normal glucose values. Therefore, glucose values should be monitored regularly.Some guidelines made additional recommendations. For example, the ADIPS guideline,25 stateHowever, there was one important difference between the guidelines. Four guidelines recommended that delivery should not take place before full term unless there are complications-28. In cThe last domain is preconception counselling for women with pre-existing DM. The recommendations in this domain were similar for most guidelines. The first recommendation was that all women with DM1 or 2 in reproductive age should receive counselling. This counselling should include information about the risks in pregnancies complicated by diabetes. Also the importance of normal glucose values before conception should be stressed,17,23-31The use of clinical guidelines is likely to have a positive influence on the management of diabetes during pregnancy,11. ThisIt is important that guidelines are of high quality. According to the AGREE instrument, most guidelines inadequately reported on editorial independence, stakeholder involvement and rigour of development. Especially the low score on rigour of development is concerning, because explicit descriptions of how the available evidence was identified and selected is essential for the development of valid and reliable evidence-based recommendations.Also descriptions of the updating procedures of the guidelines were poor, although it is important to keep the recommendations based on the best available evidence. Regarding stakeholder involvement, it might be important that views and preferences of patients are taken under consideration and that guidelines are piloted among target groups. This may increase success of implementation and thereby improve the management of diabetes during pregnancy.The low quality of most guidelines could be explained by the fact that the AGREE instrument was not used by the committees that were developing or updating the guidelines. Only the committee of the NICE guideline used an It should be noted that the score on the AGREE instrument does not only depend on the methodological quality of the guideline, but also on the quality of reporting. It is possible that guidelines of high methodological quality score low on the AGREE instrument due to poor reporting. One should bear this in mind while interpreting the results of the current study. However, most guidelines were published years after the AGREE instrument was first published. One would assume that guideline developers are aware of the most up to date discussions and literature about quality of developing and quality of reporting guidelines.Although there is some debate about using the AGREE instrument for assessing the quality of guidelines and about a 50% cut-off value, other papers on back pain and acute gastroenteritis have used this approach before,14. ObviRegarding the recommendations, there were some discrepancies between guidelines. These differences might be a result of lack of evidence or weak associations. For example, recommendations regarding screening on GDM in the guidelines diverged as was also found in other studies,34. ThisNonetheless, more variety between recommendations was expected because of the variety in health care systems, culture in various countries and the differences in membership of the guideline committees. Therefore, current scientific evidence on the management of diabetes seems to be appropriate to generalize conclusions to these different groups. Moreover, previous studies also showed that international guidelines were consistent in most of their recommendations, especially on preconceptive care in women with diabetes.The similarities between the guidelines included in this study could partly be explained by the fact that they all have been developed between 2001 and 2010. Moreover, the recommendations of the ADA guideline,17 and tThe quality of most guidelines on the management of diabetes during pregnancy can be improved. A more systematic approach in the development and reporting of these guidelines is recommended. Extra attention for updating procedures is advised. Also involvement of different health care professionals and patients in the development and evaluation of guidelines is necessary to obtain successful implementation. In addition, more attention for piloting of guidelines is recommended. In order to obtain and evaluate the improvements as described above, the AGREE instrument can be a helpful tool.However, guidelines of good quality do not ensure good quality of management in daily practice. Therefore, further research is important to develop efficient implementation strategies to increase appropriate uptake of guideline recommendations by health care professionals.The authors declare that they have no competing interests.All authors have made substantial contributions and gave final approval of the conceptions, drafting, and final version of this manuscript. MG and NE contributed equally to the data collection, review of the guidelines, interpretation of the data and the writing of this manuscript. MT provided the idea for this project, supervised the procedures in the study and reviewed the drafts and final version of this manuscript in concert with MW. All authors have seen and approved the final version of the manuscript.Ethics approval was not needed for this systematic literature review.No funding was received.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2393/12/58/prepub


Kumanan Wilson and colleagues explain how the rapid response to XMRV as a novel pathogen has highlighted some challenges pertaining to policy-making and editorial responsibilities. The impact on policy and the propagation of the initial scientific information may not cease if the evidence is disproven and retracted from the peer-reviewed literature, which creates a challenge for regulators and scientific journals.Please see later in the article for the Editors' Summary The rapid response to XMRV as a novel pathogen has highlighted some challenges pertaining to policy making and editorial responsibilities in a policy environment influenced by the precautionary principle.Once published, preliminary scientific evidence can result in rapid changes in policy and can undergo widespread dissemination via both the Internet and social media.The impact on policy and the propagation of the initial scientific information may not cease if the evidence is disproven and retracted from peer-reviewed journals.Regulators should consider the use of frameworks to guide the use of the precautionary principle and a separate, more flexible policy stream for precautionary policies.Editors should continue to develop strategies to place preliminary scientific evidence of potential public health relevance in context for the public and for policy makers.Science postulating that XMRV was a causative agent for chronic fatigue syndrome (CFS) set forward a cascade of decisions that resulted in the implementation of blood donor deferral policies targeting individuals with any history of CFS The xenotropic murine leukaemia virus-related virus (XMRV) controversy has made evident novel challenges related to integrating scientific evidence into policy making that concerns the safety of blood products and public health in general. The initial publication of an article in the journal Science reported that the virus had been identified in 68% of patients with CFS versus only 4% of healthy controls The story of how XMRV was first identified as a potential transfusion-transmissible infection and the subsequent rejection of this hypothesis has been well documented The theory that individuals with CFS might harbor XMRV and that the virus could be transfusion transmissible prompted some blood operators to take a precautionary approach and implement additional donor deferral strategies to protect against this threat .At present, no countries are screening for XMRV or have banned individuals who test positive for XMRV from donating blood, organs, or other tissues. However, since it remains possible that CFS is caused by a retroviral agent, several countries adopted strong precautionary approaches Unlike other cases where high-risk groups protested being the target of donor deferral, the CFS community embraced the restriction. Rather than stigmatizing CFS sufferers, the identification of a possible infectious basis was seen as validation for a disease often characterized as a type of psychological disorder. The CFS community advocated for the implementation of these additional donor deferral policies as well as for donor education and self-deferrals within their communities Three years later, despite a thorough evaluation of risk and a series of publications discrediting the threat of XMRV, donor deferral policies still exist that target individuals with any past or present diagnosis of CFS. In many of these jurisdictions, these retained policies are likely a consequence of governance or regulatory processes that make it difficult to reverse policy. Nevertheless, they highlight challenges related to the elimination of policies that were introduced on a precautionary basis. By themselves, the CFS deferral policies are not likely to have a significant impact on the supply of blood products as only a very small portion of blood donors are affected. However, failing to revisit precautionary decisions once new evidence becomes available could result in the accumulation of scientifically unjustified policies. This could contribute to blood shortages by unnecessarily deferring groups of potential blood donors and could lead to self-deferral by potential donors due to the ambiguity of existing policies.XMRV highlights a new dilemma relating to the publication of preliminary evidence in matters of public health concern. This dilemma has been created because of a change in the way public health decisions are being made and how preliminary scientific information is being disseminated. One of the legacies of the transfusion transmission of HIV and hepatitis C was the adoption of precaution as a guiding principle in blood safety decisions and in public health in general Further complicating matters, preliminary scientific evidence may be rapidly disseminated via the Internet and, in particular, social media. The Internet and social media have been invaluable in allowing individuals to access information about health, and as a means for scientific evidence to be disseminated. However, this is a double-edged sword. Stakeholder groups may disseminate and distort scientific evidence and the meme may persist even after the refutation of the original evidence. Perhaps the most infamous illustration was the publication of the since withdrawn article postulating a link between the MMR vaccine and autism The XMRV story illustrates challenges with acting on early scientific evidence. Policies implemented under precaution are essential to maintaining public health safety as well as public confidence in the system The experience with XMRV, like the past experiences with vaccines and autism, illustrates some of the emerging challenges related to the publication of early evidence in areas of public health concern. The primary responsibility for addressing this challenge lies with the regulatory process. However, scientific journals publishing basic research need to take into consideration the dual impact of the dissemination of information via the Internet/social media by advocacy groups and the precautionary principle policy-making paradigm in public health .The use of frameworks to guide the initial and ongoing use of the precautionary principle by policy makers is a useful first step to address this challenge Frameworks can also be useful to guide the transitioning of precautionary policies when new evidence becomes available. A fundamental component of the European Union's communication on the precautionary principle is that the policy be “subject to review, in the light of new scientific data” To overcome this obstacle, we recommend that threats that qualify for the use of precaution are brought through a separate policy process from policy decisions made on more definitive evidence. A distinctive policy process could funnel decisions through a less onerous process in order to be changed when new evidence becomes available. For example, in the instance of XMRV, the American Association of Blood Banks (AABB) chose to issue an advisory to its members recommending that they defer blood donations from individuals with any history of CFS. This approach facilitated the process of revising and ultimately removing the recommendation as more evidence became available. We further recommend that precautionary-based decisions have an expiry/stop date at which the evidence is reviewed and the decision be made into a permanent policy, removed completely, or continued for another set period. Such an approach would guard against the accumulation of measures with limited scientific basis.What steps can scientific journals take to navigate the current public health policy-making environment? Even if the regulatory process is changed to be more responsive to new evidence that negates existing precautionary policies, there is still the risk that the communication of preliminary evidence may have a lasting impact, particularly where there are advocacy groups that support and disseminate the evidence. These new realities, however, should not discourage the publication of provocative novel findings.Journals have already taken several steps to correct or clarify scientific evidence. Some of these steps have included encouraging authors to add balanced information to papers, permitting post-publication comments on their websites, as well as issuing expressions of concern and retractions through these media. The National Library of Medicine has similarly enabled authors to comment and discuss publications through the creation of PubMed Commons. To supplement these, we would also suggest some further initiatives at and prior to publication for articles of potentially high policy impact and public interest. High policy impact publications include those that present findings relevant to the environment or public health, domains influenced by the precautionary principle. High public interest articles that may be rapidly disseminated among advocacy groups include those that concern areas where the public perception of risk associated with the topic is high, i.e., those addressing risks of an involuntary or catastrophic nature The potential transfusion transmission of XMRV has highlighted novel challenges pertaining to policy making and the publication of preliminary scientific evidence on matters of public health. In particular, it demonstrates challenges in an era in which decision making concerning public health is increasingly influenced by the precautionary principle, and where scientific findings linked to areas of public interest are rapidly disseminated via the Internet and social media.


Dissemination is the targeted distribution of information and intervention materials to spread knowledge and evidence-based interventions to a larger audience . Implementation is the use of strategies to promote the systematic uptake of evidence-based practices into routine practice and healthcare policy to improve the quality and effectiveness of health services . The dissemination and implementation (D&I) lexicon includes many terms like translational research, knowledge translation, knowledge exchange, improvement science, and technology transfer. Dissemination and implementation researchers and practitioners must carefully consider strategies for translating evidence into practice to optimize health care delivery. D&I science focuses on translating knowledge into practice by facilitating stakeholder access to findings using a variety of strategies and designs that include pragmatic trials, evidence-based quality improvement, health technology assessment, systematic reviews, randomized clinical trials, and comparative effectiveness research. This collection of articles begins with broad-level perspectives such as priorities, collaboration, and IRB regulations and moves to specific examples of D&I research.Given the tremendous possibilities for D&I research, where should a nation or organization focus its resources? The manuscript by K. Stevens and J. Ovretveit addresses developing national improvement priorities for D&I research to guide researchers and funders. Results of this study suggest that, at least for the United States, the most important and urgent needs include care coordination, implementation of evidence-based practice, improving structure and clinical processes, and developing a culture of quality and safety. These types of research studies require transdisciplinary teams and an infrastructure that supports academic-practice partnerships. The article by F. Puga, K. Stevens, and D. Patel identifies best practices in developing a healthcare improvement research network that integrates various theories, methods, and perspectives of each discipline into a cohesive unit able to focus on complex research issues and topics. A companion article by D. Patel, K. Stevens, and F. Puga identifies variation in institutional review board approval process for D&I studies especially when these studies focus on quality improvement initiatives across multiple sites.Two manuscripts describe specific efforts to implement evidence-based practices. The manuscript by S. Daniels et al., describes the efforts of one Veterans Administration hospital to implement screening for dysphagia in patients who presented to the emergency department with symptoms of stroke. Multidisciplinary team cooperation and organizational support were major facilitators of this quality improvement study, while lack of adequate training perceived lack of time was seen as barriers to implementation. The manuscript by A. Wallace et al. describes the process and framework used to integrate diabetes self-management support into routine diabetes care provided in four community health clinics. The final manuscript by Y. Ogbolu et al. assessed the level of nurse compliance with evidence-based guidelines for preventing mother-to-child transmission of HIV in a resource-limited country. Although making up the greatest portion of the health care workface in most countries, educational and scope of practice barriers often hinder their effectiveness in improving health outcomes. By compiling these papers, we hope to enrich our readers with respect to the need for and variety of D&I studies. We also hope to stimulate thought for future studies to enhance the translation of evidence into practice and to improve health outcomes for populations. Deborah VincentDeborah VincentMarie Hastings-TolsmaMarie Hastings-TolsmaKathleen R. StevensKathleen R. Stevens


Recent years have seen the emergence of values-based practice as the “philosophy into practice” cutting edge of the new interdisciplinary field of philosophy of psychiatry.In this editorial I start with a brief outline of the relationship between values, values-based medicine, and values-based practice in clinical decision-making. I then describe a number of key developments in policy, training, and research in values-based practice in the UK and internationally. Finally, in a brief concluding section, I indicate the way in which values-based practice, along with related developments in the wider field of philosophy of psychiatry, is showing the way forward for a closer and more effective partnership between values-based and evidence-based approaches, not just in psychiatry but in medicine as a whole.Perhaps the most familiar values in medicine today are ethical values. Certainly, few would doubt that ethical problems are widespread in medicine. However, values encompass much more than ethics. They include ethical values, but also values of many other kinds—preferences, needs, hopes, expectations, and so forth—and all these are important areas of values in medicine.et al., in their training manual on evidence-based medicine: “By patient values we mean the unique preferences, concerns and expectations each patient brings to a clinical encounter and which must be integrated into clinical decisions if they are to serve the patient” . NIMHE is the section of the UK government's Department of Health that has the responsibility of implementing policy in mental health. As such, the NIMHE Values Framework has subsequently become the basis for a series of specific policy and service development initiatives concerned with improving multidisciplinary and multi-agency teamwork as the basis of more effective patient-centered care  but with a distinctive twist—values-based reasoning is used not to support a particular ethical position but to explore the range of often very different values that may be present in a given situation  against that of beneficence . This can be very helpful in resolving ethical dilemmas. But principles reasoning, as fully set out by Knowledge: One of the links between values-based and evidence-based approaches is that values-based practice is, as far as possible, evidence-based! Many people think that values can just be taken for granted. But it is recognized in values-based practice that it is just as important to “listen to the evidence,” rather than rely on intuition alone, when finding out about values as it is in the more traditional areas of evidence-based practice such as the effectiveness of different treatment options.There are many ways of getting information regarding values. These include, for example, personal narratives of patients and family carers and a number of powerful philosophical methods—phenomenology , hermeneThese different ways of getting knowledge about values are of course complementary. Thus, among the examples noted above, phenomenological and hermeneutic methods both provide powerful skills-based methods for exploring unfamiliar areas of people's experience and behaviour, where these are the basis of psychopathology. Phenomenological methods, building on the work of Communication skills: Communication skills are central to effective decision-making in values-based practice and, in particular, for bringing evidence and values together in individual cases  that need to be balanced when coming to particular decisions about compulsion in individual situations.This work, which is being led by Malcolm King, one of the trainers who contributed to the development of the original training manual,  Values? , uses thResearch: The research frontier for values-based practice is diagnosis. In medicine, we tend to think that diagnosis is an area of decision-making that is “purely” scientific and hence value-free. However, when it comes to applying a number of key diagnostic criteria in psychiatry, it is clear that diagnostic assessment depends not only on the facts (the evidence we are presented with) but also on a number of value judgments that we make based on those facts. This is clear, for example, in the case of the criteria of clinical significance in the American Psychiatric Association's Diagnostic and Statistical Manual (DSM): the judgments of dysfunction on which these criteria depend are essentially value judgments—for example, it is a matter of individual and cultural values whether working very long hours at the expense of your family life is a “good” thing; similarly, someone who leaves his home and work and goes off to meditate in the desert maybe thought to be functioning well in a society that values religious retreat, but to be functioning badly in a society that is more work-oriented. So values are important here, at the very heart of the DSM, but they are also present throughout the DSM and, indeed, other major psychiatric classifications (ications .http://www.dh.gov.uk/en/Consultations/Liveconsultations/DH_080913).NIMHE, working in partnership with a number of international organizations, including both the World Psychiatric Association and the Mental Health and Substance Abuse Section of the WHO, has supported a series of international research seminars that have brought together clinicians, patients, and policy makers to explore the role of values in psychiatric assessment and diagnosis. These seminars have culminated in a national consultation by the Department of Health, the aim of which is to develop a model of assessment that brings together the different approaches of different professional groups within the multidisciplinary team in a shared process with the individual service user concerned  , has beeskills-based approach to working with complex and conflicting values, is at the practical cutting edge of a new interdisciplinary field involving philosophy and psychiatry.As noted at the start of this editorial, values-based practice, although a To many, it came as a considerable surprise that the new field of philosophy of psychiatry should have emerged when it did, in the 1990s, heralded as this decade had been as the “decade of the brain” . But theSo, nothing could be further from the truth than the idea that philosophy and neuroscience run counter to each other! Indeed, as the American neuroscientist and psychiatrist Nancy Andreasen  has arguWhen it comes to values, in particular, there are many reasons why work on the philosophy of values, and its practical counterpart in values-based practice, should have been pushed to the top of our agenda. Some of these reasons are to do with changes in society as a whole—the increasingly multicultural nature of society, for example, and the ever more diverse cultural and social values this brings with it. Other more directly medical reasons have to do with changes in professional practice—the extension of multidisciplinary team working, for example, with different clinical disciplines bringing, often, very different sets of professional values to the clinical encounter.et al., from whose book on evidence-based practice I quoted at the start of this editorial, underline the importance of this, writing that it is only” (w)hen these three elements  are integrated, (that) clinicians and patients form a diagnostic and therapeutic alliance which optimizes clinical outcomes and quality of life (The most important reason, however, for the increasing importance of values in medicine has to do with the emergence of a model of patient-centered practice in which the values of individual patients are central to evidence-based clinical decision-making. Sackett Psychiatry, therefore, in being first in the field with policy, training, and research developments in values-based practice as an essential partner to evidence-based practice, is leading the way towards a medicine for the 21st century that is both firmly science-based and also genuinely patient-centered.This editorial has illustrated some of the ways in which work in the new interdisciplinary field of philosophy of psychiatry—particularly as developed through the skills-based approach to working with complex and conflicting values called values-based practice—is complementary to, and supports developments in, evidence-based practice in providing clinical care in psychiatry that is equally science-based and person-centered.Prof K.W.M. Fulford, Dphil, FRCP, FRCPsych is Professor of Philosophy and Mental Health, University of Warwick; Member of the Philosophy Faculty, Honorary Consultant Psychiatrist, and Fellow of St Cross College, University of Oxford; Co-Director, Institute for Philosophy, Diversity and Mental Health, Centre for Ethnicity and Health, University of Central Lancashire; Editor, Philosophy, Psychiatry, & Psychology; Special Advisor for Values-Based Practice, Department of Health, London; and is on the Honorary International Editorial Advisory Board of the Mens Sana Monographs.


Protocol-based care of the tracheostomised patient is important, as adverse events confer a high rate of mortality. Little is known regarding the existence of formal evidence-based guidelines on tracheostomy care. The aim of this study was to perform a systematic review for evidence-based guidelines on adult tracheostomy care.A systematic search of PubMed, MEDLINE, guideline clearinghouses, centres of evidence-based practice, and professional societies' guidelines relating to care of adult patients with a tracheostomy was performed by two reviewers. In addition, a Google search of publicly available tracheostomy care guidelines was performed. Search terms: (tracheostom* OR tracheotom*) AND . Filters: English language, human, from 1 January 1990 to date, adult patients. Guideline appraisal criteria: the quality of guidelines retrieved was assessed using the Appraisal of Guidelines Research and Evaluation II (AGREE II) instrument [The search results are summarised in Table Five evidence-based guidelines on adult tracheostomy management were identified. This may represent a paucity of evidence on the subject, suggesting that further clinical trials on the topic are needed to contribute to the evidence base. This also highlights the need for international consensus on the topic, to reduce duplication of efforts, standardise practice, and improve outcomes.


Guidelines traditionally focus on the diagnosis and treatment of single diseases. As almost half of the patients with a chronic disease have more than one disease, the applicability of guidelines may be limited. The aim of this study was to assess the extent that guidelines address comorbidity and to assess the supporting evidence of recommendations related to comorbidity.We conducted a systematic analysis of evidence-based guidelines focusing on four highly prevalent chronic conditions with a high impact on quality of life: chronic obstructive pulmonary disease, depressive disorder, diabetes mellitus type 2, and osteoarthritis. Data were abstracted from each guideline on the extent that comorbidity was addressed , the type of comorbidity discussed , and the supporting evidence of the comorbidity-related recommendations . Of the 20 guidelines, 17 (85%) addressed the issue of comorbidity and 14 (70%) provided specific recommendations on comorbidity. In general, the guidelines included few recommendations on patients with comorbidity . Of the 59 comorbidity-related recommendations provided, 46 (78%) addressed concordant comorbidities, 8 (14%) discordant comorbidities, and for 5 (8%) the type of comorbidity was not specified. The strength of the supporting evidence was moderate for 25% (15/59) and low for 37% (22/59) of the recommendations. In addition, for 73% (43/59) of the recommendations the evidence was not adequately translated into the guidelines.Our study showed that the applicability of current evidence-based guidelines to patients with comorbid conditions is limited. Most guidelines do not provide explicit guidance on treatment of patients with comorbidity, particularly for discordant combinations. Guidelines should be more explicit about the applicability of their recommendations to patients with comorbidity. Future clinical trials should also include patients with the most prevalent combinations of chronic conditions. Traditionally, medical care is focused on the prevention, diagnosis and treatment of single diseases The emphasis of CPGs on single diseases may be problematic. Almost half of patients with chronic diseases have more than one disease To the extent that CPGs focus on single diseases, they may offer insufficient guidance to physicians about care for patients with multiple conditions. Lack of applicability of CPGs due to comorbidity may pose an important barrier to guideline adherence among physicians Although prior studies suggest that physicians may find it challenging to provide care to patients with comorbidity, there are few systematic assessments of the comorbidity-related content of CPGs, and in particular the quality of the evidence that supports that content. The aim of this study was to explore the applicability of CPGs to patients with comorbidity by assessing the extent to which CPGs on high-prevalence chronic conditions address comorbidity and by assessing the quality of the evidence cited in support of recommendations related to comorbidity.Two publicly-available international databases, the National Guideline Clearinghouse (NGC) and the Guidelines International Network Library (G-I-N),were used to select the guidelines.In selecting the conditions, we focused on highly prevalent chronic diseases that have a high impact on quality of life. Both major depressive disorder Guidelines were included if they:included a set of recommendations with an explicit link to their supporting evidence;were published in 2005 or later;addressed the treatment or management of the selected conditions;were published in English;were accessible in the public domain.CPGs were excluded if they focused on a specific subgroup of patients .One of the investigators (ML) abstracted data from the selected CPGs and the abstraction process was checked by a second investigator (JB). Any disagreement was resolved by discussion. General data were retrieved from the CPGs, and more detailed information was collected on the specific recommendations addressing comorbidity and their supporting evidence:General characteristics of the guideline: title; organization; country; target group; year of publication; number of pages and references; number of treatment recommendations.Characteristics of the guideline related to comorbidity: issue of comorbidity addressed ; discussion of patient-centered aspects , inclusion of specific comorbidity-related treatment recommendations (number and proportion). A recommendation was defined as a statement whose apparent intent is to provide guidance about the advisability of a clinical action Type of recommendation: type of treatment addressed ; inclusion of patient-centered aspects.Number of comorbid conditions addressed;Type of comorbidity addressed: concordant or discordant. Concordant conditions were defined as representing the same overall pathophysiological risk profile and being more likely to be the focus of the same disease and self management plan Link with underlying evidence described; Number of underlying studies;Level of evidence of underlying studies: high, moderate, low, not available. As grading systems differ per guideline, we considered the highest level of evidence as high, the lowest level as low, and intermediate levels as moderate.Translation of evidence: good, moderate or poor/unclear. Our judgment was based on the directness of the evidence and on whether the strengths and limitations of the evidence were discussed in the guideline. The translation was graded as: ‘good’ if the supporting evidence of the studies focused (at least partly) on the comorbidity part of the recommendation and the strengths and limitations of the supporting evidence were discussed in the guideline; as ‘moderate’ if either the supporting evidence of the studies focused (at least partly) on the comorbidity part of the recommendation or the strengths and limitations of the supporting evidence were discussed in the guideline; and as ‘poor or unclear’ if neither the supporting evidence of the studies focused on the comorbidity part of the recommendation nor were the strengths and limitations of the supporting evidence discussed in the guideline.A total of 20 CPGs met our inclusion criteria, having been published in English and in the public domain since 2005 . Six of Eight CPGs were retrieved from the G-I-N database, six from the NGC database and six were available in both databases. The largest share of these 20 CPGs was produced in the United States (n = 7). Nine CPGs were produced by governmental agencies; five by professional societies and six by other types of organizations. The CPGs were predominantly developed in 2008 (7/20) and in 2007 (5/20).Of the 20 guidelines, 17 (85%) addressed the issue of comorbidity . Eight gFourteen (70%) guidelines provided specific treatment recommendation for patients with comorbid conditions. The number of recommendations varied from 1 to 26 per guideline, with an average of 3 per guideline. The guidelines on COPD and osteoarthritis provided the fewest numbers of recommendations (0.7 per guideline), whereas the guidelines on diabetes mellitus type 2 included an average of 6.3 comorbidity-related recommendations.The 20 guidelines provided a total of 59 comorbidity-related treatment recommendations . SeventyFifty-four percent of the comorbidity-related recommendations concerned drug therapy (32/59); 25% related to other types of treatment such as psychotherapy or oxygen therapy (15/59). Few recommendations focused on surgery  and on life-style advice . Twelve percent of the recommendations (7/59) provided specific guidance on patient-centered aspects such as patient preferences, burden of disease and priority setting.The link between guideline recommendation statements and the supporting evidence was described for 97% of the recommendations 57/59). The number of underlying studies varied between 1 and 12 per recommendation. The level of evidence of the studies was generally weak: 37% of the recommendations (22/59) had a ‘low’ level of evidence; for 25% of the recommendations (15/59) the level of evidence was described as ‘moderate’  and 5.7/59. TheFor 73% of the recommendations 43/59), the evidence underlying the studies was not adequately translated into the guideline with 48% (28/59) graded as ‘moderate’ and 25% (15/59) as ‘poor or unclear’  and 5. T9, the evPatients with multiple comorbid conditions are very frequently encountered in clinical practice. However, our results suggest that evidence-based guidelines on four relatively prevalent chronic diseases may have limited applicability to patients with comorbid conditions. Most of these guidelines do not provide explicit guidance on treatment of patients with specific combinations of diseases. If comorbidity is addressed in the guidelines, it is often discussed in general; few specific treatment recommendations for patients with comorbid conditions are provided, particularly for discordant combinations. Moreover, the evidence supporting the available comorbidity-related recommendations was generally limited, had moderate to poor quality, and was often not adequately translated into the guidelines.Among the guidelines in our study that included specific comorbidity-related recommendations, these recommendations were more likely to focus on concordant comorbidities with related treatment plans. We also found that none of the comorbidity-related recommendations specified the preferred action for patients with more than one concurrent condition. These results are consistent with previous American An important finding of our study is the limited evidence base that supports comorbidity-related recommendations. If specific recommendations for patients with comorbidity are provided, they are often based on limited evidence that is of moderate or poor quality. In addition, the supporting evidence rarely focuses directly on the groups of patients with comorbid conditions. Furthermore, the limitations of this evidence are not usually described in the guidelines. The failure to describe limitations of evidence in a guideline could give clinicians misplaced confidence in guideline recommendations.Consistent with previous studies, our findings indicate that the evidence base for patients with multiple chronic conditions is limited In light of the general absence of research evidence on patients with multiple conditions, guidelines should be more explicit about the applicability of their recommendations to patients with the most prevalent comorbid conditions and discuss the quality and directness of the evidence for these patients. This explicit approach should replace the implicit assumption that guideline recommendations are applicable to patients with comorbid conditions unless conflicting evidence is available Our findings indicate that no systematic approach is used by guideline development groups for addressing comorbidity in guidelines. Compared to the guidelines on COPD, depressive disorder, and osteoarthritis, the guidelines on diabetes mellitus type 2 had better reporting of issues of comorbidity. Even for guidelines on the same condition, we found large variation between guidelines in the approach to addressing comorbidity. This applies to all levels of abstraction . A previous study comparing diabetes guidelines from different countries, also found much variation in the supporting evidence, whereas the recommendations were similar The main strength of our study is that we systematically assessed the content of an international sample of evidence-based national and international guidelines in terms of addressing comorbidity. The guidelines included in our study are among the best in the clinical areas of interest and were produced by prominent governmental agencies or professional organizations. Furthermore, by simultaneously assessing the underlying evidence of the comorbidity-related recommendations, we were able to determine whether guidance was provided on treatment of patients with comorbid conditions and also to what extent this guidance was based on high-quality evidence.best available evidence. Future research on the selected conditions could be useful to draw firm conclusions on the availability of evidence for patients with multiple conditions, complementing the findings of our study.Our study has several limitations. First, a limited number of chronic conditions were included in our study. Inclusion of a different set of chronic conditions could have yielded different results. However, we do not expect guidelines on other diseases to be more applicable to patients with multiple conditions than those for the included common conditions. Second, the number of selected guidelines varied between the conditions, with an overrepresentation of diabetes guidelines. This reflects the available number of high-quality guidelines on the selected diseases in the databases. Third, we did not assess all available comorbidity-related evidence for the included chronic conditions, but only the evidence that was described in the guidelines. A systematic search for evidence would be necessary to determine whether the guideline recommendations are based on the Among a selected set of high-quality current evidence-based guidelines on prevalent chronic diseases, there is limited guidance on treatment of patients with comorbid conditions. Although the issue of comorbidity is recognized by guidelines, very few specific recommendations are provided and these are generally based on limited evidence of low or moderate quality. The supporting evidence often does not focus directly on groups of patients with comorbid conditions and it is rare that guidelines adequately describe the limitations of the evidence. Given the increasing prevalence of patients with multiple chronic diseases, guidelines should at least be explicit and transparent about the applicability of their recommendations to populations of patients with the most common combination of diseases. A guide for guideline developers could facilitate a systematic and uniform approach.File S1Classification of concordant and discordant comorbidities.(DOC)Click here for additional data file.


There are calls for low and middle income countries to develop robust health financing policies to increase service coverage. However, existing evidence around financing options is complex and often difficult for policy makers to access.To summarize the evidence on the impact of financing health systems and develop an e-tool to help decision makers navigate the findings.After reviewing the literature, we used thematic analysis to summarize the impact of 7 common health financing mechanisms on 5 common health system goals. Information on the relevance of each study to a user’s context was provided by 11 country indicators. A Web-based e-tool was then developed to assist users in navigating the literature review. This tool was evaluated using feedback from early users, collected using an online survey and in-depth interviews with key informants.The e-tool provides graphical summaries that allow a user to assess the following parameters with a single snapshot: the number of relevant studies available in the literature, the heterogeneity of evidence, where key evidence is lacking, and how closely the evidence matches their own context. Users particularly liked the visual display and found navigating the tool intuitive. However there was concern that a lack of evidence on positive impact might be construed as evidence against a financing option and that the tool might over-simplify the available financing options.Complex evidence can be made more easily accessible and potentially more understandable using basic Web-based technology and innovative graphical representations that match findings to the users’ goals and context. Against a background of calls for robust domestic health financing to attain and sustain increased service coverage , financiIt is probable that the ideal health financing approach is a nuanced mix of methods appropriate to a given economic, social, political, and epidemiological context, and designed to best meet the most urgent health system priorities without significant negative consequences -7. HowevThe last comprehensive review of the evidence on domestic health financing was conducted more than 7 years ago by Palmer et al , with LaIn this paper we describe our development of an e-tool that summarizes the available literature quickly and easily in both graphical and tabular form, with the added ability to access the underlying evidence from anywhere within the tool. We describe the methods used to extract the literature, synthesize it into the e-tool and evaluate the overall usefulness of the final product. In the results we describe the final e-tool and briefly summarize the key findings of the literature review to provide the reader with a sense of the depth and complexity of the evidence incorporated into the Web-based platform. Finally, we reflect on the feedback from early users of the tool to highlight critical benefits, limitations, and lessons learned.This section outlines the methods used for the literature review and synthesis of that evidence, the methods used to construct the e-tool using the review material, and the methods used to generate and synthesize user feedback.Literature review methods were adapted from the EPPI-Centre  and GreeIn the context of our review, a heath financing mechanism  is defined as a mechanism intended to raise domestic revenue for health including national/government/social health insurance, taxation, community-based insurance, private insurance, user fees, and equity funds. Papers were only included if published in peer-reviewed journals, available in English, focused on low and middle income countries, and specifically evaluated or discussed the outcomes of at least one health financing method. Opinion papers, editorials, conference proceedings, and letters to the editor were excluded. Articles discussing the potential for the implementation of a method, evaluating willingness to pay or providing overviews or descriptions of health financing programs without discussing or evaluating the outcomes of implemented programs, were similarly excluded. Papers were not excluded on the basis of study design as research in this field uses a wide range of qualitative and quantitative methods. Similarly, papers were not scored on any quality of research metric as there are few widely accepted criteria for doing so in the field of economics that would span both qualitative and quantitative research outputs. Our intention was to avoid value judgments and conduct as inclusive a review as possible, given that users of the e-tool are able to identify the source of any evidence simply by hovering over a dot, and can access the paper itself with a single click.From an initial shortlist of 151 papers, a total of 78 articles were included in the final database. A thematic analysis of the papers included in the final review was used to construct a data extraction form to systematically extract relevant information from each article reviewed. A subset of extracted data was independently reviewed by 3 researchers  to confirm that the extracted data accurately reflected the papers’ content. This review thus takes a rigorous and systematic approach of searching, data extraction and synthesis, resulting in comprehensive findings that provide a valuable contribution to the existing body of knowledge in this area.The possible outcomes of a health financing method were condensed into 5 domains or goals as shown in some evidence for” poverty reduction. The 3 authors assigning scores then compared their findings, and resolved any discrepancies through group discussion. The final scores were transferred to Microsoft Excel to form the basis of the e-tool. During this process we did not make any judgements about the validity of conclusions regarding impact or program effect, nor did we make any assessment of study quality. Our scores are intended purely as a visual summary and an aid to further investigation. The decision to have a qualitative rather than a quantitative impact score is intended to make this clear to the user. The evidence available was qualitative, descriptive, and heterogeneous.Authors  independently used the extracted summary information to assign impact or outcomes scores based on the conclusions of included studies. For instance, if a study concluded that a health financing tool reduced out-of-pocket payments then this was considered “evidence for” poverty reduction. If the authors had reported only slight reduction in these payments this would have been considered “As the evidence for any financing method varied significantly by context, we sought to inform the user how closely the countries analyzed in each study matched their own. To this end, a subset of the study team (JSW and CP) produced an initial long list of country indicators relevant to health financing policy, and on which countries could be matched. It was considered important that indicators be easily available for most countries and transparent to users so that understanding these data did not constitute a barrier to using the tool. The long list was then reduced to a final set of eleven indicators judged by the full study team to provide independent information relevant to financing policy and appropriate for matching contexts.I, into a value, T(I), between 0 and 1 according to T(I)j}, where j runs from 1 to 11. These values can be thought of as a single point on an 11-dimensional graph, and we use the 11-dimensional distance, dYZ, given in These indicators, given in context matching criteria were checked for a subset of countries to ensure there was face validity but there was no formal validation of the measure. Again, the use of this measure was to aid the user to visually sort the available evidence (comparing more closely matched to less closely matched evidence). The exact ranking of countries with respect to their “context match” of another country was not intended to be an important output.scattar plot, incorporating elements of both scatter and radar charts. Each such display focuses on one goal of a health financing policy and shows the evidence available for all 7 health financing mechanisms in the context of the (user-specified) country of interest. The next stage in the process was to explore ways of displaying the available evidence in an intuitive and informative way. After several iterative discussions within the development team and experimentation with different ways of displaying the data, we developed a scattar plot indicates how closely the countries within each study match the user-specified country  as reported in the cited study. These colours range from green for positive impact to red for negative impact, with orange indicating that there was definite evidence of no impact. Dots coloured in grey correspond to studies that considered a given health financing tool but did not consider the impact on the goal under consideration. We felt it was important to include these on the graphical display as they give an indication of where evidence is lacking. All possible plots would always have the same number of dots . The position of the dots within the ring will change according to the user-specified country and the colour of the dots will change according to the user-specified goal.In September 2011, the tool was launched by Save the Children, through an email to policy makers, international agencies, and researchers. Feedback was collected using a mixed methods approach including an online survey (n=19) and semi-structured key informant interviews (n=8). Due to the small quantitative sample, the results will be treated qualitatively and only percentages over 50% will be reported in the findings. The small sample of survey respondents is acknowledged as a limitation of this study and it is further acknowledged that the survey respondents may not constitute a random or representative sample of potential users of the tool. However, despite the small number of respondents to the survey, we were able to obtain responses from a wide spectrum of stakeholders including government policy advisors, consultants, staff from national and international non-governmental organisations (NGOs), as well as students and academics. Key informants included respondents from:United Nations Children’s FundWorld Health OrganisationThe UK Department for International DevelopmentThe Bill and Melinda Gates FoundationImperial College LondonNGOs including; Research 4 Development, Oxfam, World Vision, Save the Children UK The findings from the key informant interviews were synthesised using thematic analysis.From an initial shortlist of 151 papers, a total of 78 articles were included in the final analysis. The health financing methods included in the tool, together with the number of papers providing evidence of impact of this tool on a health financing goal are as follows:Equity funds and discount cards (2 papers)Tax-funded systems (2 papers)Private health insurance (4 papers)User fees - which we segmented into: (1) the implementation, increase, or maintenance of fees (21 papers), and (2) the reduction or elimination of fees (10 papers)Community-based health insurance (CBHI) (24 papers)National/government-run health insurance (NHI) including social health insurance (25 papers)This review provided an opportunity to update the evidence on a wide range of health financing methods, generating a number of key insights. Firstly, the breadth of the review highlighted that the weight of evidence is unevenly distributed between health financing methods. In particular, little has been written since 1995 about the impact of tax-based financing despite the recognition that most countries that have achieved universal risk protection have done so through tax financed systems. Secondly, no single method emerges as having the greatest positive impact on utilisation, service quality, equity and risk pooling, poverty, and revenue, although the tool highlights the positive and negative impacts of each method on these goals. Importantly, no financing method effectively removes or redresses the indirect costs faced by the poor when accessing health services. Thirdly, the small body of evidence on private health insurance raises concerns about adverse, unintended consequences. Fourthly, the large body of evidence on CBHI and NHI offers a mixed perspective on their use. Compared to Palmer et al [Finally, compared to Lagarde and Palmer , a substIn After consulting informally with potential users, it was decided that the most accessible platform for the tool would be a website where users could navigate easily between different countries and goals. Additional advantages of an online tool were that it presented a familiar interface to users-it would be easy to access, it would be easy to update and maintain version control, and it provided an ideal environment to cross-reference between studies, countries, tools and goals. The website was registered under Save the Children’s branding, since they funded and commissioned this work .scattar plot , we hope that we have made clear its exploratory intent. In a sense the website is intended as a directional magnifying glass to help users identify the evidence that they might find useful quickly according to their particular questions and interest.Feedback from the survey was very positive, with 90% (17/19) of respondents stating that the website was either very or extremely easy to navigate. The most commonly used features of the website were the graphical summaries  and the country information . Respondents particularly liked the graphical summaries and the summary tables and found the colour-coded system useful and intuitive. Although most respondents had not visited the website with a particular question in mind, 90% (17/19) of respondents did find the website helpful and 63% (12/19) of respondents are either very or extremely likely to recommend the website to others.Findings from the in-depth interviews supported this positive view, although a number of constructive criticisms and suggestions were proposed. Firstly, there was concern that a lack of evidence might be construed as evidence against a financing option. There were calls for the tool to more clearly distinguish between negative evidence and lack of evidence. Secondly, respondents expressed a concern that the tool might encourage users to take an over-simple view of financing options as it does not offer the option of integration or mixing financing methods and does not take into account of the context in which they are implemented. This is indeed a limitation of the tool imposed on the production team by the paucity of evidence on mixed methods financing approaches. Thirdly, it was suggested that the power of the tool is not immediately obvious and that a guide or manual available online might be a useful resource. Finally, one respondent suggested that new literature might already have emerged which would warrant inclusion on the site. This latter point was considered critical by the team producing the tool and has been a consideration from the outset of the project.The health financing debate is moving on in low and middle income countries, from asking whether user fees should be removed, to exploring how to finance healthcare to achieve universal risk protection whilst achieving equity, efficiency, and quality of care. A conventional literature review will always be challenged by the breadth and complexity of the evidence on health financing, and the need to condense that evidence into a single journal article. Additionally, a published literature review is not necessarily the easiest way for a policy maker, or other user outside of academia, to access the evidence. We have developed a new e-tool that helps users  to navigate the complex evidence by focusing on a single intelligent snapshot of the literature. Our tool is easy to access, and provides a rapid search of the evidence by country and goal. The tabular summary also allows the user to search the evidence according to a variety of criteria such as finance mechanism, country, or impact among others. Given its structure and Web implementation, the tool is also designed to be easily updated as new evidence emerges and country indicators change. These positive aspects of the tool were mentioned in the feedback received from early users during the evaluation stage of this process.That said, to structure the tool in a comprehensible and navigable form, it was necessary to make certain simplifications or groupings within the evidence–particularly with regards to the assignment of impact. We attempted to minimize the loss of detail by allowing users to link through to the original articles. This loss of complexity is a common tension when synthesising evidence and is highlighted in the feedback from users as a risk of our tool . Understanding more fully how users interpret and use the output of a tool such as this may be a rich area for future research. However, while we needed to simplify the evidence somewhat, we would argue that this form of e-tool requires less simplification than a static journal article. We would also argue that our tool is evidence based, and the failure of our tool to shed light on the benefits of mixing financing methods reflects a failure of the academic literature to shed light on this option.At every stage in building the tool we tried to be transparent about our assumptions and methods and always provide links for the user to the original evidence. Thus, the tool is intended to be used for exploration, allowing users to drill quickly down to the evidence most relevant to their needs, and not to make any finite recommendations for policy or health financing mechanism for a given country. While the tool has only been recently launched, it is hoped that it will become an important supplement to the existing literature on health systems financing. We also hope that this methodology could be used to bridge the gap between academic knowledge and practice for other complex policy questions.


Effective provider-parent communication can improve childhood vaccination uptake and strengthen immunisation services in low- and middle-income countries (LMICs). Building capacity to improve communication strategies has been neglected. Rigorous research exists but is not readily found or applicable to LMICs, making it difficult for policy makers to use it to inform vaccination policies and practice.The aim of this project is to build research knowledge and capacity to use evidence-based strategies for improving communication about childhood vaccinations with parents and communities in LMICs.This project is a mixed methods study with six sub-studies. In sub-study one, we will develop a systematic map of provider-parent communication interventions for childhood vaccinations by screening and extracting data from relevant literature. This map will inform sub-study two, in which we will develop a taxonomy of interventions to improve provider-parent communication around childhood vaccination. In sub-study three, the taxonomy will be populated with trial citations to create an evidence map, which will also identify how evidence is linked to communication barriers regarding vaccination.In the project's fourth sub-study, we will present the interventions map, taxonomy, and evidence map to international stakeholders to identify high-priority topics for systematic reviews of interventions to improve parent-provider communication for childhood vaccination. We will produce systematic reviews of the effects of high-priority interventions in the fifth sub-study. In the sixth and final sub-study of the project, evidence from the systematic reviews will be translated into accessible formats and messages for dissemination to LMICs.This project combines evidence mapping, conceptual and taxonomy development, priority setting, systematic reviews, and knowledge transfer. It will build and share concepts, terms, evidence, and resources to aid the development of communication strategies for effective vaccination programmes in LMICs. Particularly relevant examples of demand-side components are those addressing barriers to vaccination associated with parental knowledge, understanding, attitudes, beliefs, and behaviours [Vaccination is one of the most cost-effective public health interventions to significantly reduce childhood mortality and morbidity . It has haviours -10, suchhaviours . In resehaviours ,12.Despite increases in vaccination rates in many countries in the last decade, great inequities exist between and within countries. Besides this, more than 24 million children still do not have access to basic immunisation services ,13. IncrThe Communicate to Vaccinate (COMMVAC) project is a part of the Global Health and Vaccination Research (GLOBVAC) programme, funded by the Research Council of Norway. The main aim of the COMMVAC project is to build research knowledge and capacity to use evidence-based strategies for improving communication about childhood vaccinations with parents and communities in low- and middle-income countries (LMICs).Effective communication has the potential to improve childhood vaccination uptake, address partial immunisation, further strengthen routine immunisation services, and increase the use of new and underused vaccines in LMICs.A communication intervention can be defined as a purposeful, structured, repeatable, and adaptable strategy  to inforA range of such interventions may be utilised in vaccine programmes. These may operate at individual, community, or societal levels, and target people in their role as parents or community members. In the context of childhood vaccination policy and programmes, communication strategies may encompass a variety of interventions, such as: public information campaigns ; educatiEvidence is available from individual studies on the effects of a range of communication interventions, but there are few systematic reviews that have critically appraised and summarised existing research. Furthermore, LMIC programme managers and policy makers who try to seek guidance for developing new approaches to addressing barriers to vaccination uptake may find that the available information does not appear to be applicable to LMICs because these studies were conducted in very different social contexts and health systems settings. Systematic identification and review of the range of interventions used in practice is therefore needed urgently. This should describe the scope of interventions available and provide information on how they operate, how best to deliver them, and their effects across different settings. It should also examine the applicability of these findings across different contexts.This project will draw from and build upon existing specialised knowledge resources for describing, categorising, and evaluating interventions to improve communication with people about their health and healthcare ,25. The The COMMVAC project is an international collaboration, with project partners in Norway, Australia, South Africa, France, and Switzerland. The project's principal investigator is located in Oslo, Norway (SL).The project is divided into six stages, or sub-studies. Each sub-study will build upon the outputs of the previous sub-studies i.e., country and region, urban, or rural); vaccination delivery strategy, details of vaccine dose and coverage; and age of infants or children2. Population features: population group; setting of vaccination services ; training required; setting; frequency or timing of communication; and cost3. Communication intervention features: intervention purpose; direction of communication ; parties4. Outcome features: main outcomes measured (where applicable); and side effects.i.e., controlled trials) will be evaluated on additional characteristics using existing checklists. These data will allow us to describe where, in relation to the interventions map, robust evidence of effectiveness is available, informing later project sub-studies.Rigorous effects studies  and linked to identified communication barriers.The output of sub-study one is a detailed map, scoping features of communication interventions for vaccination , of communication interventions will help to: understand the relationships between different types of interventions in the field; facilitate conceptual mapping of these interventions; clarify the key purposes and features of interventions, thereby assisting with implementation and evaluation; and identify areas where evidence is strong and where there are gaps. While the intervention map (sub-study one) will provide a descriptive overview of the 'landscape' of communication for vaccination, the taxonomy will provide a relatively discrete set of types of interventions and illustrate relationships between differently described interventions.We will build on taxonomies already developed, including: a comprehensive listing of all interventions for communication in health, organised by direction of communication ; and a tThe output of sub-study two is a formal taxonomy of communication for vaccination interventions that can be used as a tool by health sector stakeholders to identify gaps and research priorities, build future evidence, and clarify purposes for communication.A key step towards building a knowledge base is being able to identify, in relation to the categories of communication interventions identified in the taxonomy: where high-quality evidence of effectiveness exists; where there are potentially useful interventions but little high-quality evidence of their effects; and where interventions are being mentioned but have not been evaluated.The literature identified in sub-study one will be used to populate the taxonomy with citations of trials, or less rigorous evaluations where trials do not exist. We will then examine in detail each of the taxonomy categories to ascertain where rigorous effectiveness evaluations exist and where there are major knowledge gaps regarding effects. We will first consider the global evidence and then the evidence available from LMICs.The output of sub-study three is a report on levels of available evidence to inform the deliberative forums described in sub-study four below.Resources to conduct high-quality systematic reviews of effects are limited. The involvement of key stakeholders in setting priorities for systematic reviews of effect will help to ensure the relevance of review outputs for future service provision. Stakeholders include government and non-government agencies, bilateral and multilateral agencies, global health initiatives, and programme personnel, as well as consumer groups.We will hold a series of deliberative forums for key stakeholders ,35. The Outputs of sub-study four include: identification of ranked priorities for systematic reviews of interventions to improve communication for vaccination; identification of additional barriers to vaccination; and agreement on how information on less rigorous evaluations should be disseminated to the field. Feedback on the taxonomy will be incorporated into updated versions of the outputs of sub-studies two and three through an iterative process  of reducing child mortality . While mThe authors declare that they have no competing interests.SL and SH led the conceptualisation and design of the project, prepared the original project proposal and obtained funding. CJ, GH, PR, VL, and XBC contributed to the original proposal. SH and JK developed this manuscript from the project proposal with input from SL, VL, NW, and CSW. All authors provided input into various aspects of the project, provided ongoing feedback and approved the final version of the manuscript.