Evidence-based clinical practice guidelines support clinical decision-making by making recommendations to guide clinical practice. These recommendations are developed by integrating the expertise of a multidisciplinary group of clinicians with the perspectives of consumers and the best available research evidence. However studies have raised concerns about the quality of guideline development, and particularly the link between research and recommendations. The reasons why guideline developers are not following the established development methods are not clear.We aimed to explore the barriers to developing evidence-based guidelines in eleven hospitals in Australia, Indonesia, Malaysia, the Philippines and Thailand, so as to better understand how evidence-based guideline development could be facilitated in these settings. The research aimed to identify the value clinicians place on guidelines, what clinicians want in guidelines developed in hospital settings and what factors limit rigorous evidence-based guideline development in these settings.Semi-structured, face-to-face interviews were undertaken with senior and junior healthcare providers  from the maternal and neonatal services of the eleven participating hospitals. Interviews were audio-recorded, transcribed and a thematic analysis undertaken.Ninety-three individual, 25 pair and eleven group interviews were conducted. Participants were clear that they want guidelines that are based on evidence and updated regularly. They were also clear that there are major barriers to this. Most of the barriers were shared across countries, and included lack of time, lack of skills in finding, appraising and interpreting evidence, lack of access to relevant evidence and difficulty arranging meetings and achieving consensus.Barriers that were primarily identified in Australian hospitals include cumbersome organisational processes and a feeling that guidelines are being developed for bureaucratic ends. Barriers that were primarily identified in South East Asian hospitals include difficulty accessing evidence due to limited resources available for computers, internet and journal subscriptions and limited skills in computing and English.The clinicians in these eleven very different hospitals want evidence-based guidelines. However they are frustrated by guideline development processes that are enormously time, skill and resource intensive. They feel strongly that "there's got to be a better way".The fact that the great majority of the identified barriers were shared across settings may provide an opportunity to develop a more pragmatic way of developing guidelines that can be applied in many contexts. Evidence-based clinical practice guidelines (EBCPGs) support clinical decision-making by integrating the expertise of a multidisciplinary group of clinicians with the perspectives of consumers and the best available research evidence, to make recommendations to guide clinical practice.As part of the move towards evidence-based health care, health organisations and clinician groups are increasingly required to develop and implement EBCPGs. There is some evidence to support the role of EBCPGs, with research demonstrating that in some situations, with rigorous development and thorough implementation, EBCPGs can improve both the quality and outcomes of careThere are several guides to EBCPG development -7 and thExisting methods of EBCPG development have largely been produced at a national or international level, for use by organisations creating EBCPGs to guide widespread practice. The processes they describe often take years and hundreds of thousands of dollars to complete. This amount of time and money is not usually available in hospital settings, and so there are immediate significant barriers to EBCPG development at this level.We undertook a needs analysis to explore the experience of guideline development and the enablers of and barriers to developing evidence-based guidelines in perinatal units in hospitals in Australia, Indonesia, Malaysia, the Philippines and Thailand, so as to better understand how evidence-based guideline development could be facilitated in these settings, and to explore how barriers to the development EBCPGs varied between settings.The research aimed to address three questions:• What value do clinicians give evidence-based clinical practice guidelines in hospital settings?• What do clinicians want in evidence-based clinical practice guidelines developed in a hospital setting?• What factors limit rigorous evidence-based clinical practice guideline development in hospital settings?http://www.seaorchid.org) which aimed to improve the quality of maternal and neonatal health care by increasing the generation, synthesis and use of health research. The existing low levels of evidence-based clinical practice guideline development and barriers to development specific to these hospitals have been reported previously ." Senior Doctor, Australia, Male.Some clinicians in each of the countries expressed doubts about whether guidelines were being used.Q: "Do you think guidelines are useful?"A: "It is useful ...if most of us read them."Q: "Do you think they are used?"A: "I don't think so." Senior Doctor, Malaysia, Male.Participants provided strong direction about what they needed in guidelines.All the participants were very clear that guidelines must be based on the best available research evidence if they are to be useful. They felt strongly that evidence should be used to ensure the guidelines are accurate and reliable, not only to ensure best practice but also to provide support in case of legal action."Well if they're not based on evidence, who is saying it's the right way to do it?. If all the evidence says you should do it this way and this hospital decides to do it that way, from a medico-legal perspective it can't be very good." Senior Nurse, Australia, Female.In all hospitals, participants noted that most locally-developed guidelines were not developed in a rigorously evidence-based manner."In house [guidelines are] just handed down from colleague to colleague and not evidence-based necessarily, but just current practice and what works and maybe what other hospitals do locally, but nothing really technically evidence-based." Allied Health Clinician, Australia, Female.The key message about the format of guidelines was that they should be clear, well-written, short and provide a quick answer to clinical decision of interest. Participants often suggested that a logical, step-by-step progression was important and that algorithms or flowcharts were useful.Many Australian participants were deeply frustrated by guidelines in which the clinically relevant information was preceded by several pages of what they perceived as less important information about organisational requirements or administrative processes. Clinicians wanted the key clinical recommendations to be presented at the front of the guideline."I find that often the information that you want is towards the end of it and it can be very long-winded and stuff that you don't need and ... especially if you're in emergency ... and you really need to find out something, it's not that easy to find." Junior Nurse, Australia, Female.Two very different thoughts were expressed by interviewees about the ideal format of guidelines: that they must be simple and quick to read and that they should be detailed and thorough. Many participants felt that a flowchart or algorithm alone was not enough, and that these should be followed by more detailed information explaining the reasoning behind the recommendations of the guideline and providing links to the original papers from which the evidence was drawn."I quite like structures where the guideline exists in several layers. There's a very simple layer which is your day to day decision making where you don't necessarily even want to understand what underpins it. But you can dig deeper and deeper as you wish to do, particularly if you're faced with a point in the guideline that you're struggling to accept that it does actually apply to the clinical situation where you actually really do go back and say, 'okay, well what was the evidence at that point?"' Senior Doctor, Australia, Male.Participants wanted credible guidelines, with recommendations that were trustworthy. Assessment of the credibility of a guideline was based on a number of factors including respect for the developing organisation, approval of the guideline by the health service and clarity of the development methods, including clear searches for research evidence, broad consultation and piloting of the guideline."I think it probably gets back to the process of how the guideline was formulated, so if it has been consultative, if there's been some evidence to support it or not support it. And then if it is trialled for a certain period of time." Allied Health Clinician, Australia, Female.In Australia there was variation between senior and junior participants about whether guideline development should involve clinicians from across disciplines. All senior doctors and nurses, and most allied health professionals felt that it was essential that guideline development should be multidisciplinary, should involve both junior and senior staff, and that there should be wide consultation. Some junior doctors and nurses agreed, however several were surprised that multidisciplinary guideline development would be undertaken and were unclear about the value of input from clinicians from other disciplines."I imagine that the nurses and physiotherapists and audiologists, they do have their guidelines. I can't see why a medical person would have to have too much input into development of that." Junior Doctor, Australia, Male.In most of the hospitals in South East Asia, having a multidisciplinary group responsible for guideline development, as is recommended by evidence-based guideline development methods, was not usual practice, nor was it explicitly valued. Most often the guidelines were largely developed by the senior medical staff.Q: "Are nurses involved in writing the protocols?"A: "No. Consultants. Consultants and the specialists they are the ones who go in a closed room I think. ... Then they come up with the protocol." Senior Nurse, Malaysia, Female.However in some hospitals this was not the case, or was beginning to change and involvement of nurses and midwives in some aspects of the guideline development process was felt to be valuable."Actually when we make the guidelines we invite the midwives to give their opinion, when like we're brainstorming..., the midwives give their questions too. And it's very important..." Senior Doctor, Indonesia, Female.Most participants in both Australia and South East Asia were unconvinced that consumer involvement in guideline development was important. They felt that while involving consumers in guideline development was potentially useful in some situations, it was not essential, particularly in technical areas, and it could create problems if consumers had difficulty understanding the concepts or could not remove themselves from their personal experience, so as to provide broader input."To be honest I struggle to see where the value is, but I'd be willing to be convinced." Senior Doctor, Australia, Male.Participants from all settings were very clear that guidelines need to be kept up-to-date. They suggested that guidelines should have expiry dates and that there should be a process of regular review when searches for additional evidence were undertaken. Several suggested that this review should be annual."It would have to be a fluid document that could be changed as knowledge was gained. Because that is the problem with a lot of these things. They get done, but they don't get updated." Allied Health, Australia, Female.The participants were very clear that there were some major barriers to development of guidelines to meet the needs they identified, and that as a result, these needs were not currently being met.Unsurprisingly, the most frequently mentioned barrier to guideline development in all settings was time. Participants noted that rigorous guideline development takes many months and believed that neither they nor their staff or colleagues had the time to develop guidelines in methodologically rigorous ways. Participants emphasised that it was very difficult to quarantine or prioritise time for activities like guideline development when there were already enormous clinical pressures on their time."There's just not enough time. We're busy enough as it is caring on the floor let alone being allotted the time to develop these guidelines." Senior Nurse, Australia, Female.In Australia, several participants suggested that one of the reasons for the time-consuming nature of guideline development was the process required to obtain organisational approval for guidelines, particularly when the committees involved met only infrequently.The long time periods required to ensure broad consultation were another frequently mentioned reason for the substantial time required to develop guidelines.A lack of the skills required to develop guidelines in the local clinical environment was a commonly mentioned barrier. In Australia, participants perceived a lack of high-level skills in finding, appraising and interpreting research evidence, as well as in writing the guideline documents. Although several participants had experience in some of these aspects, few were confident that they or their colleagues had the level of these skills required to develop reliable evidence-based guidelines.Q: "In this unit, does your team have the skills that they need to, if time wasn't an issue?"A: "Well the obvious answer to that is no." Senior Doctor, Australia, Male.Participants, and particularly nurses, in South East Asia frequently noted that lack of skill in English and lack of skill in using computers and the internet limited their ability to search for evidence"I do this ... search from website Cochrane Library but I have the problem with English, it's a little bit difficult for me to read." Junior Nurse, Indonesia, Female.As well as limited skills in finding evidence, participants also noted that for some clinical areas there was no evidence available on which to base guideline recommendations. In Australia, this was mentioned as a barrier to guideline development both in situations where evidence would be useful, but trials had not yet been conducted, and also in situations whose nature meant that trials would never be undertaken.In South East Asia, interviewees were also limited in their ability to find and use research evidence because of limitations on availability of computers, internet access and full text journal articles."We have internet access here, but our computer is non-functional right now. ... we're using only one for about 50 people actually." Junior Doctor, The Philippines, Female.Another barrier common to all settings was that guideline development meetings with broad representation were hard to organise."So if you want to meet with the four of us, it's almost impossible to have everybody free at one time. We can make a minimum of three, but ... it's so difficult actually, sometimes they have something on, and then we have something on, and it gets postponed. And it dies off." Senior Doctor, Malaysia, Male.The process of achieving consensus on the recommendations of the guideline was felt to be very important, especially in terms of enabling the implementation of the guideline, but also a potential barrier to development if agreement could not be reached.A: "In our case, we are stopping the guidelines because there have been some problems ..."Q: "So you've had to stop for a while, is it for clinical reasons? Because you were too busy or?"A: "No, not the clinical reason [laughs]...I think it's more on conflicting ideas". Junior Doctor, The Philippines, Female.There was also a concern among Australian participants that consensus processes were too easily dominated by more confident group members. Participants were concerned that nurses and more junior staff were less likely to feel comfortable to be assertive and contribute their perspectives, particularly if these were in conflict with views expressed by others. This was tempered by suggestions that they might become more comfortable if they had more experience in these situations.Participants also talked about adapting guidelines from other hospitals or organisations for use in their own settings. While participants from all settings were generally positive about this approach, there were different levels of acceptance, with several participants suggesting that they would look at other guidelines to get background information or to confirm that local practice was in line with that recommended elsewhere, but that they didn't feel it was appropriate to use them directly.Participants from all countries were concerned about both the relevance of externally developed guidelines to their clinical setting and also the lack of high-quality guidelines.This research highlights that while guidelines are valued, there are major barriers to developing EBCPGs in hospitals. These include lack of time, skills, information technology (IT) infrastructure and access to research. These barriers reflect and build on those identified by other researchers.Lack of time and skills have also been identified as barriers to EBCPG development by national professional bodies -19. It hPrevious research has established that IT resources are a basic requirement for finding and using research and that these are often not available in resource-poor settings ,23. The "the trade-off between rigor and pragmatism that currently challenges the guideline movement." [Awareness of these barriers to developing EBCPGs has led to a call for more feasible methods of developing guidelines that balance rigour and pragmatism, and for research to examine vement."  Some autvement." . This apThis study has some limitations. The relatively small number of hospitals included limits the extent to which the results can be applied to other settings. However the hospitals were very diverse, including both rural and metropolitan environments in a high-income country and a variety of low and middle income countries. The consistency of the results reported across these hospitals suggests that the results may be applicable beyond the settings in which the research was conducted.Similarly, the interviews were all undertaken in maternal and neonatal healthcare settings and so the results may not be generalisable to other clinical areas. However the substantial gap between research and practice and the resulting rates of preventable maternal and child morbidity and mortality, particularly in Asia and the Pacific where these studies were undertaken, make maternal and neonatal healthcare a priority for research .Further research is required to determine the extent to which the results of this study reflect the value placed on, and experience of, EBCPG development in other contexts and clinical areas. Research is also required to develop pragmatic EBCPG development methods that are feasible in hospital settings and which produce guidelines which are trustworthy.The clinicians in these eleven very different hospitals all value guidelines and want EBCPGs that provide rapid access to reliable, up-to-date information to help them make the best possible decisions. However they feel that established EBCPG development processes that are enormously time, skill and resource intensive, are not feasible in their settings. They feel strongly that a more feasible way of developing guidelines, or of getting evidence into practice, is needed.Most of the barriers to evidence-based guideline development identified by these participants were shared across all hospitals, however there were a few that were specific to particular contexts. The fact that the great majority of the identified barriers were shared across settings may provide an opportunity to develop a more pragmatic way of developing guidelines that can be applied in many contexts, with awareness of the specific additional barriers that are relevant in particular settings.The author declares that they have no competing interests.TT conceived of the project, developed the methods, undertook the interviews and the analysis, prepared the first draft of the article, revised it, read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1472-6963/9/235/prepubTable 1. Table displaying the indicative questions used in the study.Click here for fileTable 2. A list of key points from the study.Click here for file


The optimal role for primary care in providing follow-up for men with prostate cancer is uncertain. A systematic review of international guidelines was undertaken to help identify key elements of existing models of follow-up care to establish a theoretical basis for evaluating future complex interventions. Many guidelines provide insufficient information to judge the reliability of the recommendations. Although the PSA test remains the cornerstone of follow-up, the diversity of recommendations on the provision of follow-up care reflects the current lack of research evidence on which to base firm conclusions. The review highlights the importance of transparent guideline development procedures and the need for robust primary research to inform future evidence-based models of follow-up care for men with prostate cancer. The numbers of men living with a diagnosis of prostate cancer will continue to increase as the population ages, and cancer is detected earlier with the more widespread use of prostate-specific antigen (PSA) testing.Incidence rates of prostate cancer are rising in many countries, including the United Kingdom. It is now the most commonly diagnosed cancer in men in Europe  and permanent (low-dose) brachytherapy. Hormone therapy  may also be given as neoadjuvant, adjuvant or a stand-alone treatment for non-metastatic disease. Active surveillance is an option for men with low- or intermediate-risk localised disease that involves close monitoring to target curative treatment to those who would benefit most. Watchful waiting is a way to manage men who are unsuitable for curative treatment that involves relatively lax monitoring and palliative treatment when symptoms develop . MetastaTraditionally, follow-up care has been hospital based and provided by clinical specialists in urology and oncology outpatient clinics. In practice, follow-up is provided in both primary and secondary care, and is not always well coordinated  – this iVarious alternative models of cancer follow-up care have emerged, including nurse specialist and primary-care-led follow-up, and ‘shared care’ approaches. Only specialist nurse-led prostate cancer follow-up has been evaluated in randomised trials, which found it to be a safe alternative to consultant-led follow-up  describing the guideline content, methods, development process or dissemination strategy, and tools for implementation were assembled for each included guideline.One reviewer extracted data using a pro-forma that was checked by a second reviewer if the guideline was published in English. Data extraction from guidelines not published in English was based on translations. Data were extracted for the recommendations on follow-up (including strategies for active surveillance and watchful waiting as well as post-treatment follow-up), sources of evidence, criteria used to grade the quality of the evidence and strength of the recommendations, and the composition of the guideline development group.www.agreecollaboration.org). It has 23 items in six domains: scope and purpose, stakeholder involvement, rigour of development, clarity and presentation, applicability and editorial independence. Assessing a guideline involves assigning each item a score of 1 (low) to 4 (high) and calculating a composite score for each domain. Domain scores are not aggregated. Two reviewers independently assessed the guidelines published in English. Assessment of foreign language guidelines was based on translations, supporting materials available in English and direct appraisal by native speakers to obtain, as far as possible, two independent appraisals.The Appraisal of Guidelines Research and Evaluation instrument was used to assess the quality of the included guidelines  guidelines failed to describe their scope and purpose adequately, omitting details of the patient population to whom the guideline applied, the expected health benefits and the clinical questions they addressed. Six appeared to have been developed exclusively by clinical specialists  following treatment with curative intent fall into three categories: either it is not recommended (as long as PSA is stable) ( stable)  or it is stable)  or less  stable)  (Table 3 stable)  in contr stable) . The NIC stable) . Guideli stable) .Biopsy, and imaging and biochemical tests other than PSA feature irregularly in follow-up recommendations. Four European guidelines agree that routine biopsy and imaging is unnecessary following treatment with curative intent if patients are asymptomatic and PSA is low and stable (AFU, 2005; SOR, 2006; Specific recommendations on the evaluation of complications and treatment-related adverse effects appear infrequently in guidelines: those for Nova Scotia singularly recommend establishing a specific schedule of follow-up visits after radical treatment to discuss and manage urinary incontinence, erectile dysfunction and sexual health, and suggest routine screening for men considered to be at high risk for psychosocial distress throughout the course of the disease . UK guidThis study is the first to review prostate cancer guidelines systematically and to summarise international guideline recommendations on follow-up. Although monitoring PSA remains the cornerstone of follow-up for men with prostate cancer, the diversity of guideline recommendations on the frequency and duration of PSA testing, and components of follow-up other than PSA testing, reflects the current lack of research evidence on which to base firm conclusions. The guidelines provide only broad frameworks for evaluating potential intervention models of follow-up care, particularly in terms of the setting and the composition of the health-care team.In conducting this review, we had a specific interest in the role of primary care in prostate cancer follow-up. The included guidelines illustrate the disagreement that persists on the extent to which primary care should be involved. The recommendations in recent guidelines that highlight primary-care-based follow-up would require considerable effort and investment to implement – in terms of education, protocols and strategies to change established practice (The paucity of high-quality studies in the literature on prostate cancer follow-up has important implications, particularly for primary care, because recommendations based on explicit and non-conflicting scientific evidence are adhered to more in general practice (Our review has some limitations to consider. Identifying guidelines largely through electronic sources may have introduced bias towards English language guidelines and guidelines produced by larger, well-established organisations. Conversely, searching multiple sources, using foreign language search terms and pre-defining inclusion criteria on guideline developers, should have reduced the risk of language bias and failing to identify guidelines from eligible sources. We acknowledge that all relevant information may not have been included in the translations of foreign language guidelines and that quality assessment based on translations may not be entirely accurate. Nevertheless, our findings are consistent with earlier studies that have noted conflicting guideline recommendations on prostate cancer diagnosis and treatment (The methodological quality of the guidelines included in our review was heterogeneous and in most cases moderate to poor. We used the AGREE instrument as the indicator of guideline quality because it is validated and considered to be the international standard in guideline assessment .Most of the guidelines in our review combined an evidence-based approach with informal consensus – reflecting the status of the international literature in this field . When reReviews of international guidelines such as ours often find that recommendations are shaped or constrained by the structure and organisation of their country's health-care systems, even when the evidence is incontrovertible  have empUltimately, the usefulness of a guideline needs to take account of the impact on patient outcomes of applying the recommendations in local settings. Systematic appraisal can aid informed judgment on guideline quality: guideline recommendations can only be rigorously tested by incorporating them in the development of interventions for evaluation in randomised trials.This review shows the current status of international guidelines in prostate cancer follow-up. The variability in recommendations to some extent reflects the lack of definitive evidence from research in this field. Choices over management in prostate cancer, including follow-up, can only be informed to a limited extent by evidence from high-quality trials.The review illustrates the importance of rigorous and transparent guideline development processes when research evidence is limited, without which it is difficult to assess factors such as independence and impartiality. It also highlights the need for robust primary research to improve the evidence base for prostate cancer follow-up – particularly research to inform best practice models of care. Only then can the many new models of care emerging internationally be shaped in a rational, evidence-based way.


Clinical practice guidelines have been elaborated to summarize evidence related to the management of knee osteoarthritis and to facilitate uptake of evidence-based knowledge by clinicians. The objectives of the present review were summarizing the recommendations of existing guidelines on knee osteoarthritis, and assessing the quality of the guidelines using a standardized and validated instrument – the Appraisal of Guidelines Research and Evaluation (AGREE) tool. Internet medical literature databases from 2001 to 2006 were searched for guidelines, with six guidelines being identified. Thirteen clinician researchers participated in the review. Each reviewer was trained in the AGREE instrument. The guidelines were distributed to four groups of three or four reviewers, each group reviewing one guideline with the exception of one group that reviewed two guidelines. One independent evaluator reviewed all guidelines. All guidelines effectively addressed only a minority of AGREE domains. Clarity/presentation was effectively addressed in three out of six guidelines, scope/purpose and rigour of development in two guidelines, editorial independence in one guideline, and stakeholder involvement and applicability in none. The clinical management recommendation tended to be similar among guidelines, although interventions addressed varied. Acetaminophen was recommended for initial pain treatment, combined with exercise and education. Nonsteroidal anti-inflammatory drugs were recommended if acetaminophen failed to control pain, but cautiously because of gastrointestinal risks. Surgery was recommended in the presence of persistent pain and disability. Education and activity management interventions were superficially addressed in most guidelines. Guideline creators should use the AGREE criteria when developing guidelines. Innovative and effective methods of knowledge translation to health professionals are needed. Osteoarthritis of the knee affects an important part of the population, causing disability in many individuals and engendering significant costs . Its preThe present review had the following objectives: to summarize the recommendations of existing guidelines on knee osteoarthritis; and to assess the quality of the guidelines using the AGREE criteria.The following databases were searched in order to find relevant guidelines: Medline, Embase and National Guideline Clearinghouse (guidelines.gov). The search strategy used was osteoarthritis and guideline(s) in the title and/or abstract and/or MESH heading. For selection, the guidelines had to meet the following criteria: published or updated between 2001 and August 2006, major focus on knee osteoarthritis, addressing the treatment of the condition, published in English or French, and available electronically.Six guidelines were identified using this search strategy -11. One These guidelines were distributed to four groups of three or four evaluators. Each group reviewed one guideline, with the exception of one group that reviewed two guidelines. One independent evaluator reviewed all guidelines. In total, 13 clinician researchers  participated in the review. In addition to the guidelines, each evaluator was asked to read the AGREE instrument training manual  and receThe AGREE instrument is composed of 23 items organized into six domains: scope/purpose, stakeholder involvement, rigour of development, clarity/presentation, applicability, and editorial independence. Guidelines with a clear scope/purpose specifically describe objectives and patient applicability. Stakeholder involvement is successfully addressed when all relevant groups, including patients, are included in the guideline development process, with target users defined and guidelines piloted among them. Guidelines with rigour in their development use systematic methods to search and select evidence, with an explicit link between evidence and recommendation formulation. In guidelines effectively addressing clarity/presentation, specific and unambiguous key recommendations and management options are easily identifiable. Applicability involves discussing cost and organizational implications of the guideline, and providing monitoring tools. Editorial independence is effectively addressed when conflicts of interest and independence from funding bodies are clearly stated.A domain score is calculated by adding the scores of the items in a domain and by standardizing the total out of 100%. Domain scores greater than 60% are considered effectively addressed, a cutoff value used in the AGREE instrument for overall assessment . The guiEach evaluator independently reviewed the guideline that was assigned to their group, using the AGREE instrument. Each group then met on two separate occasions with electronic and telephone exchanges between the meetings. At the last meeting, disagreements on ratings of the individual items were discussed until a consensus was reached on all items.Table In general, there were few disagreements among reviewers on AGREE scores, and all disagreements were resolved after discussion. Table The Ottawa Panel guideline and the CCC guideline can be considered to have the highest quality among the guidelines, since they effectively addressed two domains and came close to effectively addressing two others (≥ 50%). The Ottawa Panel guideline effectively addressed scope/purpose and rigour of development, but poorly addressed applicability and editorial independence. The CCC guideline effectively addressed clarity/presentation and editorial independence, but poorly addressed scope/purpose and applicability.Next in quality would be the EULAR and ICSI guidelines, both effectively addressing two domains and coming close to addressing another one. The EULAR guideline effectively addressed rigour of development and clarity/presentation, but poorly addressed stakeholder involvement, applicability and editorial independence. The ICSI guideline effectively addressed scope/purpose and clarity/presentation, but poorly addressed stakeholder involvement, rigour of development, and applicability.Finally, both the AAOS and the Schnitzer/ACR guidelines only came close to effectively addressing two domains. The AAOS guideline poorly addressed stakeholder involvement, rigour of development, applicability, and editorial independence. The Schnitzer/ACR guideline poorly addressed stakeholder involvement, rigour of development, clarity/presentation, and applicability.On the basis of these scores, none of the guidelines were strongly recommended. The Ottawa Panel guideline, the CCC guideline, the EULAR guideline and the ICSI guideline were recommended, while the AAOS guideline and the Schnitzer/ACR guideline were not.Clarity/presentation was the domain most often effectively addressed by the guidelines (three out of six guidelines), followed by scope/purpose and rigour of development (two out of six guidelines). Editorial independence was effectively addressed in only one guideline. The most poorly addressed domains were stakeholder involvement and applicability, with no guideline effectively addressing these.Tables Exercise was recommended in all guidelines that studied this intervention Table , with thAcetaminophen was recommended as initial pain treatment in all guidelines Table . NSAIDs Corticosteroid or hyaluronic acid injections were recommended in four of the guidelines ,7,9,10 , but witThree guidelines provided recommendations regarding surgery ,7,10, wiFive adjunct treatments, consisting of heat/ice, compression/elevation, transcutaneous electrical nerve stimulation (TENS), massage and acupuncture, were recommended in one guideline  Table 1. None ofThree categories of equipment were recommended in four of the guidelines ,7,9,10: Education and weight loss was recommended in four guidelines ,7,9,10 , althougThe present review highlights the relatively large number of types of interventions available to clinicians and patients when managing knee osteoarthritis. Types of interventions included in the guidelines varied, reflecting choices made by development teams. It appears that interventions with the strongest evidence tended to be addressed in most guidelines (such as exercise and medication), while other interventions with less evidence tended to be addressed in a minority of guidelines. There was also variability in the level of details of interventions, with some guidelines dividing a category of intervention into various forms, and others succinctly describing only the category. The interests, mandate and resources of the development team probably guided the type and extent of interventions addressed.When comparing guidelines, there generally seemed to be agreement in recommendations on the interventions addressed. Acetaminophen was generally recommended for initial pain treatment. Introducing more potent medication, such as NSAIDs, was also generally suggested if acetaminophen failed to control pain. The gastrointestinal risks associated with NSAID intake was stressed in the guidelines, however, especially with patients with high gastrointestinal risk factors. Only the most recent guideline  discusseExercise and education were also generally recommended throughout all disease stages. The type of exercise recommended varied among guidelines, but it appears the important notion is to keep active, whatever the type of exercise. Although education was frequently suggested, its elements were not well described in the guidelines, apart from one . PerhapsSurgery was generally recommended as a last resort in the presence of persistent pain and disability. Other interventions were suggested in some of the guidelines, such as intraarticular injections, supplements, equipment and passive therapies, but their role and place in the management of knee osteoarthritis was unclear. This is probably related to the weaker evidence regarding the effectiveness of these interventions. The role of these interventions should be specified in future guidelines.The AGREE evaluation demonstrated that the guidelines effectively addressed only a minority of domains. Although scope/purpose, rigour of development and clarity/presentation were the most often effectively addressed domains, the majority of guidelines failed to appropriately address these domains. Guideline developers should focus on the AGREE criteria constituting these domains in the elaboration of future guidelines.Three domains were particularly not well addressed by the guidelines: stakeholder involvement, applicability, and editorial independence. In an AGREE evaluation of low-back pain guidelines, very similar results were obtained . It therAs for stakeholder involvement, it appears that a change in the attitude of guideline developers could be needed. Guideline developing teams tended not to include all relevant stakeholders and patients. It is, however, suggested that involving stakeholders in guideline elaboration tends to improve applicability of the recommendations and to facilitate appropriation among end users . AlthougAs for guideline applicability, barriers in guideline use should be taken into account during guideline development, in order to facilitate use and uptake ,21. ExpeIt appears that the AGREE criteria are more and more taken into account when elaborating guidelines. The two most recent guidelines ,11 had tTherapeutic interventions addressed in the guidelines varied, with no guideline addressing all interventions. When an intervention was addressed in two or more guidelines, the corresponding clinical management recommendation tended to be similar among guidelines. Acetaminophen was recommended for initial pain treatment, combined with exercise and education. NSAIDs were recommended if acetaminophen failed to control pain, but cautiously because of gastrointestinal risks. Surgery was recommended in the presence of persistent pain and disability. Education and activity management interventions were superficially addressed in most guidelines and should be detailed in the future. Guidelines effectively addressed only a minority of AGREE domains. In order to improve applicability and to increase uptake by end users, stakeholder opinions and barriers in use need to be taken into account during guideline development. The apparent slowness of guideline development processes to integrate and disseminate new knowledge means that innovative methods of knowledge translation to health professionals should be developed.AAOS = American Academy of Orthopaedic Surgeons; ACR = American College of Rheumatology; AGREE = Appraisal of Guidelines Research and Evaluation; CCC = Canadian Consensus Conference; EULAR = European League Against Rheumatism; ICSI = Institute for Clinical Systems Improvement; NSAID = nonsteroidal anti-inflammatory drug.The authors declare that they have no competing interests. This research was funded by Laboratoires Expanscience, Courbevoie, France, which manufactures one of the medications discussed in the present review (avocado/soya unsaponifiables). The views or interests of the funding body did not influence the content of the manuscript.All authors participated in conception and design of the study, in the acquisition and interpretation of data, and in the revision of the manuscript. All authors read and approved the final manuscript. SP additionally drafted the manuscript


However, activities for PlnDI, in solution, have not been reported. In this study, we assessed the ability of soluble forms to modulate vascular endothelial growth factor-165 (VEGF165) enhanced capillary tube-like formation, and VEGF receptor-2 phosphorylation of human bone marrow endothelial cells, in vitro.Immobilized recombinant perlecan domain I (PlnDI) binds and modulates the activity of heparin-binding growth factors, 165 in a heparan sulfate and pH dependent manner. Capillary tube-like formation is enhanced by exogenous PlnDI; however, PlnDI/VEGF165 mixtures combine to enhance formation beyond that stimulated by either PlnDI or VEGF165 alone. PlnDI also stimulates VEGF receptor-2 phosphorylation, and mixtures of PlnDI/VEGF165 reduce the time required for peak VEGF receptor-2 phosphorylation (Tyr-951), and increase Akt phosphorylation. PlnDI binds both immobilized neuropilin-1 and VEGF receptor-2, but has a greater affinity for neuropilin-1. PlnDI binding to neuropilin-1, but not to VEGF receptor-2 is dependent upon the heparan sulfate chains adorning PlnDI. Interestingly, the presence of VEGF165 but not VEGF121 significantly enhances PlnDI binding to Neuropilin-1 and VEGF receptor-2.In solution, PlnDI binds VEGF165 can enhance VEGFR-2 signaling and angiogenic events, in vitro. We propose PlnDI liberated during basement membrane or extracellular matrix turnover may have similar activities, in vivo.Our observations suggest soluble forms of PlnDI are biologically active. Moreover, PlnDI heparan sulfate chains alone or together with VEGF Perlecan, a heparan sulfate proteoglycan with preferred localization to vascular basement membranes, is comprised of a ~480 kDa protein core with five distinct domains (I - V). Domains II-V share structural homologies with other protein modules . In cont165 to coordinate developmental angiogenesis by modulating VEGF165/VEGFR-2 signaling  reduces PlnDI binding to NRP-1 more than 60%. In contrast, PlnDI binding to VEGFR-2 was poorly competed away by heparin . Moreover, since six or seven oligosaccharide residues are sufficient to fully occupy the HS binding site for VEGF165 . For assays conducted in the absence of cell surface heparin sulfate, human bone marrow endothelial cells were cultured for 15 minutes under serum free conditions in RPMI 1640 media supplemented with heparinase cocktail , and total protein concentrations determined (micro BCA assay). For Western blotting, 30 μg of each sample was loaded onto 7% Tris-acetate gels, electrophoresed under reducing conditions, then transferred onto nitrocellulose. Membranes were probed with anti-phospho-VEGFR-2 (tyrosine residue (Tyr)-951), phospho-Akt, anti total-VEGFR-2, total-Akt, and anti-GAPDH antibodies. Primary antibodies were detected and visualized as described for Western blotting.Bone marrow endothelial cells, cultured to 80% confluence, were rinsed twice with serum free media, and then cultured for 24 hrs under serum free conditions. Cells were pre-incubated with a heparinase cocktail to remove cell surface heparan sulfate (as described above) then incubated with serum free media containing supplements  for either 0, 2.5, 5, 10 or 20 minutes. After washing (ice-cold PBS), the cells were lysed  was added. After 2 h, and several washes with PBS containing 0.05% Tween 20, the plates were incubated with anti-PlnDI antibodies (1:500 dilution) for 1 h. Primary antibodies were detected with anti-rabbit IgG secondary antibodies conjugated to HRP (1:8000). Each well was subsequently incubated with tetramethylbenzidine  for 10 min under gentle agitation. Color development was stopped with 50 μL of 0.5 N H2SO4. Binding was quantified by measuring absorbance at 450 nm. Unless indicated, all incubations were performed at room temperature.Recombinant proteins (NRP-1 and VEGFR-2) were allowed to bind overnight (4°C) in 96-well plates . After several washes and blocking with PBS containing 3% BSA, PlnDI (5 μg/well) with or without VEGFAs done previously , PlnDI . Differences were considered significant at P < 0.05. All results are presented as means ± standard error of the mean.All experiments were conducted in triplicate, repeated at least three times, and analyzed by two-tailed paired Student's CS: chondroitin sulfate; GAG: glycosaminoglycan; HSPG: heparan sulfate proteoglycan; HS: heparan sulfate; NRP-1: Neuropilin 1; PlnDI: recombinant perlecan domain I; VEGF: vascular endothelial growth factor; VEGFR-2: vascular endothelial growth factor receptor-2; p-VEGFR-2: phosphor-VEGFR-2; t-VEGFR-2: total-VEGFR-2.AM performed all experiments described herein. RRG conceived the study, and participated in its design and coordination. All the authors contributed equally to data analysis, interpretation, and communication of the findings. All authors have read and approved the final version of the manuscript.


In 2005, draft guidelines were published for reporting studies of quality improvement interventions as the initial step in a consensus process for development of a more definitive version. This article contains the full revised version of the guidelines, which the authors refer to as SQUIRE . This paper also describes the consensus process, which included informal feedback from authors, editors and peer reviewers who used the guidelines; formal written commentaries; input from a group of publication guideline developers; ongoing review of the literature on the epistemology of improvement and methods for evaluating complex social programmes; a two-day meeting of stakeholders for critical discussion and debate of the guidelines’ content and wording; and commentary on sequential versions of the guidelines from an expert consultant group. Finally, the authors consider the major differences between SQUIRE and the initial draft guidelines; limitations of and unresolved questions about SQUIRE; ancillary supporting documents and alternative versions that are under development; and plans for dissemination, testing and further development of SQUIRE. A great deal of meaningful and effective work is now done in clinical settings to improve the quality and safety of care. Unfortunately, relatively little of that work is reported in the biomedical literature, and much of what is published could be more effectively presented. Failure to publish is potentially a serious barrier to the development of improvement in health and medical care and improvement science generally, since public sharing of concepts, methods and findings is essential to the progress of all scientific work, both theoretical and applied. In an effort to strengthen the evidence base for improvement in health care, in 2005 we proposed draft guidelines for reporting planned original studies of improvement interventions.Inadequate reporting of work in clinical improvement has been documented in several ways.Our initial draft guidelines were, of course, not a tested approach to judging the quality of the improvement literature, since that draft was based largely on the authors’ personal experience with improvement work, and was intended only as an initial step towards an established standard. We have now refined and extended that draft, as planned. In the current article we present a revised version, which we refer to as the Standard for QUality Improvement Reporting Excellence, or SQUIRE . We also–The SQUIRE development process proceeded along six general lines. First, we obtained informal feedback on the utility, strengths and limitations of the initial draft guidelines by using them in seminars with potential authors in both the United States and other countries; others have gathered similar information from journal reviewers.6Informal input about the draft guidelines from authors and peer reviewers generally recognised their practical value, in comments such as “These guidelines … can guide the writing of the article, so it may be prudent to distribute [them] to the authors of papers,” and “I … have used them and find them most helpful”.et al, unpublished). Within that context, our consensus process has made it clear that the SQUIRE guidelines can and should apply to reporting in the first category: formal planned empirical studies on the development and testing of improvement interventions.Publications on improvement in health care appear to be emerging in four general categories: empirical studies on development and testing of quality improvement interventions; stories, theories and frameworks; literature reviews and syntheses; and the development and testing of improvement-related tools . The SQUIRE guidelines, in contrast, are concerned with reporting studies in a defined content area—improvement and safety. The two guideline types are therefore complementary; when appropriate, other specific design-related guidelines can and should therefore be used in conjunction with SQUIRE.Quality and Safety in Health Care gained experience with the initial draft guidelines by using them to help judge the completeness and transparency of submitted manuscripts, and encouraging their use by authors in revising their papers.15–The editors of the journal Written commentaries on the draft guidelines raised several additional major points. On the one hand, the guidelines’ focus on “pragmatic science” was seen as an important complement to traditional experimental clinical science.10In our view, it would not be useful (even if it were possible) to address every relevant content issue in a concise set of guidelines for reporting improvement studies. We do agree, however, that disparities in care are not considered often enough in improvement work, and that improvement initiatives should address this important issue whenever possible. We have therefore specifically cited the issue of care disparities among important outcomes to consider  questions about improvement: what is it about the mechanism of a particular intervention that works, for whom and under what circumstances?24–Unlike the “conceptually neat and procedurally unambiguous” interventions—drugs, tests and procedures—whose efficacy is traditionally studied in clinical research, improvement is essentially a social process. Its immediate purpose is to change human performance, and it is driven primarily by experiential learning.With generous support from the Robert Wood Johnson Foundation we undertook a critical appraisal of the draft guidelines at a two-day meeting in April 2007. Thirty people, including clinicians, improvement professionals, epidemiologists, clinical researchers and journal editors attended, several from outside the United States. Before the meeting we sent participants a reading list and a concept paper on the epistemology of improvement. In plenary and small group sessions, participants at the meeting critically discussed and debated the content and wording of every item in the draft guidelines, recommended changes and provided input on plans for dissemination, adoption and future uses of the guidelines. Working from transcribed audiorecordings of all meeting sessions and flip charts listing the key discussion points, a coordinating group  then revised, refined and expanded the draft guidelines.Following the consensus meeting, we circulated sequential revisions of the guidelines for further comments and suggestions in three cycles of a Delphi process. The group involved in that process included the meeting participants plus roughly 20 additional expert consultants. All participants in this process were then asked whether they would be willing to endorse the final consensus version (SQUIRE).whether improvement interventions work (by minimising bias and confounding) and the elements of methods that assess why interventions are or are not effective (by marking out contexts and mechanisms of change). And fourth, this version explicitly addresses the ethical dimensions of improvement and improvement studies. Further differences between the initial draft guidelines and the SQUIRE guidelines are provided in Several features of SQUIRE are worth noting in particular. First, it distinguishes clearly between the practice of improvement  and the evaluation of those interventions . Second, SQUIRE highlights the essential and unique properties of improvement interventions, particularly their social nature, focus on changing performance, context-dependence, complexity, non-linearity, adaptation and reflexiveness. Third, this version specifies both the elements of study design that assess –28–Medical Journal of Australia published a series of analytical articles, each devoted to an individual CONSORT guideline item, which were later collected into a book.31The SQUIRE guidelines have been characterised as providing both too little and too much information: too little, because they fail to represent adequately the many unique and nuanced issues in the practice of improvement ,24That said, we recognise that the SQUIRE item descriptions are significantly more detailed than those of some other publication guidelines. In our view, the complexity of the improvement process, plus the relative unfamiliarity of improvement interventions and of the methods for evaluating them, justifies that level of detail, particularly in light of the enormously diverse backgrounds of people working to improve health care. Moreover, the level of detail in the SQUIRE guidelines closely resembles that in the guidelines for reporting observational studies, which also involve substantial complexities of study design.In this supplement, we advance an E & E document that provides the rationale for including the item in SQUIRE, as well as examples of reporting practice for each guideline item, with commentary on strengths and weaknesses of the examples.www.squire-statement.org) will provide an authentic electronic home for the guidelines themselves, a medium for their progressive refinement and an electronic community for authors, students, teachers, reviewers and editors who are interested in the emerging body of knowledge on improvement. Plans for the site include full and short versions of SQUIRE; its accompanying E & E document; commentaries; background readings on the epistemology and science of improvement; a listserve; links to related sites ; an edited Wiki section made up of topic areas anchored in SQUIRE; and perhaps a section where authors can post drafts of manuscripts of improvement studies for critical peer review and assessment before journal submission.The SQUIRE website (Although the primary purpose of SQUIRE is to improve the reporting of original, data-driven improvement studies, we believe the guidelines can also serve useful educational purposes, particularly as a framework for understanding the epistemology of improvement and the methodologies for evaluating improvement work. We believe, similarly, that they can be helpful in planning improvement interventions and studies of those interventions, and therefore plan to support SQUIRE-related educational efforts in those areas.The value of publication guidelines has been assessed primarily by measuring their impact on the completeness and transparency of relevant publications.Published reports of medical quality improvement are relatively few, and reporting is often inadequate.The SQUIRE guidelines presented here were developed to encourage more and better reporting of formal improvement studies.This paper describes the consensus process used to develop the SQUIRE guidelines.The current paper also considers limitations, questions and future directions of the SQUIRE project.http://www.equator-network.orgThe EQUATOR Network. Enhancing the QUality And Transparency Of health Research. Available at http://www.squire-statement.orgThe SQUIRE guidelines. Standards for QUality Improvement Reporting Excellence. Available at