Busy clinicians need easy access to evidence-based information to inform their clinical practice. Publishers and organizations have designed specific tools to meet doctors’ needs at the point of care. The aim of this study was to describe online point-of-care summaries and evaluate their breadth, content development, and editorial policy against their claims of being “evidence-based.”We searched Medline, Google, librarian association websites, and information conference proceedings from January to December 2008. We included English Web-based point-of-care summaries designed to deliver predigested, rapidly accessible, comprehensive, periodically updated, evidence-based information to clinicians. Two investigators independently extracted data on the general characteristics and content presentation of summaries. We assessed and ranked point-of-care products according to: (1) coverage (volume) of medical conditions, (2) editorial quality, and (3) evidence-based methodology. We explored how these factors were associated.r = -0.001, P = .99; evidence-based methodology and volume, r = -0.19, P = .48; editorial and evidence-based methodology, r = 0.43, P =.09).We retrieved 30 eligible summaries. Of these products, 18 met our inclusion criteria and were qualitatively described, and 16 provided sufficient data for quantitative evaluation. The median volume of medical conditions covered was 80.6%  and varied for the different products. Similarly, differences emerged for editorial policy  and evidence-based methodology scores  on a 15-point scale. None of these dimensions turned out to be significantly associated with the other dimensions (editorial quality and volume, Spearman rank correlation Publishers are moving to develop point-of-care summary products. Some of these have better profiles than others, and there is room for improved reporting of the strengths and weaknesses of these products. In 1996, Richard Smith sought to identify the main characteristics that medical information sources developed over the next decade should have to guide doctors in their practice . He concThe unquestionable advantage of online point-of-care tools is that they facilitate the selection and summary of research findings and provide friendly interfaces to improve retrieval, synthesis, organization, and application of this information . The modIn the context of the 5S paradigm, summaries have been described as having a pivotal role as they can integrate the best available evidence from lower layers (drawing on studies and synthesis) to provide information on management options for a given health condition. Summaries are also the basis on which more interactive computerized decision support tools, or “systems,” are usually developed .Most online summaries are promoted as “evidence-based”  implyingThe objective of this study was to describe online EBP point-of-care summary providers and to evaluate their content and editorial policy against their claims of being “evidence-based.” As for all research, the quality of point-of-care summaries needs to be evaluated to ensure the real usefulness of these products for clinical practitioners. We arbitrarily postulated that coverage of medical knowledge, editorial policy, and content quality (three desirable criteria) would have been among the properties of the best products, being fully aware that basing our evaluation on these criteria would constitute a content-centred evaluation rather than a user-centered or experience/satisfaction evaluation.This study focused on providers of EBP point-of-care summaries, which can be broadly defined as web-based medical compendia specifically designed to deliver predigested, rapidly accessible, comprehensive, periodically updated, and evidence-based information  to clinicians  AND ) AND (("online systems"[Mesh]) OR ("point-of-care systems"[Mesh])).We collected additional information from the references cited in the papers retrieved. Google was extensively used as the search engine to explore products not reported in the medical literature but available on the market. The following terms were used: “medical information system,” “point of care,” and “evidence-based medicine.” We also screened several publisher and librarian association websites, such as the Council of Science Editors , the WorWe repeated our search and collection during the one-year period from January through December, 2008.For each provider, two reviewers independently retrieved information through an analysis of the official website. As reported in detail below, for any EBP point-of-care summary provider we extracted general characteristics, volume and breadth of the conditions considered, and information regarding the quality of the editorial process and EBP approach to content development (evidence-based methodology). Decisions to select items describing these features were informed by evidence whenever possible. Detailed operational definitions are reported in The features selected were qualitatively described; for editorial and evidence-based methodology indicators, an empirical quantitative evaluation was also included in order to assign a score for each item and rank the EBP point-of-care summary providers. For each quality indicator a point score was assigned: 3 points if the quality indicator was completely fulfilled, 1 point if partially fulfilled or unclear, and 0 points if not fulfilled or not reported. See  and 3. WWe first sought general information, such as product name, year of first release, and vendor and/or publisher. We also reported the marketing claim as stated in the homepage and/or in the “about us” section. We collected information on different formats  and whether the website is open-access or a subscription fee is required to access the whole content. In the latter case, we reported the costs for a single-user subscription per year and the types of subscription available, that is, single user, institutional, “à la carte” , or pay per view. We also described the primary target audience, for example, general practitioners, specialty physicians, or other health care workers who could benefit from the contents. See .We described the content presentation in terms of type of output , formal ontology of information, and output summary flexibility. We analysed whether the output included references, and if so, whether these were general, that is, suggestions of further sources on a particular topic, or specific, that is, they supported particular statements. We also explored whether, in addition to providing information, these summaries provided recommendations to practitioners, and if so, whether a formal grading system for the strength of the recommendations was used. Lastly, we sought whether the content of products included continuing medical education programmes or other educational resources and whether a plain language information document or handout had been specifically developed for patients. See International Classification of Diseases, Tenth Revision (ICD-10) was represented in the product. This provided a rough proxy assessment of the comprehensiveness of each product . Of the 22 ICD-10 chapters, 4 (20%) were randomly selected. These were: “Certain infectious and parasitic diseases,” “Diseases of the skin and subcutaneous tissue,” “Diseases of the genitourinary system,” and “External causes of morbidity and mortality.” We assessed whether sections (blocks) of diseases and conditions in these ICD-10 chapters were covered in each EBP point-of-care summary [We sought to describe the breadth of the medical conditions considered in terms of areas covered by the summaries . As we were not able to identify a reliable measure of database volume , we estimated the number of diseases covered by analyzing whether a random sample of chapters of the  summary .In addition, we reported whether summary providers included information on topics other than medical conditions  and more complex technologies, such as electronic medical records, drug databases, and calculators.To evaluate the methodological quality of the editorial process, we selected specific indicators of transparency: authorship, peer reviewing procedure, updating, disclosure of authors’ conflicts of interest, and commercial support of content development. To create an indicator of editorial quality, points were assigned: 3 points were assigned if the dimension was judged “adequate,” 1 point if judged “unclear,” and 0 points if judged “not adequate” or “not reported.” See To obtain information on the evidence-based approach to content development of each product, we specifically selected evidence-based methodology indicators. The indication of whether contents were based on a systematic literature search or surveillance aimed at identifying relevant, valid research evidence was considered of primary importance. The critical appraisal methodology was also judged, and we focused on the cumulative or discretionary approach to the evidence, reporting whether systematic reviews, particularly Cochrane reviews, were preferred over other types of publication. We also looked at the availability of a system to assess quality of evidence. Finally, if expert opinion was included in the content development, we analyzed whether this contribution could be easily recognized within the body of evidence. Similar to our method of scoring the quality of the editorial policy, we scored each indicator of the quality of the evidence-based approach: 3 points were assigned if the dimension was judged “adequate,” 1 point if judged “unclear,” and 0 points if judged “not adequate” or “not reported.” See Data were extracted by two independent reviewers (authors RB and LT) who used an ad hoc predefined form. We obtained general features and information on the editorial policy and content development from a thorough analysis of the website pages that were freely available . When subscription to a product was not available at our institution, the free trial and sample topics were used to acquire further information on the content characteristics of the product and the type of output. We assumed that sample topics would likely provide users with the “best” of the product as these parts are often written with the most zeal and attention. When necessary, product editors were contacted by email. When we could not access the content, the products were excluded from the analysis. Disagreements were resolved by discussion between the reviewers and a referee (author LM).We registered and stored within an electronic archive (December 2008) all the Web pages used to extract data.ICD-10 chapters); (2) the editorial quality  the number of diseases covered .Displayed together in A brief presentation of these results is reported in As of December 2008, we had found 18 EBP point-of-care summary providers. This suggests that several publishing groups and public health organizations are interested in investing time and resources into the development of these products. The overall characteristics of these products tended to vary, and evaluation of their quality is still in its infancy despite the emerging consensus that such information tools are professionally and scientifically essential . Only a One mainstay of evidence-based information mastery is the combination of tools that filter literature for relevance and validity and present summaries easily and in a quickly accessible form at the point of care . Since dWe developed a content validity scale using an evidence-based approach whenever possible. Desirable dimensions were included if there was evidence that not addressing that particular dimension would result in an increased risk of bias. Dimensions were also included where it was clear that information about that dimension was necessary to appraise the reliability of a point-of-care product. For some quality indicators, such as the literature retrieval process and updating, we borrowed our criteria from research on systematic review reporting methods ,27, assuOne of the limitations of our study stems from a lack of a clear definition of these products which could have led to a possible selection bias. We set eligibility criteria to select evidence-based summary products defined as portable and comprehensive  that HayThe major limitation of our study was the arbitrariness of the scoring system. We chose a continuous scale instead of a classical star rating system to allow scores on individual categories to be correlated. Category scores have not been added to make an overall score. Scores allow readers to group EBP point-of-care summary providers according to quality and to detect top performers within categories. Our scoring system can be considered a preliminary approach to rating EBP point-of-care summary providers; other categories could be added.ICD-10 chapters as a proxy of the comprehensiveness of a summary may not necessarily be representative of what each provider offers. However, comprehensiveness is a crucial aspect of any information tool when used to answer clinical questions. Further research on the comprehensiveness of these information tools is needed.We did not formally analyze website navigability and usability as this was beyond the scope of our study. Such an analysis might be valuable from the users’ perspective because information on the Web can be communicated in many ways—such as diagrams, animations, and linked pages—which may improve comprehension. These analyses should be carefully interpreted as they suffer from the multiplicity bias as occurs when users are asked to compare known systems with new ones. EBP point-of-care summaries also largely differ according to the comprehensiveness of each topic. Choosing a random sample of None of the associations we postulated turned out to be statistically significant. Thus, on the basis of the criteria we used, editorial quality, evidence-based methodology, and volume appear to be independent. For example, BestBETs scored among the worst on volume (comprehensiveness), with an intermediate score for editorial quality, and the highest score for evidence-based methodology. The search for associations between various desirable factors can be seen as “work in progress,” suggesting that publishers have to balance these aspects, and achieving excellence in all three aspects is difficult.In the global trend for point-of-care products to inform clinical practice, there is room for improving the quality and increasing the coverage of diseases. Publishers should provide users  with transparent, easily accessible, and rigorously determined information regarding editorial processes and content development. Our assessment is intertwined with the quality of reporting. It is possible that publishers favored conciseness of information on their websites and omitted important editorial and methodological details. For instance a publisher may plan to disclose author conflicts of interest, but then does not report this key information on its website, thus diminishing the trustworthiness of its product.Efforts have been made in the last two decades to improve the quality of reporting of the results of randomized controlled trials and systematic reviews ,27,32. HAt present, clinicians who want to select an EBP point-of-care summary to use regularly need to find a balance among several desirable characteristics to inform their choice: according to our criteria, no product appears to be the best. Faced with a choice of summaries, one criterion should prevail. The judgement is complex because in addition to various desirable criteria, many other dimensions could be attractive and drive the choice, such as whether the summary can be used for continuing medical education, contains information addressed to patients, or can be integrated with more sophisticated technologies. Having access to high-quality and well-summarized evidence-based information will not answer all the questions that arise in the doctor-patient relationship, but these summaries help doctors to identify the best options in therapy, diagnosis, or prognosis for their patients. Even the most innovative information system must rely on sound evidence to improve clinical practice; the technology is only the vehicle to make the information accessible. Quality indicators that can be used to evaluate new EBP point-of-care summary providers can be valuable for clinicians, but these can also be useful for librarians, hospital managers, and policy makers who must choose the most appropriate point-of-care summaries to meet their needs.


P450 3A4 pathway (CYP3A4), the potential exists for pharmacokinetic (PK) drug interactions with the numerous agents that modulate CYP3A4 isozyme activity. We investigated the effects of ketoconazole, a potent CYP3A4 inhibitor, on the PK profile of i.v. temsirolimus in healthy adults. Coadministration of 400 mg oral ketoconazole with 5 mg i.v. temsirolimus had no significant effect on temsirolimus maximum concentration (Cmax) or area under the concentration curve (AUC). However, mean AUC increased 3.1-fold and AUCsum (sum of temsirolimus plus sirolimus AUCs) increased 2.3-fold compared with temsirolimus alone. A single 5-mg dose of temsirolimus with ketoconazole was well tolerated, and there were no unexpected safety results. Therefore, in cancer patients receiving 25 mg i.v. temsirolimus, concomitant treatment with agents that have strong CYP3A4 inhibition potential should be avoided. If a concomitant strong CYP3A4 inhibitor is necessary, a temsirolimus dose reduction to 12.5 mg weekly should be considered.Intravenous (i.v.) temsirolimus, a novel inhibitor of mammalian target of rapamycin, is approved for the treatment of advanced renal cell carcinoma and is being studied in patients with mantle cell lymphoma. Because temsirolimus and its primary metabolite, sirolimus, are metabolised by the cytochrome  In vitro, the activity of temsirolimus is facilitated by its binding to the cytosolic FK506 binding protein-12, which in turn binds to mTOR and inhibits its kinase activity , improves overall survival and progression-free survival in patients with advanced renal cell carcinoma (RCC) compared with interferon (Cmax) in whole blood was 595 ng ml−1 (coefficient of variation (CV)=17%), and mean area under the curve (AUC) was 1580 ng h ml−1   temsirolimus in humans is sirolimus, which also displays mTOR inhibitory activity. Clinically relevant pharmacokinetic (PK) exposure to i.v. temsirolimus is considered to be a composite of both temsirolimus and sirolimus. Following administration of a single 25-mg dose of temsirolimus in patients with RCC, temsirolimus mean maximum concentration (e faeces . BecauseP450 3A4 (CYP3A4)  (Ki=2 μM). Orally administered sirolimus exhibits a substantial PK drug interaction with ketaconazole, resulting in increased whole blood exposure to sirolimus (Temsirolimus and sirolimus are metabolised by cytochrome (CYP3A4) . Becauseirolimus . Oral stThis drug interaction study was conducted in healthy adults to assess the PK profile of a single i.v. dose of temsirolimus when coadministered with multiple oral doses of the potent CYP3A4 inhibitor ketoconazole Because of the potential for increased exposure when given with ketoconazole, a 5-mg dose of i.v. temsirolimus was chosen to mitigate safety concerns of using the 25-mg clinical RCC dose in healthy subjects. The lower dose is also a more sensitive indicator of PK drug interaction potential.−2 and body weight of 50 kg or more were eligible for participation in this trial. Women were required to be of non-childbearing potential due to hysterectomy and/or oophorectomy or in menopause for more than 1 year, with an oestradiol concentration of 20 pg ml−1 or less and a follicle-stimulating hormone level of at least 40 mIU ml−1. They also were required to have a negative serum pregnancy test within 48 h of the first temsirolimus administration (study day 1). Subjects with significant cardiovascular, hepatic, renal, respiratory, endocrine, immunologic, dermatologic, haematologic, neurologic, or psychiatric disease or a surgical or medical condition that could interfere with the absorption, distribution, metabolism, or excretion of the study medications were not enrolled. Those with positive HIV antibodies, hepatitis B surface antigen, or hepatitis C virus antibodies were also excluded. A normal physical exam, vital signs, 12-lead electrocardiogram (ECG), and clinical laboratory tests were required for inclusion in the study. Subjects with an acute illness within 7 days of study day 1 were excluded. A history of smoking fewer than 10 cigarettes per day and the ability to refrain from smoking during the in-patient portion of the trial were required for participation in the study. Subjects were excluded if they had a history of drug or alcohol abuse  within 1 year of study day 1, and a negative urine drug screen was required. Those with hypersensitivity to temsirolimus or sirolimus, ketoconazole, or diphenhydramine were also excluded. Use of investigational or prescription drugs within 30 days of study day 1 or use of caffeine-containing products, grapefruit, grapefruit-containing products, or alcoholic beverages within 48 h of study day 1 was not allowed. Subjects could not take over-the-counter medications or herbal supplements within 14 days of study day 1. All participants gave written informed consent before the trial.Men and women aged 18–45 years, inclusive, with a body mass index between 18 and 30 kg mIn this open-label, non-randomised, single-centre, two-period, sequential study, subjects received temsirolimus  alone, followed by temsirolimus in combination with ketoconazole after a 14-day washout period. On study day 1 of the first period, subjects received 25 mg i.v. diphenhydramine, followed 30 min later by 5 mg i.v. temsirolimus over 30 min. Subjects remained in the clinical unit until the 72-h blood collection (study day 4) and returned for subsequent blood draws at designated time points over the next 4 days (study days 5–8). Study days 9 through 13 were part of the washout period. During the second period, subjects returned to the clinical unit on study day 14. On study day 15, they received 400 mg oral ketoconazole, followed 90 min later by a 25-mg i.v. dose of diphenhydramine. Thirty minutes later, subjects were administered a 30-min i.v. infusion of 5 mg temsirolimus. Subjects remained in the clinical unit until the 72-h blood draw (study day 18) and returned for all subsequent blood draws. They continued to take 400 mg ketoconazole orally each day through study day 21. Subjects fasted for 10 h before receiving temsirolimus and for 4 h afterward.Blood samples were collected predose, immediately before the end of the infusion (0.5 h), and at 1, 3, 8, 24, 48, 72, 96, 120, 144, and 168 h after administration of temsirolimus on study days 1 and 15. Samples were collected in evacuated tubes containing ethylenediaminetetraacetic acid (EDTA) and gently mixed, then stored upright at −70°C until shipment. Samples were shipped on ice to Taylor Technology  for measurement of temsirolimus and sirolimus concentrations.The concentrations of temsirolimus and sirolimus in blood were measured simultaneously using validated liquid chromatography/tandem mass spectrometry combination procedures with deuterated internal standard  were determined visually from the concentration–time curves. The terminal elimination rate constant, zλ, was estimated by log-linear regression of the terminal portion of the whole blood concentration–time curves. The terminal elimination half-life (T1/2) was calculated as 0.693/zλ. The area under the concentration–time curve (AUCT) was calculated using the trapezoidal rule for the ascending portion of the curve, and the log-trapezoidal rule for the descending portion of the curve. Total AUC was estimated using the following equation: AUC=AUCT+CT/zλ, wherein CT is the last observed blood concentration at time T. The AUCratio is the ratio of sirolimus AUC to temsirolimus AUC (AUCsirolimus/AUCtemsirolimus). Clearance (CL) is the volume of plasma cleared of the drug per unit time (dose/AUC). Apparent clearance was corrected for the fraction of the dose that was metabolised (CL/fm). The apparent volume of distribution during the terminal phase (Vz) was calculated by (CL/fm)/zλ. The calculation of the steady-state volume of distribution (Vdss) incorporated dissociation and association rates of protein and tissue binding. Vdss was defined as (dose/AUC)MRTu, where MRTu is the mean residence time of the unbound drug in the plasma  with treatment as a fixed effect and subject as a random effect, using the WinNonlin Enterprise application version 4.1 Linear Mixed Effects Wizard . The geometric mean relative bioavailability of Seventeen subjects were enrolled in the study, and all but one were men and most were white subjects . During Cmax and AUC of <16% for temsirolimus and <33% for sirolimus.The temsirolimus PK profile was evaluable for 16 subjects in period 1 and for 14 subjects in period 2. Exposures to temsirolimus and sirolimus were associated with a modest degree of intersubject variability, with a CV for Mean concentration–time curves for temsirolimus in blood were nearly comparable following treatment with ketoconazole in combination with temsirolimus compared with temsirolimus alone . In contCmax and AUC for temsirolimus were observed in subjects receiving temsirolimus alone or in combination with ketoconazole (−1 (approximately 10%), but this decrease was not manifested as changes in mean Cmax and AUC.No substantial differences in mean conazole . Mean vofm) was more substantial, decreasing 3.2-fold with ketoconazole treatment and resulting in an increase in mean half-life from 75 to 113 h. Carryover of sirolimus from treatment period 1 to 2 was minimal, contributing 1.9% to the mean total AUC calculated for this treatment period (range 1.1–3.7%). Ketoconazole increased sirolimus mean Cmax by 2.2-fold and AUC by 3.2-fold compared with temsirolimus alone.In contrast, for sirolimus, the change in mean apparent metabolic clearance , 109% , and 110% , respectively. For sirolimus, the least squares geometric mean ratios (90% CIs) for Cmax, AUCT, and AUC were 224% , 252% , and 310% , respectively ) relative to the reference of a single dose of 5-mg i.v. temsirolimus alone for ectively .Adverse events, defined as those occurring or worsening after receiving study medications, occurred in 71 and 57% of subjects receiving temsirolimus and the combination of temsirolimus and ketoconazole, respectively . The mosTemsirolimus is a novel targeted therapy for the treatment of patients with RCC and is currently in clinical studies for treatment of various haematologic and solid malignancies. Patients with advanced cancers often receive concomitant therapies to manage disease symptoms and the side effects associated with anticancer agents. It is therefore important to characterise the potential for PK drug interactions in patients receiving i.v. temsirolimus and to provide guidance on dose modifications, when appropriate.Cmax or AUC. The 90% CIs for the least squares geometric mean ratios of Cmax, AUCT, and AUC for temsirolimus were within the 80–125% range, indicating no clinically significant PK drug interaction. However, for the metabolite sirolimus, 90% CIs for the least squares geometric mean ratios of Cmax, AUCT, and AUC were greater than 200%, indicating a clinically significant PK drug interaction. These increases in sirolimus Cmax and AUC were accompanied by a 69% reduction in sirolimus apparent clearance.We report that coadministration of ketoconazole, a strong CYP3A4 inhibitor, with 5 mg i.v. temsirolimus in healthy subjects had no effect on temsirolimus ratio 2.9-fold (from 1.35 to 3.94). Despite greater exposure to sirolimus, increases in toxicity were not evident in these healthy subjects. The most common adverse events were headache, neutropaenia, pain, and insomnia. Notwithstanding the lower 5 mg dose administered in this study, the types of adverse events observed were not dissimilar to those seen in studies of temsirolimus in patients with cancer, although a greater percentage of cancer patients had thrombocytopaenia, rash, and mucositis (sum and adverse event severity were observed for thrombocytopaenia (P=0.007), pruritus (P=0.011), and hypertriglyceridaemia (P=0.040) , as well as a 45% reduction in sirolimus AUC  have been previously described by This is the first report of the effects of concomitant CYP3A4 inhibitors on the PK of temsirolimus. However, the effects of CYP3A4 inhibitors, including various macrolide antibiotics and azole antifungal medications, on the metabolism of oral sirolimus , benzodiazepines (commonly used in cancer patients for anxiety), and calcium channel blockers (commonly used antihypertensives). Although antifungal agents that are strong inhibitors of CYP3A4  should be avoided in patients receiving temsirolimus, moderate CYP3A4 inhibitors  may not have as much interaction potential. For example, in RCC patients treated with 25 mg i.v. temsirolimus, fluconazole (commonly used for treatment of chemotherapy-induced mucositis) may be a reasonable management approach for temsirolimus-related mucositis. Nevertheless, CYP3A4 inhibitors should not be given concomitantly with higher temsirolimus doses, such as those being investigated in clinical trials .Cmax or AUC; however, a strong PK interaction leading to increased exposure of the primary metabolite sirolimus  was observed. Based on these results, it is recommended that concomitant use of strong CYP3A4 inhibitors should be avoided  in cancer patients receiving 25 mg i.v. temsirolimus once weekly. Grapefruit juice may also increase plasma concentration of sirolimus. If a concomitant strong CYP3A4 inhibitor is necessary, a temsirolimus dose reduction to 12.5 mg weekly should be considered. If the strong CYP3A4 inhibitor is discontinued, a washout period of approximately 1 week should be allowed before the temsirolimus dose is adjusted back to the dose used before initiation of the strong CYP3A4 inhibitor.In conclusion, coadministration of ketoconazole with i.v. temsirolimus had no effect on temsirolimus


Evidence-based medicine requires the integration of clinical judgment, recommendations from the best available evidence and the patient's values.Surgical literature can be broadly classified as those articles with a primary interest in therapy, prognosis, harm, economic analysis or those focusing on overviews to name a few.Available therapeutic literature can be broadly categorized as those studies of an observational nature and those studies that have a randomized experimental design.6Meta-analyses of randomized controlled trials in effect use the data from individual RCTs and statistically pool it.59In contrast to this, the lowest level on the hierarchy (aside from expert opinion) is the case report and case series.The next level of study is the case-control. The case-control starts with a group who has had an outcome of interest and looks back at other similar individuals to see what factors may have been present in the study group and may be associated with the outcome. Let us take a hypothetical example. Those patients who have a nonunion following a tibial shaft fracture treated with an intramedullary nail. If one wanted to see what prognostic factors may have contributed to this, a group that was matched for the known prognostic variables such as age, treatment type, fracture pattern etc. could then be compared and an analysis of other prognostic variables such as smoking, nonsteroidal anti-inflammatory use or fracture pattern could be done to see if there was any association between these and the development of nonunion. The drawback to this design is that there may be unknown or as yet unidentified risk factors that would not be able to be analyzed. However, in those that are known, the strength of association may be determined and given in the form of odds ratios or sometimes relative risks. Other strengths of this study design are that they are usually less expensive to implement and can allow for a quicker “answer” to a specific question. They also can allow for analysis of multiple prognostic factors and relationships within these factors to help determine potential associations to the outcome of choice (in this case nonunion).In contrast to the case-control and slightly higher on the levels of evidence hierarchy,It is important to understand distinctions between study designs. Some investigators argue that well-constructed observational studies lead to similar conclusions as RCTs.681313Thus the type of study design used places the study broadly into a hierarchy of evidence from the case series up to the randomized controlled trial. There is also, however, an internal hierarchy within the overall levels of evidence and that is usually based on the study methodology and overall quality.Concepts of study methodology are important to consider when placing a study into the levels of evidence. There are some that advocate dividing the hierarchy levels into sub-levels based in part on study methodology, while others suggest that poor methodology will take a study down a level.2151819As randomization is the key to balancing prognostic variables, it is first necessary to determine how it was done. The most important concepts of randomization are that allocation is concealed and that the allocation is truly random. If it is known to which group a patient will be randomized it may be possible to potentially influence their allocation. Examples of this would include randomizing by chart number, birthdates or odd or even days. This necessarily introduces a selection bias which negates the effect of randomization. This makes concealment of allocation a vital component of successful randomization. Allocation can be concealed by having offsite randomization centers, web-based or phone-based randomization.In surgical trials blinding is obviously not possible for some aspects of the trial. It is not possible  to blind a surgeon, nor is it usually possible to blind a patient to a particular treatment. However, there are other aspects of a trial where blinding can play a role. For instance, it is possible to blind outcome assessors, the data analysts and potentially other outcomes' adjudicators. Thus it is important to understand who is doing the data collecting and ask, are they independent and were they blinded to the treatment received? If not, possible influences (either subconscious or not) on the patient and subsequent results can happen.The number lost to follow-up is very important to know as clearly this can affect the estimate of treatment effect. While some argue that only a 0% loss to follow-up fully ensures benefits of randomization,21Scales have been devised that can rate a study based on its methodology and assign a score.When truly does assessing the quality of a study in relation to the levels of evidence matter? It matters when a grade of recommendation is being developed. A very important concept is that a single high-level therapeutic study (in our case) does not imply a high grade of recommendation for treatment. A grade of recommendation can only be developed after a thorough systematic review of the literature and in many cases discussions with content experts.242The GRADE working group suggests a system for grading the quality of evidence obtained from a thorough systematic review . This shThe GRADE working group suggests that when making a recommendation for treatment four areas should be considered: 1) What are the benefits vs. harms? Are there clear benefits to an intervention or are there more harms than good? 2) The quality of the evidence, 3) Are there modifying factors affecting the clinical setting such as the proximity of qualified persons able to carry out the intervention? and 4) What is the baseline risk for the potential population being treated?2Thus one can see that a grade of recommendation in contradistinction to a level of recommendation is made based on the above four criteria. Inherent in the above criteria are a thorough review of the literature and a grading of the studies through knowledge of study design and methodology. Evidence-based medicine is touted as being a decision-making based on the composite of the triumvirate of clinical experience, the best available evidence and patient values. One can see that knowledge of the levels of evidence, the pros and cons of different study designs and how study methodology can affect the placement of a study within the hierarchy encompasses one aspect of this. The development of grades of recommendation based on the GRADE working group system gives one the tools to convey the best available evidence to the patient as well as help the literature guide the busy clinician. Also, different harms and benefits of various treatments are given different value judgments by individual patients. Discussions with patients about what is important to them, mixed with surgical experience and “what works in my hands” helps round out the decision-making when developing a treatment plan.


Although many believe that evidence-based practice (EBP) has great potential, critics have identified limitations including a focus on randomized clinical trial (RCT) evidence to the exclusion of other evidence types and a disregard for the art of medicine. Others have argued, however, that proper application of EBP involves reasoned consideration of a wide variety of information; thus, the dichotomy between medical science and art may be false. We explore the views of executive-level policymakers from the Veterans Health Administration, a leader in the EBP movement, regarding what constitutes evidence and the relative importance of evidence versus practical needs when determining clinical policy.We conducted 26 semi-structured qualitative interviews and performed a content analysis.Although informants generally believed in the value of EBP and the role of RCTs within it, they also valued other types of evidence. Further, they had concerns that were sometimes antithetical with strict adherence to an evidence-based approach. These included practical concerns, fit with organizational values and with local circumstances, resources, political pressures and patient needs. They were especially concerned about how to address medical conditions that affect many individuals or high-risk populations that have no evidence-based treatment.When possible, health care practice should be evidence-based. When this is not possible, health care providers must turn to the art of medicine by using consensus-based best practices. Further, it is important for policymakers and researchers to work in concert to develop EBPs that are practical and meet needs. Historically, health care practitioners have considered their work as much an art as a science, drawing upon clinical intuition honed by years of experience . Since tMuch of the concern focuses on the assumption among many EBP proponents that randomized clinical trials (RCTs), especially double-blind trials, should provide the gold standard for clinical evidence. Critics of this stance have argued that typical patients are often more complicated and less compliant than those included in RCTs ,9–14. MoInterestingly, despite many EBP advocates' claims that RCTs provide the highest quality evidence, findings from observational studies actually converge more often than do findings from RCTs . FurtherA number of health services researchers have observed that qualitative methods  provide particularly viable approaches for exploring the needs and preferences of health consumers who do not fit neatly into the types of groups RCTs require. These include those with co-morbid conditions or complex life circumstances ,22,23,24There are also quantitative methods other than RCT that can provide valuable information regarding disease process, treatment, and prevention. Although only experimental methods, such as RCT, can establish causal relationships, quantitative correlational methods are also valuable tools, especially where experiments may be unethical. For example, physicians generally recommend that patients do not smoke based on the well-established correlation between smoking and lung disease rather than on any experiment definitively demonstrating that smoking causes such disease. Finally, Buetow and Kenealy proposed that EBP should include not just research evidence, whether it is qualitative or quantitative, but also theoretical, practical, experiential, expert, judicial and ethical evidence .Also of concern is the nature of research publication and funding. As journal editors prefer to publish statistically significant positive results, reviews of the research literature may over estimate true effect sizes. This issue, known as the ‘file draw’ problem or effect because negative findings do not enter the literature but rather literally languish in investigators' file draws, affects all sciences. Quite simply, it is far easier to learn of trials where treatments do work than it is to learn of those where they do not. Further, there is more research funding for commercially viable interventions  than for interventions with limited commercial value (e.g. lifestyle and dietary changes). Additionally, some treatments  are more amenable to EBP methods, such as double-blind RCT, than others . Thus, there may be more published evidence created for certain types of treatments than for others, regardless of their actual value ,4,7,11. On the other hand, numerous health services researchers and policy analysts have argued that proper application of EBP does not involve dogmatic adherence to RCT results alone. Rather, EBP should include consideration of evidence from a wide variety of sources, as well as individual patient and provider experiences and local context ,25,27,28In this article, we explore the views of US Veterans Health Administration (VHA) executive-level policymakers regarding the relative importance of research evidence and of patient and other needs when determining clinical policy. We also explore their views on what they believe constitutes evidence. We believe the VHA provides a particularly important context for exploring these issues because it is one of the world leaders in the development and implementation of EBP. Most notably, the VHA established the Quality Enhancement Research Initiative to foster the translation of research evidence into clinical care . FurtherAs part of a study concerned with understanding how to implement and sustain organization-wide clinical quality improvement (QI) programmes, we identified a purposive sample of 28 current and former executive-level VHA policymakers and key members of their staff. Twenty-six of these agreed to participate in the study and we were able to conduct 12 of these interviews face-to-face at informants' offices during two site visits to the VA Central Office in Washington, District of Columbia, USA. We interviewed 14 informants who were unavailable for face to face interviews or who had offices in locations other than Washington via telephone.Three highly experienced qualitative interviewers, a psychologist, a psychiatrist and a social worker, conducted all the interviews. Two of these three interviewers participated in each interview with one serving as the lead interviewer and the other serving as a back-up interviewer taking notes and ensuring that the lead interviewer covered all crucial topics. The three interviewers took turns serving in these capacities.We conducted all interviews utilizing a qualitative semi-structured protocol. Our protocol was semi-structured in that we developed a topic list but we did not ask exactly worded questions in an exact order and we did not have a closed response set. Qualitative methods are useful when there is limited a priori knowledge regarding the constructs of interest and the researchers seek to discover new information rather than confirm existing hypotheses. Topic areas for this study included fostering partnerships between VHA policymakers and researchers, integrating new clinical programmes into the VHA structure, and the balance between evidence and need in determining VHA policy. The latter topic is the focus of this article. We audio-recorded all interviews and produced verbatim transcripts.Utilizing Atlas.ti, a qualitative data management software package, we conducted a content analysis of the verbatim transcripts . SpecifiFirst, two investigators reviewed the interview transcripts and inductively developed top level codes that described major themes. These included: (1) what convinces informants to support programmes; (2) how to integrate programmes into the VHA structure; (3) issues related to various VHA departments; (4) barriers to researchers partnering with clinical managers and VHA central office policymakers; and (5) the balance between evidence and clinical need in determining clinical policy. The two investigators then each coded one half of the transcripts and reviewed 100% of each other's coding and resolved any differences.Second, working in teams of two, investigators reviewed all quotes linked to a particular top level code and inductively created subcategories or sub-codes that described the content of the quotes. Utilizing this sub-coding scheme, they each sub-coded one half of the transcripts. Finally, they reviewed 100% of each other's coding and resolved any differences.In this article, we focus on the sub-codes for the ‘balancing evidence and need’ top level code. Sub-codes concern: (1) value of EBP in determining policy; (2) types of evidence valued; (3) limits to EBP and the role of the art of medicine when addressing concerns ; (4) types of needs identified; (5) the ways in which clinical evidence may not meet existing needs; (6) methods for meeting needs in the absence of an applicable or complete evidence base; and (7) utilizing needs to guide the direction of research so as to collect useful evidence.All else being equal, our informants generally believed that basing clinical policy upon research evidence enhances quality. Many believed that RCT provides the highest standard evidence:Well, obviously I think the level one evidence [RCTs] is the most compelling … [I]f they show us a research results that are from random control trials, those speak volumes …At the same time, they understood that RCTs were not always viable:As … someone … committed to the evidence-based psychotherapies … there's some things you have to push against, like the assumption that the gold standard is a randomized controlled double-blind trial. Because, obviously, you can't do psycho-social research … blind.Further, they also valued other types of evidence including qualitative:I want to see actually all of that . And I value all of that. So I wouldn't just want to see it from just necessarily one approach. I don't think that addresses the whole issue.[Case studies] play huge training roles … [R]eading the case studies can give you more of a feel for what's this like and what's the emotional experience of the patient, of the therapist, you know, what are the choice points you reach and how are those dealt with, how do you understand that approach to therapy in a richer way.I think that the other evidence that I'm always interested in is [the new practices'] acceptability to the patient. And some of those things are sort of embedded in research reports but are perhaps not emphasized. So drop out rates, you know. Sometimes they're just treated as a source of kind of error but I think they're pretty profoundly meaningful.As much as they valued evidence, however, informants also believed there are other concerns when making policy decisions. First, clinical programmes have to be practical:[T]he practicality of it is a big part … has it been tested in a typical environment or multiple typical environments … And I wouldn't say that we should always rely on … the rigor of the most pure science because then we would probably never get done because it is usually so narrow that it's hard to put your arms around it and say that it applies to multiple settings if it's been tested in one setting … [S]ince we're a provider organization, a practice environment, it has to work in the practice environment.How well practices fit with local clinical and individual values, circumstances and context also factored into informants' decision making:[T]he evidence is only one part of evidence-based care … other components … include understanding and incorporating … values, hopefully the patient's values, and the context … [T]his fellow is left-handed and has red hair and there's no one in the clinical trials who's left-handed and has red hair. So is the context such that the evidence can be applied to this person here and now or not? That's a matter of very fuzzy clinical judgment … [T]he values in Memphis may be different than … values in Cleveland, and that should affect what you do. And the context may be different as well and to fit between the hard evidence and the soft patient may vary so much that it begs the case … I think there's still more to clinical care than applying evidence only.Informants also believed it is important to consider organizational resources:There are great ideas that we could do and they could be very expensive and in the end the benefit is arguable, negligible.I want to know that they've thought through the resources that it would take … [T]oo many times, you know, people want to do something, but they don't think through that you're adding it on top of already busy people, and this is something that is collateral duty now or is it something that's going to replace something else.Further, health care organizations, especially government funded ones such as VHA, must be cognizant of the political climate when making policies:I think that we always remember where we work and who our various bosses are. And we have the White House [U.S. President] three blocks from here and then those folks at the east end of Pennsylvania Avenue [U.S. Congress]. And so a lot of what we end up doing as a government agency is driven by those particular dictates.[W]hat's priorities for the groups that support us, Congress, [Veteran Service Organizations], et cetera. Sometimes you get initiatives that … from our perspective may not be the top impact clinically, but for other reasons … are strongly being … recommended.Finally, informants considered the needs of patients paramount in determining policy:[I]f you go back to our vision statement for our system, it reads, to be a patient-centered system … I think all of these things should be characterized as we're pursuing this because this is an intervention that is needed by our population or at risk for these things.I like to hear the volume of the patients that this will impact, and I also want to know if this is a high-risk population, because you can't just go by volumes. Sometimes you need to do it because it may be a small amount, but it's a high-risk population.Given that informants believed that some needs are so compelling that it is important to attempt to meet them even in the absence of research evidence, it is necessary to identify other information to assist with decision making. For most, clinical consensus was the best approach in these instances:[S]ometimes the highest level of evidence is consensus, and you have to understand that that may be all you get … If you wait for level-one evidence for everything, you would do hardly anything…. The NCCN [National Comprehensive Cancer Network] guidelines for cancer, for example, they'll tell you right up front they're consensus guidelines. But it doesn't mean you shouldn't do it just because they're consensus guidelines. That's the best thing we had, so that's what you use.In such instances, however, informants would encourage proponents to establish an evidence base:If the public health need is serious and urgent enough, I will go for less well-established evidence. But if I do that, then I would push that somebody ought to be parallel with the implementation actually work on establishing the evidence base. In other words, I will use so called best-practices, so often anecdotal but then I would say to the proponents that you need to at least show me that you are working on this to establish its effectiveness or efficacy.To further the goal of increasing the percentage of EBP, many of our informants believed that clinical needs, rather than the interests of academics, should guide research, at least in organizations with clinical missions:[W]e're looking much more carefully at veteran centricity and applicability of what we do across all the services … [Y]es, we want to attract this wonderful investigator who does basic science research [but] … If they want to do research, they have it's got to be much more hands on and veteran centric.Ultimately, however, the informants saw the need for balancing the immediate needs of patients and the long-term scientific goals when setting research agendas:I think it has to be interactive and sometimes the process should be driven by the needs of the programme or policy, and sometimes it should be driven by the scientific opportunities that are ready for development. You know, I don't speak either/or … But, gee, you know, I'm just I think we have to use the evidence as well as we can to meet the real needs. It would be silly, I think, to do otherwise.Finally, policymakers argued that following a particular line of evidence blindly is unlikely to achieve sustainable QI. In other words, to remain faithful to the spirit of the QI initiative, health care organizations must listen and learn from the field, as well as the laboratory, and modify their practices accordingly:So in essence, you know, the way to sustain is to actually change. The way to maintain fidelity is actually to change what it means to be faithful … because I think some of the things that may actually represent lack of faithfulness to the intervention may actually be responses to needs that the original model didn't fit … I think it's very simplistic to say … fidelity means doing things just like in that trial. I mean, you could pick apart anything … even the studies that have been done … [V]ery few studies actually get into the level of the ingredients of the intervention and … what inside the black box is truly needed and how much of each of those things … [W]e … know … it's nice to lower LDL cholesterol. We actually really don't know to what level we should lower LDL cholesterol and necessarily how we should lower it.It did not surprise us that these VHA executive-level policymakers were strong proponents of EBP. As we mentioned earlier, VHA is a leader in promoting EBPs. Further, and as we also indicated, VHA's nation-wide network of medical centres is affiliated with medical schools and academic medicine has embraced EBP. Interestingly, although these policymakers generally believed that RCTs are valuable, they also believed that other forms of evidence, including qualitative evidence, can be useful. Additionally, they observed that it is not possible to conduct RCTs for certain types of treatments.The individuals that we interviewed, however, were also responsible for developing policy for and administering a large public health system. Thus, they had many concerns that were sometimes in conflict with strict adherence to an evidence-based approach. First, they believed that practices have to be practical in real world clinical settings. They also believed that practices have to fit with organizational values and with local circumstances. Further, they understood that as a government funded agency, VHA must respond to political pressures. These include addressing the needs of elected officials and the groups that lobby those officials. Finally and most importantly, they believed it is important to attempt to meet compelling patient needs. They were most concerned about conditions that affect large numbers of individuals or affect high-risk populations. When there was no clear evidence regarding how to address those needs, they believed health care organizations must turn to the art of medicine by using the collective wisdom of the field in the form of consensus-based best practices.What these policymakers seemed to imply is that just as it would be foolish to ignore research evidence when adopting clinical policies, it would be equally foolish to ignore practical concerns, values and the needs of health care consumers. For serious conditions that have no clear EBP, practitioners must alleviate suffering by using the art of medicine in the form of best practices. Further, if individuals do not seem to respond to the usual treatment, then clinicians must try something else. And even when following the evidence, we must realize that we are always refining what we know. The best practice is an ever-evolving one that makes the best use of science and art to provide the best care possible to many varied individuals. It is also one that makes reasoned and critical use of all the available information. Lewis may have put it best when he wrote:Where knowledge is definitive, rely on the algorithm; where knowledge is provisional and incomplete, redouble the scientific effort; where uncertainty looms large, engage the right side of the brain p. 171) [1 [7].All of this implies that those concerned with building the evidence base and those concerned with delivering patient care must work in concert, designing interventions that are broadly applicable to actual clinical practice –34. Rese


Evidence-based dermatology is the application of high-quality evidence to the care of individual patients with skin diseases. The Centre of Evidence-Based Dermatology in the UK promotes activities in this field through its three interlinking cogs, composed of the international Cochrane Skin Group, the UK Dermatology Clinical Trials Network (UKDCTN), and the UK national electronic library for skin disorders. The Cochrane Skin Group summarises what is already known about health care interventions by supporting systematic reviews of relevant randomized controlled trials (RCTs). The UKDCTN then addresses the key research gaps identified in systematic reviews by coordinating and carrying out well-designed RCTs. The Skin Disorders specialist library then plays a key role in disseminating new knowledge from systematic reviews and RCTs to a community of clinical users. The electronic resources at the Centre of Evidence-Based Dermatology are all freely available to Indian Dermatologists who can use the resources in a way that could benefit their patients. Such new knoweldge only has value if it is shared and used. It was my first visit to India, and I found it a moving, humbling and enjoyable experience, and I am sure it will not be my last [In 2008, it was a great honor for me to be invited by Dr. A.J. Kanwar and colleagues to visit the 36 my last . A numbeThis article is very much a personal reflection on how the work we do at the Centre of Evidence-Based Dermatology in the UK might be relevant and useful to colleagues in India. It is not a systematic review or an in depth critique of a body of literature, but simply a description of our work and how it might be applicable to dermatology, venereology, and leprology in India. I hope that the article does not sound patronising. There is one thing I have learnt from visiting other countries and that is that we share very similar problems – by that I mean our collective ignorance of how best to prevent and treat skin diseases. We all share the same challenge of translating new knowledge about skin disease treatment that is based on groups of patients participating in clinical studies to the particular circumstances of an individual with a skin problem who has come to you for help at that particular time. So rather than talk about countries and their differences, I am going to focus on what pulls us all together – our concern for improving the welfare of people with skin diseases.Put simply, evidence-based dermatology is the application of external high-quality evidence to the care of individual patients. It is a Evidence-based dermatology implies a hierarchy of evidence that starts with systematic reviews at the top with anecdotes and case reports at the bottom . It placEvidence-based dermatology is not a restriction on clinical freedom if one defines clinical freedom as the ability to do the best for one's patients as opposed to doing what you have been doing for the last 30 years simply because it has always been done that way. History is replete with examples of well-meaning doctors causing harm to their patients because of their failure to conduct RCTs and to then summarise those RCTs within systematic reviews. The use of oral corticosteroids for acute brain injury is a good example. The use of oral corticosteroids to reduce edema in acute brain injury was a standard practice until a very large trial showed that it was killing more people than it helped. The sameP-value reaches the “magic” P = 0.05 level, it follows that around one in twenty trial reports reaching that level of evidence will falsely claim a real difference when none really exist. Therefore, with around over 17,000 trials relevant to skin already published, there will be a lot of studies out there that claim an effect when the results are really due to the play of chance. That is why the Food and Drug Administration (FDA) requires two identical trials to be conducted for licensing purposes for a new drug in order to reduce the chances of a single false positive result. The tendency to selectively publish positive studies (publication bias) means that the results of single trials, even when large and published in prestigious journals, are frequently contradicted when the totality of subsequent evidence is considered.[Even though randomised controlled trials offer the best study design to minimise the risk of bias when evaluating the efficacy of a new treatment, one RCT is rarely enough for three reasons. The first is that a positive result could have simply arisen through chance. Given that most trial reports claim that the result is statistically significant if the nsidered. SystematTraditional expert reviews might sound appealing, but they frequently fail to mention important studies and they may be prone to selective citation to support the expert's prejudice simply because they have not been done in a systematic and explicit way. A systemCochrane Library relevant to dermatology. Some have criticised Cochrane reviews for always concluding that there is insufficient evidence to recommend anything. Whilst this might be true for a lot of skin conditions where the evidence has been characterising by lots of small, poorly reported studies, a recent review found that Cochrane dermatology reviews fond that clear clinical recommendations were made in around 40% of cases.[Cochrane Library, which also contains the largest database of clinical trials in the world and other useful methodological resources. And here is the most fascinating thing about the whole endeavour: During one of my talks at the 36th National Conference of the Indian Association of Dermatologists, I asked members of the audience about the Cochrane Library. Several had heard of it but none claimed to have access to it. Yet 10 minutes before that lecture, I tried accessing the Cochrane Library from a terminal at the meeting by typing in www.thecochranelibrary.org and found full access to the Cochrane Library that was completely free. So there is no excuse for not at least looking at Cochrane reviews because the Indian Government has made it possible to gain full and free access from any computer with an internet connection in India.It was the failure of the medical profession to systematically collate evidence from high quality randomised controlled trials that prompted the late Professor Archie Cochrane to challenge doctors to do something about it in the 1970s. The International Cochrane Collaboration was formed 25 years later in response to this challenge. The Cochrane Collaboration is a non-profit organisation of individuals that now contains over 50 review groups covering all aspects of human medicine. The Cochrane Skin Group  is one sof cases. CochraneSometimes, Cochrane systematic reviews come up with clear clinical messages on what should or should not be used in clinical practice . But moreThe UK Dermatology Clinical Trials Network (UK DCTN) was formed in February 2002 with the aim of conducting high quality, multi-center clinical trials that answer questions of importance to clinicians and patients. It involves a collaborative network of dermatologists, dermatology nurses, health services researchers, and patients throughout the UK and Southern Ireland. The Network is completely independent of the pharmaceutical industry. This should not be taken as meaning that the Network is against industry studies, but simply that dermatologists in the UK wanted to study questions that industry would never fund. These include trials of orphan skin diseases like pyoderma gangrenosum or studies of non-pharmacological interventions such as water softeners for childhood eczema or studies of low cost generic treatments like tetracyclines versus oral prednisolone for bullous pemphigoid – all funded studies that are currently being run through the UKDCTN. The UKDCTN is a registered charity that is run by a network manager, senior trials manager, and an administrative assistant. The organization is very democratic and accepts suggestions for new trials from all of its members. Those are then prioritized by a panel and developed into pilot studies and full funding applications. The UKDCTN took some time to get off the ground because it invested time in getting its structures and processes right, and now it is running five national studies . The UKDMuch of the philosophy and processes for setting up and running an organization like the UKDCTN could be replicated in India, and in time, there will opportunities for such similar organizations to take part in collaborative studies that require very large numbers of patients from all over the world.Producing lots of information is of little use unless it is filtered, organised, and made available for those working in clinical practice. Such is the purpose of the National Library of Health Skin Disorders Specialist Library – a one stop shop of quality information resources all in one place and kept up-to-date on a daily basis by a full-time information scientist based at our Centre of Evidence-Based Dermatology. At this The annual evidence updates deserve a special mention since they go beyond just organisation of information. Each year, the four topics of acne, skin cancer, eczema, and psoriasis are searched in detail by our information specialist for newly published systematic reviews or trials. The new resources are then listed according to whether they deal with causes, treatment type, or effects on quality of life. For each update, experienced clinicians then provide a commentary on what the evidence might mean for clinical practice as well as drawing attention to some of the methodological limitations and misleading aspects of the evidence found.Although the Skin Disorders Specialist Library is produced primarily with UK health care practitioners in mind, it is likely that most of the information will be useful for dermatologists in India. Comprehensive information is also available in the Infectious Diseases Specialist Library for those interested in sexually transmitted diseases.At first sight, the three main activities of the Centre of Evidence-Based Dermatology i.e., the Cochrane Skin Group, the UK Dermatology Clinical Trials Network, and the Skin Disorders Specialist Library may sound like three separate and independent activities. But nothing could be further from the truth because each work aspect drives the other like cogs working together in a machine . The syswww.ebderm.org, which our Centre helps to support. Those who want to do more, please consider joining the Cochrane Skin Group. The Cochrane Skin Group is a truly international group that holds annual meetings and training events.[Perhaps the best way that any colleague in India can contribute to evidence-based dermatology is to simply look at and hopefully use the information that our Centre helps to produce. The value of such knowledge is nil unless it used in the clinic. I hope that at least some of our output can be put to good use in clinical practice in India. Even though some of the material is less applicable to skin problems in India because of some differences in the disease spectrum, resources and culture, much of it will be relevant because there are more similarities between people around the world than there are differences. There are some good online resources for learning about evidence-based medicine that are listed on our homepage including dermatology's own g events. Some wilThen there are clinical trials. At the moment, the UK Clinical Trials Network is focused on delivering independent trials in the UK, but at some stage in the future we would like to extend collaboration to colleagues across the world if we can find suitable enthusiastic investigators and funding that will make such international studies possible. Perhaps in time, you will develop your own Centre for Evidence-Based Dermatology with a portfolio of independently produced resources that are chosen by you to be relevant to your needs. Good progress in this regard has already been made by Dr. S.R. Narahari and colleagues at the Institute of Applied Dermatology by their approach to researching Ayuervedic medicines in an integrated way. It is my


PLoS Medicine:This Perspective discusses the following new Policy Forum published in doi:10.1371/journal.pmed.1000094Kavanagh B (2009) The GRADE System for Rating Clinical Guidelines. PLoS Med 6(9): e1000094. Brian Kavanagh critiques the GRADE system of grading guidelines, arguing that even though it has evolved through the Evidence-Based Medicine movement, there is no evidence that GRADE itself is reliable.Evidence-based practice requires translating research findings into clinical and policy decision making. Clinical practice guidelines (CPGs) serve this purpose by evaluating evidence and making recommendations about therapeutic and diagnostic interventions and clinical management strategies. Systematic reviews are considered the best available evidence and are often used in the development of CPGs One such framework is the grading quality of evidence and strength of recommendations (GRADE), which is commonly used by guideline panels in deriving health care recommendations. GRADE was developed to overcome some of the deficiencies of earlier efforts PLoS Medicine, Kavanagh In a new Policy Forum published in this issue of It is arguable that guideline recommendations should be based on cost-effectiveness and opportunity cost analyses. These comparative economic analyses implicitly assume, and therefore do not question, that the allocated health care budget is based on sound evidence to influence guideline recommendations sensibly. In other words, the analyses are supposed to generate reasonable health care policies within a limited budget. However, the appropriateness of the health care budget itself is not established, a priori.Although the GRADE framework recognizes that guideline panels may legitimately ignore consideration of cost in terms of comparative resource use analysis in developing recommendations, the framework appears to recommend it. This recommendation would be more meaningful if there was accompanying evidence about the appropriateness of allocation of resources towards healthcare in general and a given healthcare discipline in particular.GRADE is flawed because some guideline recommendations are inconsistent with the evidence, or there is lack of clarity in how they were reachedInvalid guideline recommendations coming out of CPGs using the GRADE framework do not necessarily imply a problem with GRADE itself. The framework might have been used inappropriately. For example, lack of transparent reporting of how GRADE led to the recommendation, or poor judgment of the quality of evidence, importance of the outcomes for which evidence was found, or benefit-harm trade-offs may be misinterpreted as a flaw with GRADE. Sound use of the GRADE approach by guideline panels is only possible when they are multidisciplinary and include clinical content experts, methodologists, and patients' representatives and have no conflict of interest Quality of evidence alone determines the strength of recommendationThis is incorrect. Recommendations also factor in the potential impact or consequences of the available evidence. Therefore, using GRADE, low quality of evidence can lead to strong recommendation(s) occasionally. For example, evidence from a hypothetical short-term randomized controlled trial with serious risk of bias showing modest benefit of an intervention without serious harms on surrogate outcomes for a fatal infectious disease in a Chinese population might be considered of low quality for whites. However, in a situation of a pandemic, strong recommendation for the intervention in this population is plausible. Another example for a strong recommendation against a treatment may be that of cerivastatin, which was withdrawn from the market due to concerns of drug-related rhabdomyolysis and renal failure based on post-marketing surveillance data Changing guideline recommendations or their strength indicates inconsistency, a limitation of the frameworkThis is incorrect. Recommendations or their strength, or both, are likely to change if different grading frameworks are used over time. Kavanagh demonstrates this in his comparison of the SSC guideline recommendations developed in 2004 with its 2008 update. Furthermore, recommendations or their strength may change with newer and higher quality of evidence and with repeated more insightful guideline panel deliberations even with the use of one and the same framework, such as GRADE. Also, different guideline panels may come up with somewhat different strengths of recommendations based on the same body of evidence given variation in their clinical and socioeconomic settings and population of interest, and valued judgments. All the above-mentioned should not be grounds for claims that the GRADE is an inherently inconsistent framework that should be discarded.In our view GRADE should be considered not an instrument for which reliability and validity must be established but rather as a systematic and transparent framework generating recommendations from available evidence as opposed to recommendations originating in an unsystematic and implicit “feel” for it. This attribute of GRADE is a strong argument in favour of using it as it lays the process of translating evidence into recommendations open for scrutiny and criticism by peers and consumers thereby increasing public confidence in guidelines.GRADE-based recommendations, generated for specific population(s) and clinical setting(s), are widely applicableWe do not believe this to be true. As recommendations are specific to populations and clinical, cultural, and socioeconomic settings, they can be misapplied when these qualifiers are not explicitly and clearly linked to recommendations in summary of guidelines. For example, a recommendation of primary percutaneous coronary intervention in the management of acute myocardial infarction may be less effective than thrombolytic therapy in some developing countries where expertise in and infrastructure for interventional cardiology are lacking. As such, recommendations of guideline panels in developed countries should not be blindly adopted by developing countries without a formal evaluation and vice versa.Once a strong recommendation against an intervention is made as per the GRADE method, future research on it will be stifledWe believe this is incorrect. Recommendations based on the GRADE approach specifically apply to clinical and not research settings. As long as there is a reasonable rationale, future research on the intervention can continue Finally, we think that the GRADE framework needs continued discussion and possibly revisions. However, currently the framework is the best available approach to deal with the inherently implicit subjectivity involved in translating.


Clinical practice guidelines have been a popular tool for the improvement of health care through the implementation of evidence from systematic research. Yet, it is increasingly clear that knowledge alone is insufficient to change practice. The social, cultural, and material contexts within which practice occurs may invite or reject innovation, complement or inhibit the activities required for success, and sustain or alter adherence to entrenched practices. However, knowledge translation (KT) models are limited in providing insight about how and why contextual contingencies interact, the causal mechanisms linking structural aspects of context and individual agency, and how these mechanisms influence KT. Another limitation of KT models is the neglect of methods to engage potential adopters of the innovation in critical reflection about aspects of context that influence practice, the relevance and meaning of innovation in the context of practice, and the identification of strategies for bringing about meaningful change.This paper presents a KT model, the Critical Realism and the Arts Research Utilization Model (CRARUM), that combines critical realism and arts-based methodologies. Critical realism facilitates understanding of clinical settings by providing insight into the interrelationship between its structures and potentials, and individual action. The arts nurture empathy, and can foster reflection on the ways in which contextual factors influence and shape clinical practice, and how they may facilitate or impede change. The combination of critical realism and the arts within the CRARUM model promotes the successful embedding of interventions, and greater impact and sustainability.CRARUM has the potential to strengthen the science of implementation research by addressing the complexities of practice settings, and engaging potential adopters to critically reflect on existing and proposed practices and strategies for sustaining change. In recent years, knowledge translation (KT) and evidence-based medicine have gained currency in health research through emphasis on moving 'knowledge off the shelves and into practice, making it relevant and accessible to practitioners and patients' . ClinicaContrary to the view that best evidence can be disseminated across time and place and can achieve planned clinical behaviour change with reasonably predictable outcomes, a number of KT models have been developed to address the multiple and interrelated contextual interests, infrastructures, and procedures that are implicated in the adaptation of research to local health care practices ,6. CommoNotwithstanding these significant strengths, many of the existing KT models suffer from particular oversights. First, while they assert an interconnection between the elements of the process of research utilization, most commonly there is no theory embedded within the models to explicate how these elements are interconnected, or how these interconnections facilitate or impede research transfer and use. Despite notable consensus that the use of theory is crucial in the design and evaluation of implementation research ,6,10-12,A third oversight of KT models is that where effective translation strategies are identified -18, artsIn seeking to transcend these oversights without forsaking the strengths of existing KT models, we advocate the integration of critical realism and arts-based methodologies into KT models that can best inform implementation research in the context of health care settings . Such inCRARUM shares a basic premise with OMRU, namely, that bridging the gap between research and practice is best achieved through the optimization of intervention and adoption strategies. As with OMRU, this is accomplished through the identification of factors and processes in the practice environment that promote and/or impede the adoption of research, and the setting-specific modifications of barriers and supports. Integral to this goal is the systematic process of assessing, monitoring, and evaluating the following six elements of research utilization: the practice environment; potential adopters; evidence-based innovation; strategies for transferring evidence into practice; evidence use; and outcomes of the process. Where CRARUM departs from OMRU is in its introduction of critical realism ,28 into Additionally, as illustrated in Figure et al. [et al. [Research utilization scholars have identified organizational context and culture as important factors influencing research use ,12,32,33et al. , Estabroet al. , and Lom [et al.  have per [et al. ,38 and l [et al. ,39. Cult [et al. ,40. Orga [et al. ,41, whic [et al. ,38,40. R [et al. ,42. It iet al. [McCormack et al.  have empet al. , for creet al.  to effece.g., situated-change theory [e.g., planned behaviour [Clearly, contexts can invite or reject innovation, complement or inhibit the activities required for success, and sustain or alter adherence to entrenched practices . While te theory  and theoe theory ), or quiehaviour  and commehaviour  theoriesCritical realism, with its commitment to elucidating both the structures which constrain and enable activities, and how individual action reinforces, challenges, or transforms structural impingements, offers a promising way to remedy the tendency to either strip agency of structure or structure of agency. Critical realism has effectively been used to evaluate cardiac rehabilitation programmes  and diagi.e., that propositions may hold true only under certain circumstances). In the domain of the actual, there are many mechanisms concurrently active where some reinforce one another, and others frustrate the manifestations of each other. In this sense, it can only be said that a certain object tends to act or behave in a certain way [Critical realism furnishes a sophisticated understanding of context. In critical realism ,28, a ditain way .et al. [Danermark et al.  use the et al. . ConsequThe  mix of conditions and events  that characterize open systems, and whose unique confluence in time and space selectively activates  causal powers (mechanisms) in a chain of reactions that may result in very different outcomes depending on the dynamic interplay of conditions and mechanisms over time and space .In illuminating these aspects of context, critical realism is a perspective that is equally pertinent to program evaluation. Proponents of critical realist evaluation ,60 have For critical realists, agential capacity is not innate or static, but relational. It is activated in the mobilization of various forms of capital: social, cultural, and material/economic . Power ie.g., gender and race relations, management-labour relations). Contemporary neoliberal 'logics' of management practice  must figure prominently in any such discussion. This kind of managerialism [Power relations may be ubiquitous, but they are expressed in different ways in different settings, in part because other mechanisms are also at play which may be local manifestations of much broader processes  in ways that, by virtue of the underlying causal powers at play, have the ability to either enhance or undermine change initiatives. Critical realism proffers a view of evidence-based practice that concentrates on an elaboration of mechanisms and the logic of causation rather than a programme-based view of what works in terms of research-manipulated interventions and independent outcome measures. It is an approach to implementation evaluation   that, whMore is at stake here than an exhortation to be mindful of context as a kind of general backdrop for interventions. In seeking to understand how mechanisms play out in a particular setting, with particular agents at a specific time, we must also take account of how reflexive agents perceive, negotiate, unwittingly reinforce or selectively resist the effects of these broader trends and influences in the context of their own life biographies, socialization, and the micro-social context of peer relations in the workplace. Critical realism is a perspective that deems the creative tactics of individuals to deal with impingements in the social and material contexts of everyday life to be of equal importance to the social structures that furnish such impingements . Deep unDiverse disciplines, practices, and literatures have identified the problematic nature of engagement as a central issue for a myriad of professional practices. Taking agency seriously means finding ways to work with practitioners to help them understand their situation, examine their values, identify barriers and opportunities for change, implement solutions, and evaluate the results while never losing sight of the ways in which generative mechanisms operate to constrain and/or enable change in particular settings. This requires a more sophisticated approach to engagement and dialogue that draws in and works with the whole person in his or her 'multiple literacies' . This ise.g., publication of research findings), to targeting and tailoring the evidence and the message for a particular audience , to systematic efforts to encourage adoption of the evidence  [There can be considerable leeway for evidence to be (mis)interpreted, resisted, adapted, and even dismissed by potential adopters . It is tnctions) . There inctions) . The artLiterature and theatrical performance are increasingly being used as a means to humanize medical education . ShapiroNo Big Deal? [Dramatic performances have been successful in helping practitioners and medical trainees reflect on the care they provide and increase their understanding of patient care issues ,78,81. Fig Deal?  found exig Deal?  have simImprovisational theatre is an important form of drama that is influencing the way social and health scientists are incorporating drama into their research . Develope.g., reflective journals from students and informal discussions), and self-report questionnaires, qualitative methods are recommended to generate a rich data set for understanding how research-based drama operates as a KT strategy.By offering the potential to foster critical awareness, to facilitate understanding, and nurture sympathy, arts-based approaches are well positioned to strengthen initiatives that seek to transform health care. In a recent review of the literature on the use of research-based drama for KT , a numbeHow would CRARUM help to guide users in successfully implementing evidence into health care settings? Following the logic of critical realism, as a necessary first step, qualitative and quantitative methods of data collection can serve to identify causal generative mechanisms of existing care. These data reveal contradictions between espoused and enacted practice, and existing barriers to best practice. Elucidating the social, cultural, and material conditions under which practice occurs enables the intervention to be meaningfully individualized to the care setting. For example, understanding the context of long-term care would be critical when implementing an educational intervention for front-line dementia care practitioners about a patient-centred approach to care. Understanding how administrators and practitioners negotiate the potential paradox of front-line staff being mandated to provide patient-centred care, despite healthcare rationalization policies that constrain their ability to do so, would further inform the development of adoption strategies for facilitating the use of the new approach to practice. Moreover, because organizational hierarchies can limit practice change ,87, engaYet, tailoring interventions to better fit local settings alone is insufficient to achieve optimal care settings. The arts provide an innovative approach to the challenge of engaging practitioners to imagine new possibilities for more humanistic caregiving practices by helping practitioners to meaningfully connect with their care recipients . The usee.g., non-pharmacological approach to behavioural management in dementia care), but also the conditions that were present to enable those outcomes . Qualitative and quantitative data collection can inform understandings of what did/did not occur within the setting relative to the intervention, and which structural and agential factors influenced adoption of, or resistance to the intervention. Thus, in addition to answering whether the intervention works, critical realist evaluation facilitates understanding of why it worked, for whom, and in what circumstances.Critical realist evaluation of an intervention would take into account both the process and context of change. This entails an exploration of outcomes (KT, which is central to evidence-based medicine, has been identified as the most important contemporary initiative committed to reshaping biomedical reasoning and practice . While tGiven the inescapably interpretive dimension of evidence  and the Given the ascendancy of KT, CRARUM has the potential to make an important contribution to implementation research. Clegg makes a compelling argument for critical realism, with its underlying themes of critique and emancipation, in that it offers a distinctive approach to the debate about evidence-based practice . We go fThe authors declare that they have no competing interests.PK and BP developed the CRARUM model. PK is the lead author and coordinator of the paper. BP was involved in drafting the paper and revising it for inclusion of critically important intellectual content. Both PK and BP read and approved the final draft of the paper.