The purpose of this study was to survey how ID physicians view cranberry for UTI prevention.In a 2010 survey of 1000 ID physicians, we presented a case vignette about prevention of uncomplicated UTIs. “Ms. Smith is a 23 y.o. female who presents with a history of recurrent bacterial UTIs. In the past, she has self-treated with antibiotics at the first sign of infection; however she is now interested in preventing future occurrences. Previous work up has revealed no predisposing factors.” We also presented a research summary of an article demonstrating evidence of efficacy of cranberry extract for UTI prevention.The overall response rate for the survey was 31%. There were 292 responses for the question “Which ONE option best reflects your usual choice of initial management of UTIs in Ms Smith?”. Fifty-four percent of respondents chose antimicrobial prophylaxis, 29% chose cranberry, and 17% chose “other”. There were 298 responses for the question “Based on the research summary, how would you rate the comparative effectiveness of cranberry product versus trimethoprim for Ms Smith?”. The majority of respondents found cranberry equally (82%) or more (4%) beneficial. Five percent felt that cranberry was less beneficial and 9% felt that it was not at all beneficial. Finally, 301 participants responded to the question “Based on the information given, which ONE statement best characterizes your impressions about integrating cranberry products into the treatment plan for Ms. Smith?”. Almost half (49%) of respondents would consider using cranberry if the patient expressed an interest but only 22% would prescribe cranberry routinely. Twenty-five percent were not sure if they would use cranberry and 4% would not use cranberry.Despite acknowledgement of the comparative efficacy of cranberry versus antimicrobial prophylaxis, the majority of ID physicians are not willing to prescribe cranberry routinely.


Wandering spleen is a rare condition in which the spleen is not located in the left upper quadrant but is found lower in the abdomen or in the pelvic region because of the laxity of the peritoneal attachments. Many patients with wandering spleen are asymptomatic, hence the condition can be discovered only by abdominal examination or at a hospital emergency department if a patient is admitted to hospital because of severe abdominal pain, vomiting or obstipation. This article aims to provide a historical overview of wandering spleen diagnostics and surgical treatment supplemented with an analyses of articles on wandering spleen included in the PubMed database. One of the first clinical descriptions of a wandering spleen was written by Józef Dietl in 1854. The next years of vital importance are 1877 when A. Martin conducted the first splenectomy and in 1895 when Ludwik Rydygier carried out the first splenopexy to immobilize a wandering spleen. Since that time various techniques of splenectomy and splenopexy have been developed. Introducing medical technologies was a watershed in the development and treatment of wandering spleen, which is confirmed by the PubMed database. Despite the increased number of publications medical literature shows that a wandering spleen still remains a misdiagnosed condition, especially among children. The ancancholia . Over huancholia , whereasancholia , an inteancholia  expresseIn 1653, Panoralus . Even thIn the nineteenth century the spleen still remained a medical enigma. The authors of German anatomy atlases, Robert Foriep (1804–1861), a doctor and an artist who followed Italian lithographers, and Theodor Richter 1824–1898), who was helped by a professional illustrator, did not pay much attention to the spleen. Interestingly, such a rare phenomenon as a wandering spleen kept arousing enormous interest among physicians. A wandering spleen resulted in the characteristic dullness of lung sounds on percussion and was proved by palpation. The greatest authorities in medical science widely described the diagnosis of a wandering spleen, including the Scottish doctor and philosopher John Abercrombie (1780–1844), who wrote “Researches on the Diseases of the Intestinal Canal, Liver and other Viscera of the Abdomen” (Edinburgh 1838) and the most prominent member of the Vienna School, Carl von Rokitansky (1804–1878), who described the phenomenon in the course-book “Lehrbuch der patologische Anatomie” (Textbook on Morbid Anatomy) (Vienna 1846) [8, who waOne of the first case reports of a wandering spleen in a child was published in 1854 by the Polish physician Józef Dietl  , Wells  directly into a leukemic spleen. However, the results of these treatments were not disclosed [Following the example of a wandering kidney, which to the end of the nineteenth century any doctor without a special indication did not want to remove, in 1895 Ludwik Rydygier (1850–1920) operated to attach a wandering spleen to the peritoneum. This surgery, which he called splenopexy (following nephropexy), was based on fixation of the lower end of the spleen in a pocket made in the parietal peritoneum . In the Previous surgery course texts also taught splenorrhaphy, which is the suturing of the spleen for any purpose . At the Attempts to explain the spleen’s importance for life were made by conducting physiological experiments on animals. In 1735 Deisch proved that dogs could live even though they had their spleens removed. He removed the spleen by means of various surgical techniques, which in his opinion would become useful in the clinical setting . SpecialSuch extraordinary spleen characteristics led Erwin Payr (1871–1946) to become interested in the spleen. In 1906 he presented to the German Surgeons’ Congress the results of experiments which referred to implanting fragments of the thyroid gland into a pouch made in the spleen into animals surgically deprived of thyroid; next, omentum was stitched over the splenic wound. Several days later the animals in the control group had their spleen with implemented fragments of thyroid gland removed, which resulted in tetanus and immediate death. Payr used these observations to treat a six-year-old girl diagnosed as a cretin and unsuccessfully treated her with thyroid tablets. He then took a sample of thyroid from the girl’s healthy mother and placed it in the girl’s spleen, which resulted in a considerable improvement in the child’s health. Similar experiments were carried out by William Halsted (1852–1922) .These experiments were of clinical importance, yet determination of the function of the spleen remained unresolved Fig. . This imAschoff and Landau’s work was of significant value for surgeons who for many years had been observing the fact that a relatively small amount of postoperative bleeding followed removal of the spleen. The examination of blood composition before and after splenectomy indicated a significant postoperative increase in the number erythrocytes and blood platelets. Spleen surgery turned out to be an underlying topic at the International Surgical Congress held in Rome in 1926. Discussions started about accessory spleens, which appeared to number several hundred in one patient, some of them the size of a walnut. Patients who underwent reoperation after splenectomy sometimes had a diagnosis of enlarged splenules; what is more, it was proved that splenules took over the functions of a removed spleen .The introduction of medical technologies represented a watershed in surgery for wandering spleen, which is confirmed by analyses of the PubMed database. Before the era of such medical technologies as isotopic imaging and angiography, the diagnosis of the torsion of a wandering spleen was difficult. Hence, in 1925–1976, publications related to this issue came out on average 0.34 times a year. In 1977–1997 publications referring to wandering spleen torsion appeared on average 3.45 times a year, and by 1998–2011, when laparoscopy became the gold standard in wandering spleen surgery, publications increased to 8.42 times per year.Twentieth century medicine described wandering spleen in patients ranging from 3 months to 82 years . AccessoAt present wandering spleen is defined as an ectopic spleen that moved from its normal anatomical location because of congenital anomalies of the dorsal mesogastrium and the absence or malformation of normal splenic suspensory ligaments . VariousThe symptoms of abnormal spleen location with torsioned pedicle are splenomegaly and hemoperitoneum. Immediate splenectomy offers very good results in this a life-threatening condition, which occurs in no more than 0.2 % of cases . Since 1Since 2000, splenopexy has been carried out laparoscopically if the wandering spleen is healthy and noninfarcted, is of normal size, and has no signs of hypersplenism. The literature describes the sandwich technique, in which two meshes are used to sandwich the spleen .To 2007 the literature indicates almost 500 cases of wandering spleen  diagnose


The World Health Organization (WHO) Department of HIV/AIDS led the development of public health guidelines for delivering an evidence-based, essential package of interventions for the prevention and treatment of HIV and other sexually transmitted infections (STIs) among men who have sex with men (MSM) and transgender people in the health sector in low- and middle-income countries. The objective of this paper is to review the methodological challenges faced and solutions applied during the development of the guidelines.The development of the guidelines followed the WHO guideline development process, which utilizes the GRADE approach. We identified, categorized and labeled the challenges identified in the guidelines development process and described the solutions through an interactive process of in-person and electronic communication.We describe how we dealt with the following challenges: (1) heterogeneous and complex interventions; (2) paucity of trial data; (3) selecting outcomes of interest; (4) using indirect evidence; (5) integrating values and preferences; (6) considering resource use; (7) addressing social and legal barriers; (8) wording of recommendations; and (9) developing global guidelines.We were able to successfully apply the GRADE approach for developing recommendations for public health interventions. Applying the general principles of the approach while carefully considering specific challenges can enhance both the process and the outcome of guideline development. The human immunodeficiency virus (HIV) epidemic is disproportionately affecting men who have sex with men (MSM) and transgender people in low- and middle-income countries,2, as weThe WHO Department of HIV/AIDS was charged with the development of guidelines for delivering an evidence-based, essential package of interventions for the prevention and treatment of HIV and other sexually transmitted infections (STIs) among MSM and transgender people in the health sector in low- and middle-income countries.WHO’s guideline development process uses thehttp://www.gradeworkinggroup.org/).GRADE presents a systematic and transparent framework for clarifying questions, determining the outcomes of interest, summarizing the evidence that addresses a question, and moving from the evidence to a recommendation or decision-14. AddiA core working group consisted of community representatives, content experts, systematic reviewers and a guideline methodologist. The group initially drafted specific guideline questions following the PICO format . For eacThe core working group held three face to face working meetings in preparation for the final consensus meeting. For the final consensus meeting, the core working group developed for each PICO question a decision table summarizing judgments about: the quality of evidence, the balance of benefits and harms, values and preferences, resource use, and feasibility  and hepatitis A and B vaccination;4. Periodic testing for asymptomatic STIs and STI syndromic management;5. Behavioral interventions ;6. HIV testing and counseling;7. Use of outreach, social marketing and the internet to reach target constituencies;8. Complementary mental health interventions to address substance use, and harm reduction programs among injection drug users and among transgender people who undertake gender enhancement procedures involving the injection of substances.The core working group conducted discussions of methodological challenges through email communications and during the three working meetings and the final consensus meeting. We subsequently identified, categorized and labeled the identified challenges. We then finalized through an interactive process of in-person and electronic communication the solutions to these challenges along with illustrative examples from the guidelines.We defined public health interventions as those targeting policymakers or public health professionals as well as affected populations, and are implemented in the form of programs. These include biomedical, behavioral, structural, and health system interventions. Clinical interventions target individual health consumers and their clinicians, are implemented by individuals, and consist mostly of biomedical interventions. Some biomedical interventions  can be implemented both as a public health intervention  and as a clinical intervention .We have identified the following nine challenges: 1) heterogeneous and complex interventions; (2) paucity of trial data; (3) selecting outcomes of interest; (4) using indirect evidence; (5) integrating values and preferences; (6) considering resource use; (7) addressing social and legal barriers; (8) wording of recommendations; and (9) developing global guidelines. We discuss below and summarize in Table heterogeThe nature of public health interventions differs from that of most clinical interventions in a number of respects. While clinical interventions can be heterogeneous, complex and used in combination, public health interventions tend to possess these characteristics more frequently and to a larger degree.We frequently identified heterogeneity in the characteristics of interventions evaluated in studies. For example, studies examining group behavioral interventions varied in the number of participants per group, in the number of sessions, and in the topics discussed .a priori based on whether they were implemented at the individual, group or behavioral level. We faced similar difficulties with the reviews of sex venue-based interventions, social marketing campaigns, and Internet-based targeted interventions.Our challenge was to decide whether these interventions were similar enough to consider  these studies together, and to ultimately issue one or multiple recommendations. In the case of behavioral interventions, we classified them Many public health interventions are implemented in combination with other interventions because of their assumed synergistic effect. For example, counseling interventions are implemented along with HIV testing to improve understanding and behavior change. In the field of HIV, this has been recently discussed as combination HIV prevention,21. FurtFor global guidelines, it is not practical to issue recommendations for all possible combinations of interventions, and it is very unlikely that studies addressing all different combinations exist. Our approach was to consider separately each individual intervention to the extent that the available evidence allowed this. The aim was to provide a menu of effective individual interventions for policymakers to choose from according to their local conditions and need. The main limitations to this approach are potentially missing any synergistic effect, and dealing with evidence assessing combinations of interventions.Another methodological challenge associated with the evaluation of these interventions is the risk of contamination  and the need for cluster randomized trials. Also, tThe scarcity of trial data and using non-trial data were a matter of debate during our guideline development process, as they have been for others involved in guideline development.The evidence for all but four questions came from observational studies resulting, according to the GRADE approach,  for public health questions might be either challenging , or impossible . Therefore, they felt that the available evidence from non-randomized studies should be rated higher-28.However, the fact that the best available evidence comes (or could only come) from observational study designs does not automatically imply that these designs provide high quality evidence. Indeed, reasons for which we have less confidence in these designs relative to RCTs are valid irrespective of whether trial data is (or could be) available. In addition, observational studies could potentially provide “moderate” and even “high” quality evidence within the GRADE framework. For exaPanelists may have been uncomfortable with the low rating of the quality of evidence because it would likely lead to a weak recommendation. There was a concern that policymakers may use both “low quality evidence”  and “weak recommendations” as excuses to forgo the implementation of the recommendation. Please refer to challenge (8) on how we used wording of recommendations to address these concerns.Although GRADE stipulates that trial data provide the least-biased evidence for the effects of interventions, it does consider other types of studies. Firstly, it considers observational studies for assessing 1) the long term and rare effects of interventions, and (2) the effectiveness data in the absence of trial data, which – as discussed above – may lead to moderate or high quality evidence . In order to achieve these goals, we developed an outcome framework for each question or group of related questions  behavioral change, 2) HIV acquisition and transmission, and (3) morbidity and mortality , the panel dealt with the indirectness of the population and of the setting, a concept also known as applicability. AlthougAs to the setting, for many PICO questions, the available evidence came solely from high-income countries. The judgment of the degree of indirectness depended on the intervention. For example, the panel judged that the evidence about the effect of condom use on HIV infection is not indirect enough when applied to low-income countries to warrant downgrading the quality of evidence. Conversely, the panel judged that the evidence about the effects of serosorting on HIV infection is indirect enough to warrant downgrading the quality of evidence, because the practice of serosorting requires regular high-quality and easily accessible HIV testing, re-testing and counseling that is frequently not available in low- and middle-income countries. Guideline panels may use more formal approaches to judging applicability.In the GRADE framework, the values and preferences of the target population are a major factor in determining the direction and strength of recommendations. For theThe above approach of integrating values and preferences of the target population has resulted in the guidelines taking the perspective of MSM and transgender people. The advantages of that approach include improving the quality of the guidelines, and increasing their chances of acceptance and implementation by the MSM and transgender communities. One disadvantage is a potential inconsistency of some of the recommendations with differing set of values and preferences in certain settings.Resource use is one factor that is considered in determining the direction and strength of recommendations in the GRADE framework. ResourcDiscrimination, stigma, punitive laws and law enforcement practices are major barriers for MSM and transgender people in accessing health services-43. ThisGood practice recommendations are typically those in which desirable effects undoubtedly outweigh any undesirable ones so that conducting a study addressing the implicit question could not be justified. Indeed,Here are the two good practice recommendations included in the guidelines:We recommend making health services inclusive of men who have sex with men and transgender people, based on the principles of medical ethics and the right to health.We recommend that legislators and other government authorities establish anti-discrimination and other protective laws, derived from international human rights standards, in order inter alia to eliminate discrimination and violence faced by men who have sex with men and transgender people, and reduce their vulnerability to infection with HIV and the impacts of HIV and AIDS.Guideline panels present their judgments about the quality of evidence and strength of recommendations using specific wordings of the recommendation statements and affixing grades to these statements . UnfortuGRADE initially suggested to use the words ‘strong’ and ‘weak’ to characterize the strength of recommendations. It has The potential advantage of the term ‘conditional’ is that it invites the user of the recommendation to consider the implications of that term. ‘Conditional’ can have four possible implications (or combinations of these), depending on which factor(s) affected the strength and/or direction of the recommendation , and the implications of an intervention  often vary substantially across settings.In order to address this challenge, the survey of values and preferences recruited participants globally. We prioritized evidence of effectiveness and of incidence of outcomes from low- and middle-income countries when available. Also, the panelists were asked to prioritize perspective of low- and middle-income countries when making judgments about values and preferences, feasibility and resource use.We identified and addressed a number of challenges during the development of WHO guidelines for the prevention and treatment of HIV and other STIs among MSM and transgender people in the health sector in low- and middle-income countries. While some of these challenges might be particularly relevant to public health guidelines  others are common to most guidelines . Consequently, the learning experience from this guideline may benefit other fields.We were able to address most of these challenges  through using the principles of the GRADE approach. The use of good practice recommendations and outcome frameworks proved to be particularly useful. Successfully overcoming some of the other challenges  requires further research in the field. Some other challenges require further methodological advancement . The GRADE working group has been committed to and engaged in this process.By requiring guideline developers to be systematic, explicit, and transparent in the assessment of the quality of evidence, and in determining the strength of recommendations, GRADE uncovers challenges such as those discussed in this paper. Indeed, these challenges relate to the quality of available evidence and to the complexity of guideline development process. The GRADE framework continues to evolve to address some of the issues specific to the field of public health.One perceived limitation of the GRADE approach is its involved handling of the evidence. However, the involvement of a GRADE methodologist and the incremental learning by the members of the core working group have played a positive role. Also, using evidence profiles and decision tables to summarize the information should facilitate this process.Finally, the GRADE approach can assist in resource mobilization. Indeed, the representative of one of the major funding bodies in the field declared at the end of the meeting that their future funding, and as a result of the rigorous process, will now take into consideration patient important outcomes such as quality of life and actual incidence of HIV, instead of reported behavioral change.We were able to successfully apply the GRADE approach for developing recommendations for public health interventions. Applying the general principles of the GRADE approach while carefully considering challenges specific to the field of public health can enhance both the process and the outcome of guideline development. Such an approach has the potential to move forward both the public health practice and research.Finally, the process highlighted the need for more research both in the subject area  and in the methodological area .Elie Akl, Tara Horvath, and Holger Schünemann are members of the GRADE working group.EAA, CK, KK, CFC, TH, GA, AD, AG, CSW, ERS, HJS, YRL made substantial contributions to conception and design of the manuscript, and to the analysis and interpretation of data. EAA drafted the manuscript. EAA, CK, KK, CFC, TH, GA, AD, AG, CSW, ERS, HJS, YRL revise the manuscript critically for important intellectual content and have given final approval of the version to be published.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2458/12/386/prepubAppendix 1. Definition, categories, and factors affecting the quality of evidence.Click here for fileAppendix 2. Definition, categories, wording, factors affecting, and implications of the strength of recommendation.Click here for fileAppendix 3. Examples of an evidence profile and of a decision table.Click here for file


Foot ulcers in people with diabetes are a common and serious global health issue. Dressings form a key part of ulcer treatment. Existing systematic reviews are limited by the lack of head-to-head comparisons of alternative dressings in a field where there are several different dressing options. We aimed to determine the relative effects of alternative wound dressings on the healing of diabetic foot ulcers.This study was a systematic review involving Bayesian mixed treatment comparison. We included randomised controlled trials evaluating the effects on diabetic foot ulcer healing of one or more wound dressings. There were no restrictions based on language or publication status.Fifteen eligible studies, evaluating nine dressing types, were included. Ten direct treatment comparisons were made. Whilst there was increased healing associated with hydrogel and foam dressings compared with basic wound contact materials, these findings were based on data from small studies at unclear or high risk of bias. The mixed treatment comparison suggested that hydrocolloid-matrix dressings were associated with higher odds of ulcer healing than all other dressing types; there was a high degree of uncertainty around these estimates, which were deemed to be of very low quality.These findings summarise all available trial evidence regarding the use of dressings to heal diabetic foot ulcers. More expensive dressings may offer no advantages in terms of healing than cheaper basic dressings. In addition, evidence pointing to a difference in favour of ‘advanced’ dressing types over basic wound contact materials is of low or very low quality.The online version of this article (doi:10.1007/s00125-012-2558-5) contains peer-reviewed but unedited supplementary material, which is available to authorised users. Foot ulcers in people with diabetes are a common, serious and costly global health issue . In 2007Dressings are widely used in wound care, with the aim of protecting and managing the wound and promoting healing. Several dressing types are available to treat complex wounds such as diabetic foot ulcers. We present a brief overview of dressing options using BNF-derived categories   with theTo date, all previous reviews are limited by the lack of direct, head-to-head comparisons of alternative dressings in a field in which there are many dressing options. Thus, we aimed to evaluate the effects of alternative wound dressings on the healing of foot ulcers in people with diabetes by synthesising all available randomised controlled trial (RCT) evidence. As well as employing standard meta-analytical techniques for head-to-head comparisons we conducted a mixed treatment comparison (MTC) , 10, whiFurthermore, while there is growing interest in the conduct of MTC and the value of resulting data for clinical decision making, there is currently no established method of appraising and presenting the quality of MTC estimates. Quality assessment tools such as Grading of Recommendations Assessment, Development and Evaluation (GRADE) are available for standard pair-wise meta-analysis ; GRADE aThis review was based on a pre-specified protocol . We planOur primary outcome was ulcer healing, measured using time to healing and/or number of ulcers completely healed within a specific time period .The search string for CENTRAL . Results were reported with 95% credible intervals (CrIs)—the Bayesian equivalent of CIs, reflecting the uncertainty surrounding estimates. Unlike 95% CIs, 95% CrIs can be interpreted as: the (posterior) probability that these limits contain the parameter mean is 95%. Fixed and random effects models were considered and model fit assessed using the posterior mean of the residual deviance and the deviance information criterion (DIC).Where head-to-head (direct) treatment comparisons were reported in one trial only, ORs and 95% CIs were calculated. Where direct comparisons of dressings were available from more than one trial, appropriate standard meta-analyses (using ORs) were undertaken using Winbugs . To provide a complete overview of the spread of decision uncertainty around the choice of a ‘best’ treatment we then presented the probability of each treatment being the second best treatment and the third best and so on. Alternatively, this can be conceptualised, for each treatment, as a cumulative probability at each rank, summarised numerically as a surface under the cumulative ranking (SUCRA) for each treatment . Thus, ap value for this test presented. We also extended the analysis to include an inconsistency model, which omitted consistency equations. Finally, potential inconsistencies between our direct and MTC estimates were also assessed by qualitatively comparing estimates of standard meta-analysis (direct) and MTC (direct and indirect). See When direct and indirect evidence exists (i.e. a loop of evidence in the network diagram), inconsistencies between the ORs and intervals of these two sources may arise. We formally assessed for inconsistencies using the back calculation method suggested by Bucher et al , 19. Brin − 1 for each analysis) and investigated the impact on the probability of which treatment was ‘best’.We evaluated the sensitivity of the network to individual trials; where links were informed by more than one trial, we removed each trial one at a time  to allow us to access and communicate the quality of this MTC-derived evidence. We worked with the five categories in GRADE that allow the quality of evidence to be decreased; however we altered the focus of some categories so they were relevant for assessing an MTC  flowchart is presented in Fig. In terms of risk of bias, four included studies were deemed to be at high risk of bias , 24, 33.A summary of the network of dressing trials that measured healing in participants with diabetic foot ulcers is illustrated in Fig. There was evidence that hydrogel dressings were associated with significantly higher odds of ulcer healing than basic wound contact dressings  , thus the least complex model, given the limited data available for analysis, was applied.There was a high degree of uncertainty in the many links in the network, especially those that were not informed by direct data Table . EvidencA valuable feature of Bayesian methods is the ability to illustrate the impact of uncertainty on decision making by assessing the probability that each dressing treatment included in the network is the best in terms of ulcer healing. Notably, the treatment associated with the greatest probability of healing was hydrocolloid-matrix  included studies were performed and the probability of each dressing being the best was assessed. Basic wound contact layer, alginate, fibrous hydrocolloid, impregnated-iodine, and silver fibrous hydrocolloid dressings continued to have very low, or no probability of being the ‘best’ treatment in any sensitivity analysis. Hydrocolloid-matrix remained the most likely ‘best’ treatment in ten of the 11 analyses , iodine-impregnated and protease-modulating dressings are more effective than basic wound contact materials in terms of ulcer healing. Thus, in the generally non-complex wounds studied, there was no evidence of a difference in healing between more expensive dressings compared with cheaper alternatives, nor between antimicrobial/antiseptic dressings and non-antimicrobial/antiseptic dressings.Conversely, evidence pointing to a difference in favour of ‘advanced’ dressing types over basic wound contact materials is of low or very low quality. Thus for dressings such as hydrocolloid-matrix, we can only conclude that there is no high quality evidence to suggest that this dressing type is more effective than any other, or alternatively that any evidence suggesting that hydrocolloid-matrix dressings are more effective in healing diabetic foot ulcers is at high risk of bias.The findings presented result from analysis of the most comprehensive evidence base available from across the world regarding the effect on healing of dressings to treat diabetic foot ulcers. While some may argue that the presence of sparse data should preclude any statistical synthesis of the evidence, we counter that clinicians cannot postpone treatment selection until high quality evidence has accumulated. Furthermore, comprehensive evidence synthesis highlights to researchers and clinicians the state of the current evidence base and its limitations as well as signposting where future research might focus. A further strength of this study is the application of an exploratory framework based on GRADE to undertake quality assessment of MTC estimates and the presentation of findings in light of this assessment.We do acknowledge that there are limitations in synthesising sparse data, particularly in preventing further exploration of the potential impact of heterogeneity, for example length of trial follow-up. However, it is important to note that this is an issue for several evidence synthesis projects in wound care where data are sparse and follow-up times vary. In other networks, this has been dealt with by assuming a constant hazard of healing over time—although this assumption is potentially also not valid. In general, the limited evidence base prevented the application of a random effects model, however, we acknowledge that in other situations this type of model may be more appropriate than a fixed effects approach.We have developed and employed a preliminary framework for quality assessment of MTC evidence based on GRADE. In this example, we aimed to assess the feasibility and highlight potential challenges of applying quality assessment to MTC evidence. We note, however, that our modified approach has not been validated and is not recognised by GRADE.It may be that other tools, rather than GRADE, would provide a better starting point for assessing the quality of MTC outputs. For example, GRADE’s remit extends to guiding clinical- and policy-level decision making, which are less relevant to MTC assessment. At the very least within our modified approach there are still several areas that need addressing, emphasising future challenges in developing such a scale: for example indirectness as a characteristic of the evidence is not easy to apply to MTC (as indirect data is a common feature that should not necessarily result in downgrading) and is perhaps more appropriately referred to as ‘inconsistency’ in this context. However, in standard GRADE, the term ‘inconsistency’ relates to unexplained heterogeneity. Within iGRADE we considered unexplained heterogeneity and inconsistency (the MTC-related meaning) together in one category. We then added a separate category that assessed the impact of sensitivity analysis on results. Our aim here was to assess the stability of the network and thus its estimates. Finally, imprecision could perhaps be omitted from this tool as it may be more useful for the reader to use their own judgement regarding the width of CrIs and what they mean. Quality assessment of MTC output is a complex area and further research is required; however, we emphasise that, currently, this work is the only example of formal quality assessment of MTC outputs.These findings comprehensively summarise all trial evidence available to decision makers regarding the use of dressings to heal diabetic foot ulcers. This highlights that more expensive dressings may offer no advantages in terms of healing than cheaper, basic dressings. The work also highlights the risk of bias in some studies and how this can impact on interpretation of MTC findings.The work provides a platform from which to consider future research. Given the large number of dressing options available to clinicians , the design of any future studies should be driven by those questions regarded as high priority by decision makers and patients, and potentially guided by the data presented here. Finally, the analysis conducted here highlights that concerted efforts should be made in wound care, as in other fields, to utilise health professional and participant time only in the production of useful and valid research data.ESM Table 1PDF 10 kbESM Table 2PDF 52 kbESM Table 3PDF 81 kbESM Table 4PDF 55 kbESM 1PDF 126 kbESM Fig. 1PDF 185 kbBelow is the link to the electronic supplementary material.


We conducted a comparative review of clinical practice guideline development handbooks. We aimed to identify the main guideline development tasks, assign weights to the importance of each task using expert opinions and identify the handbooks that provided a comprehensive coverage of the tasks.We systematically searched and included handbooks published (in English language) by national, international or professional bodies responsible for evidenced-based guideline development. We reviewed the handbooks to identify the main guideline development tasks and scored each handbook for each task from 0 (the handbook did not mention the task) to 2 (the task suitably addressed and explained), and calculated a weighted score for each handbook. The tasks included in over 75% of the handbooks were considered as ‘necessary’ tasks.Nineteen guideline development handbooks and twenty seven main tasks were identified. The guideline handbooks’ weighted scores ranged from 100 to 220. Four handbooks scored over 80% of the maximum possible score, developed by the National Institute for Health and Clinical Excellence, Swiss Centre for International Health, Scottish Intercollegiate Guidelines Network and World Health Organization. Necessary tasks were: selecting the guideline topic, determining the guideline scope, identifying relevant existing guidelines, involving the consumers, forming guideline development group,, developing clinical questions, systematic search for evidence, selecting relevant evidence, appraising identifies research evidence, making group decision, grading available evidence, creating recommendations, final stakeholder consultation, guideline implementation strategies, updating recommendations and correcting potential errors.Adequate details for evidence based development of guidelines were still lacking from many handbooks. The tasks relevant to ethical issues and piloting were missing in most handbooks. The findings help decision makers in identifying the necessary tasks for guideline development, provide an updated comparative list of guideline development handbooks, and provide a checklist to assess the comprehensiveness of guideline development processes. The Institute of Medicine, in 1990, defined the clinical practice guidelines as ‘systematically developed statements to assist practitioner and patient decisions about appropriate health care for specific clinical circumstances Several countries have adopted the pro-active policies of guidelines development at the national level. These national programs are developed in response to the perceived (and observed) uncertainties in the quality of the published guidelines The first national programs of guideline development started in the USA in the 1980s and in several other high income countries in the 1990s The methodologies followed in guideline development programs varies. Burgers et al. (2003) conducted a survey on 18 clinical guideline programs produced in the USA, Canada, Australia and 9 European countries. They observed that the more recent programs were benefitting from the methodology created by the older ones. They also recommended that the programs should put further emphasis on the dissemination and implementation of the guidelines As part of a wider initiative to design a program for the development of clinical guidelines at a national level in Iran we assessed the methods and approaches adopted by established guideline development programs around the world We systematically searched Pubmed and TRIP databases using general sensitive terms representing ‘clinical guideline development handbooks’. We also searched the Google using similar terms, aiming for the most popular handbooks (i.e. appearing on the first ten pages of Google search outputs) and literature published in English language and available on the net. We also contacted the experts and searched the reference lists of the identified literature and handbooks.We included documents (‘handbooks’) produced by national or international organizations responsible for clinical guideline development and also professional and academic bodies working on guideline development. These handbooks may have been produced for the purpose of developing clinical guidelines in general, or targeting guidelines for specific clinical conditions. We only included those handbooks that were focused on the development of evidence-based guidelines.Initially, we had planned to extract the main tasks of guideline development from NICE handbook To determine other tasks not specified in NICE handbook, we first screened fifteen identified guideline development handbooks and designed an inclusive list of the tasks. The list was discussed and revised in a few meetings to ensure consensus was achieved. Other relevant ‘tasks’ were added as a result of elaborating on the task list . Finally, the tasks were re-ordered to ensure a logical flow existed, and in cases, re-phrased to reduce potential misinterpretations.We prepared a web-based questionnaire (using Google Document), and invited nineteen experts in the field  from seven different countries to respond to the questionnaire. We asked the participants to weigh each guideline development task on a 6-point scale from 0 (not important) to 5 (very high importance). We then used the median of the scores given to each task as the task ‘weight score’.Then two authors independently reviewed each handbook and compared its elements against the task list. Each handbook was scored for each task from 0 to 2 based on the following criteria:2, if the handbooks addressed the task and provided enough information to suggest the task was given serious attention1, if the handbook briefly (or just) mentioned the task0, if the handbook did not appropriately mention the taskAll disagreements about the scores were resolved through discussion between the authors. We considered, a priori, any task that was at least mentioned (i.e. scoring 1 or 2) in 75% of the handbooks was a ‘necessary’ task for evidence-based guideline development. We also considered the tasks as ‘relevant’ if they were mentioned in a minimum of three handbooks.Then the scores given to each task for each guideline was multiplied with the task weight scores, and summed up to calculate the guideline’s total score. For each guideline we also calculated the percentage of the maximum score that was achieved by the guideline.In total twenty seven main guideline development ‘tasks’ were noted and considered in this review . NineteeWe asked the experts about any other tasks that should have been included in the list. Four experts offered additional suggestions. Some of the suggestions had been adequately addressed in the task list .We identified nineteen guideline development handbooks published in English language . Twelve The handbooks were published within the period from 1994 to 2012. The guideline development handbooks’ raw scores ranged from 22 to 50 (out of a maximum of 54) and the weighted scores ranged from 100 to 220 (out of a maximum of 236). Four handbooks achieved over 80% of the maximum possible score NICE All the tasks were mentioned in at least three handbooks . We defiSelecting the guideline topic was addressed in all of the handbooks. For example the CE handbook stated: “prioritization of guideline topics may be based on the epidemiology of health problems, health inequalities, variations in the provision and quality of care, emergence of new technologies, or other factors that create a need for high quality, updated information” determining the guideline scope, and thirteen handbooks provided enough information for a clinical guideline developer to understand how to complete that task. The NICE handbook asserted that “the scope provides a framework within which to conduct the development work. Its content briefly describes the background epidemiology relevant to the disease or condition and defines the aspects of care that the guideline will cover in terms of: population to be included or excluded, healthcare setting, interventions and treatments to be included and excluded.” Seventeen of the nineteen handbooks mentioned work plan should be prepared. Four handbooks just mentioned the task; the rest did not address it. “A key step in the conduct of ASCO guidelines is completion of the clinical practice guideline development protocol worksheet. The worksheet specifies the purpose of the guideline, the target patient population and clinical outcomes of interest, key features of the systematic literature review, and a proposed timeline for guideline completion.” Eight handbooks provided clear guidance on the way in which the Identifying relevant existing guidelines was mentioned in fifteen handbooks, appraising relevant existing guidelines in thirteen handbooks, and adapting relevant existing guidelines in fourteen handbooks. ACHR states “in addition to supporting appropriate adaptation of its own guidelines, WHO should consider adapting guidelines developed by other organizations, given the potential value of WHO endorsement and savings, if high quality guidelines already exist … given WHO’s mandate; limited resources that are available to develop high quality guidelines that are informed by the best available evidence, particularly in low and middle income countries; and the potential to reduce unnecessary duplication, WHO should continue to develop international guidelines. However, these guidelines will often require adaptation and tailoring to local contexts:” involving consumers in some way, and ten handbooks provided clear guidance. To clarify the objectives and benefits of involving consumers, NZGG handbook stated: “the following objectives are needed to achieve the guiding principles: partnership and collaboration, democratic participation, equity and fairness, accountability, acceptability, to ensure the rights of consumers are upheld, to ensure consumer input is valued” All except two handbooks addressed Forming a guideline development group was mentioned in all of the handbooks and most had clear guidance, but they varied in their proposed methods for selecting the members, size of the group etc. As SCIH handbook focused on the development of health system guidance, it recommended the following composition for the guidance development groups: “expert(s) in health systems, expert(s) in the topic of the guidance, expert(s) in research synthesis and in knowledge translation, representatives of stakeholders, representative of potential users” conflict of interests and all fourteen handbooks explained it clearly except one. For example: “all experts participating in WHO meetings must declare any interest relevant to the meeting before their participation. In the case of guideline development this means that all members of the guideline development group and the expert review panel, as well as any other experts or advisers invited to guideline development meetings, should fill in a declaration of interests form.” Fourteen handbooks addressed managing Running guideline development group is mentioned by fourteen handbooks and twelve handbooks offered clear guidance. The NICE handbook stated: “running the guideline development group is the responsibility of the national collaborating center, in consultation with the Chair. Core responsibilities for all meetings include: setting meeting dates, planning agenda items, sending out papers, keeping records of all meetings and ensuring that all GDG members have a copy of the current guidelines manual” developing questions and twelve handbooks described it in detail. NICE, SCIH, SIGN and WHO provided clear guidance on how to format questions in a patient, intervention, comparison and outcome (known as ‘PICO’) framework.Five handbooks just mentioned systematic search for evidence to gather the required information. Thirteen of them clearly mentioned developing search strategies based on questions, sources, and filters, and using stakeholder’s recommendations, although they varied in the provided detail.Fifteen handbooks addressed Selecting relevant evidence from the search results was addressed by seventeen handbooks and ten handbooks explained it in detail. NICE handbook suggested: “first, the titles of the retrieved citations should be scanned and those that fall outside the topic of the guideline should be excluded. Next, the remaining abstracts should be scrutinized against the inclusion criteria agreed by the GDG” Appraising identified research evidence was addressed by eighteen handbooks and only one handbook did not even mention it. NICE and SIGN recommend the checklists developed originally by the Method for Evaluating Research and Guideline Evidence group in Australia and modified by SIGN. NZGG and IDF recommended using the GATE Notes  developed by the Effective Practice Institute, University of Auckland to appraise the evidence. Word Confederation for Physical Therapy handbook suggested: “the Cochrane Collaboration produces robust systematic reviews and meta-analyses that can save a lot of work in assessing the literature” evidence synthesis and analysis, and eight handbooks had clear guidance. ASCO handbook stated: “in putting together a practice guideline for a specific intervention or set of interventions, an ASCO expert panel may be faced with either interpreting existing meta-analyses or initiating a meta-analysis of its own. It is important to emphasize that not all systematic reviews will justify or require a formal meta-analysis. … The decision of whether or not to combine different studies in a meta-analysis is initially a clinical one, not a statistical one. The panel should determine, before deciding on the statistical approach, whether or not it makes sense to include within the same analysis patients who are different … or treatments that are different” Thirteen handbooks mentioned conducting economic evaluation in guideline development, but only seven handbooks provided clear guidance on how to conduct it. According to NICE handbook: “economic evaluation will usually be conducted in the form of a cost-effectiveness analysis, with the health effects being measured using an appropriate non-monetary outcome indicator. In circumstances for which cost-effectiveness analysis is not appropriate, other validated methods may be used” Fourteen of nineteen handbooks mentioned Making group decisions and reaching consensus was mentioned by seventeen handbooks and thirteen handbooks provided clear explanations about it. The NICE handbook described the use of focus groups and formal consensus methods  for making group decisions grading available evidence and thirteen described it clearly. SCIH handbook stated: “grading recommendations reflects ‘the extent to which we can be confident that the desirable effects of an intervention outweigh the undesirable effects’. Strong recommendations imply that they can be adopted in most circumstances while weak recommendations will need additional considerations (e.g. decision aids)” Eighteen handbooks addressed considering ethical issues in guideline development. Only two handbooks provided reasonable discussions of the issue, in additional documents. The NICE handbook provided guidance on ethical issue in documents besides the guidelines manual Seven handbooks mentioned Creating recommendation was mentioned by all handbooks and sixteen handbooks offered well-defined guidance. SIGN used the concept of ‘considered judgment’ besides the evidence table for each key question: “under this heading, guideline development groups summaries their view of the total body of evidence covered by each evidence table” final stakeholder consultation on recommendation drafts except one handbook. Word Confederation for Physical Therapy handbook defined a validation phase, in which “the draft guidelines can be sent to potential users to test practicality and clarity, and how acceptable the recommendations are. Patients and stakeholders can also review the draft guideline. The comments should be used by the GDG to adjust the guideline” All handbooks addressed Publishing formats was mentioned in eighteen handbooks and fourteen explained this phase in detail. According to the NICE handbook: “four separate documents are published: the full guideline, the NICE guideline, a quick reference guide and ‘understanding NICE guidance’ (information for patients and careers)” guideline implementation strategies. Thirteen handbooks provided relatively detailed strategies to implement guidelines. SCIH handbook defines: “guidance implementation includes all those activities or strategies that lead to guidance actually being used in real life situations ” All of the handbooks tackled piloting, but only RCQHC handbook provided explanation on how to conduct the pilot phase and offered practical options Nine handbooks mentioned assessment of the potential impacts of guideline implementation in guideline development process. According to NHMRC “it is important that the impact of guidelines is assessed. These assessments require complex study designs and will need to be carried out by researchers in collaboration with clinicians, rather than by clinicians alone” Thirteen handbooks considered Developing clinical audit and evaluation criteria was mentioned in fourteen handbooks and eleven provided clear guidance on it.updating and correcting potential errors after guideline publication. Most of them offered defined updating processes. The IDF handbook stated: “there needs to be a statement of intention as to updating the guideline. If there is an umbrella organization to provide continuity, then it may be possible to specify a date, and plans should be made accordingly. Within the guideline it may be helpful to caution over some recommendations if major new evidence is expected in the near future.” All the handbooks except one addressed We identified twenty seven tasks that should be considered for guideline development. These twenty seven tasks include the major elements of an evidence-based development process for clinical guidelines and can be used as a checklist for comparison of guideline development handbooks. We also noted a wide range of differences among guideline development handbooks. While some handbooks covered and referred to the majority of the tasks, no handbook on its own covered all the tasks. Fifteen tasks were included in at least 75% of the handbooks and we identified them as the ‘necessary tasks’ that should be covered in all guideline development programs. Furthermore, there was considerable variation in quality and depth of attention devoted to these tasks depending on the handbooks. Closer links and joint works on guideline development handbooks  can be beneficial.Compared to previous reviews considering ethical issues and piloting. There may be different reasons for such omissions. The piloting task may have been left out due to the technical difficulties of conducting a pilot on a guideline before its release. Already, the development of a clinical guideline is a time-consuming and laborious endeavor that usually takes around a year Among the tasks, the least amount of attention was devoted to Incorporating ethical concerns into guidelines remains a challenge. Unlike piloting , where feasibility and capacity issues are the main barriers to their inclusion in guideline development, methodological and conceptual limitations seems to be the main barriers to formal consideration of ethical concerns in guideline development A further task that requires attention is incorporation of economic evaluation in guidelines. Five handbooks did not mention it at all and a further eight handbooks just briefly tapped on the issue, and only seven handbooks gave economic evaluation a decent attention. Also the experts gave the lowest weight score of 3 out of 5 to this task, implying the limited applications of the task in many guideline development programs. Guideline development programs should enhance their capacity for use of economic evaluation evidence and modeling in developing guidelines’ recommendations. It should be noted that even the guideline development entities that formally cherish use of economic evaluation evidence may find it difficult honoring their intention and ending up in patchy use of such evidence In addition to the twenty seven tasks noted above, we faced three further tasks suggested and explained in two handbooks . Such taObviously, the handbooks were not developed independently of each other but the links were not clear. SIGN, CSP and IDF handbooks referred to NICE handbook. On the other hand NICE, NHMRC, NZGG and CE handbooks mentioned the SIGN handbook. Closer links and joint works on guideline development handbooks can be beneficial.Our study has some limitations. We only included documents that were published in English. There are other national guideline development programs  that may have not published the handbooks in English language. We included handbooks produced by national or international organizations as well as professional bodies working on clinical guideline development. As such the handbooks had different audiences. On the other hand the wider inclusion criteria helped us to include more guideline development handbooks.We aimed to develop a comprehensive list of the tasks. However, depending on how detailed a task list might be, the list might include more or less number of tasks. The study was focused on ‘what’ written in the handbooks, and not what happened in reality, which might be better or worse than the handbooks. Despite these limitations, we reviewed a larger selection of handbooks using a more comprehensive list of tasks than Turner et al. and Van der Wees et al (who reviewed six handbooks each) Turner et al. (2008) described fourteen key elements and compared the guidelines by these key elements. They concluded “the key elements of an evidence-based guideline development process are addressed with strong concordance by existing guideline development handbooks” This study helps health policy maker to compare guideline development handbooks and choose more suitable ones to use. It complements previous publications that focused on developing standard approaches for reporting clinical practice guidelines


The Internet is a popular medium for disseminating information relevant to oncology practitioners. Despite the widespread use of web-based guidelines and protocols, the quality of these resources has not been evaluated. This study addresses this gap.The Appraisal of Guidelines for Research and Evaluation (AGREE-II) instrument was used to assess the quality of breast and sarcoma guidelines and protocols according to six independent domains. The oncology resources were selected from eight websites developed for healthcare settings in North America, the United Kingdom, Europe, and Australia.Mean quality scores across domains were highly variable for both guidelines (29–73%) and protocols (31–71%). Guidelines scored highly in terms of articulating their Scope and Purpose (72.6±11.2%) but poorly with respect to Applicability in clinical practice (29.0±17.3%). Protocols scored highly on Clarity of Presentation (70.6±17.6%) but poorly in terms of the processes used to synthesise underlying evidence, develop, and update recommendations (30.8±20.0%).Our evaluation provides a quick reference tool for clinicians about the strengths and limitations of oncology resources across several major websites. Further, it supports resource developers in terms of where to direct efforts to enhance guideline and protocol development processes or the communication of these processes to end-users. In recent years there has been a significant shift in the way clinicians access practice-related resources. Medical oncology, like many other specialties, has embraced web-based technology. Research from the United States, Canada and Australia demonstrates that the Internet is being used increasingly as a major information source to support the treatment decisions of cancer clinicians, and to guide the delivery of care .The literature abounds with evaluations of the ‘quality’ of web-based health information however, most research to date has focused primarily on content targeting patients . FurtherThe Appraisal of Guidelines for Research and Evaluation (AGREE) instrument  was desiTo provide a meaningful commentary on the quality of web-based oncology resources, we consulted collaborators involved in cancer care and guideline/protocol development  to identify international websites disseminating resources that potentially satisfied the following criteria:The website disseminated clinical guidelines and/or protocols. We defined guidelines as statements developed systematically to assist practitioner's decision-making in cancer care ; not containing guidelines or protocols (n=1); and containing guidelines/protocols on only one aspect of cancer care .Fourteen potential websites were identified by our collaborators and after reviewing them we found that eight websites satisfied the aforementioned criteria . Websitehttp://clinicaltrials.gov) revealed 2717 phase I, II and III breast cancer clinical trials, and 680 for sarcoma.We evaluated guidelines and protocols for two cancers with different prevalence rates; breast cancer is the most prevalent cancer globally and sarcoma has prevalence rates of less than 1% (We selected one guideline and protocol for each cancer from the eight websites (if available). We aimed to evaluate resources that were as similar as possible; however, we did encounter some variability in the scope of resources across sites. We selected adjuvant breast cancer guidelines and chose a commonly administered adjuvant protocol common to all websites. For sarcoma, we chose guidelines and protocols covering soft tissue sarcoma. In the absence of this option, we selected an alternative guideline/protocol that was most similar to the other websites  sarcoma guideline and OncologySTAT sarcoma protocol).Appraisers independently rated up to five resources each week for 6 weeks (10 January 2011–18 February 2011).Scores were entered into a database weekly and discrepancies of >2 between scores of at least two raters were identified and re-rated, blind to the scores of other raters.A fourth reviewer (SP) rated items with outstanding disagreements.Four independent appraisers  pilot tested the AGREE-II instrument using six guidelines and protocols so as to become familiar with the tool and assess its appropriateness for rating protocols. Following pilot testing, three raters  evaluated all the resources presented in this paper. Rating procedures were conducted in accordance with the AGREE-II manual and were as follows:AGREE was developed collaboratively by international researchers for use in guideline development and evaluation, and AGREE-II was launched in 2010 with improved validity and reliability, as well as a comprehensive users’ manual .α=0.64–0.89), face, construct, and criterion validity . The AGREE-II has acceptable internal consistency  from the website homepage to reach a given guideline/protocol without using an internal search engine. Two independent raters  tallied the number of clicks to navigate to each of the protocols and guidelines evaluated. Scores were crosschecked; however, there were no discrepancies.We report the pattern of scores for guidelines and protocols across eight oncology websites. It was not our intent to hypothesis test or make direct comparisons between guideline and protocol quality. As detailed in the AGREE-II manual, we calculated a percentage score for each domain using the following formula; ((score obtained by raters−minimum score possible)/(maximum score possible−minimum score possible) × 100), such that the maximum achievable score is 100% and the minimum achievable score is 0%. On the basis of our pilot testing, we excluded question 18 from the protocol evaluation, as it was deemed not applicable. This item addresses the facilitators and barriers to applying recommendations; protocols by definition are about implementation after these factors have been considered and/or treatment decisions made. The AGREE-II manual recognises that some questions may not apply to all circumstances.vs low scores. Instead it advises that scores should be interpreted within the context of the project.The AGREE-II does not provide guidance on what constitutes high We assessed inter-rater reliability of the three assessors  using intra-class correlation coefficients  accordinWe evaluated eight websites developed in North America, Europe, the United Kingdom, and Australia. All sites provided guideline access free of charge, with three websites charging additional fees for membership and/or access to other resources such as journal subscriptions. With the exception of National Comprehensive Cancer Network (NCCN), all websites provided access to protocols, free of charge. Only one website contained commercial advertising (OncologySTAT); however, most publicised relevant journals, clinical trials, and upcoming oncology conferences. The number of clicks required to navigate from the homepage to a given guideline/protocol ranged from two to five, suggesting resources were generally easy to find .The combined mean domain scores for breast guidelines compared with combined sarcoma guidelines varied by a maximum of 10%. Therefore, we report the overall mean domain scores for breast and sarcoma guidelines combined .Scores across the six domains and general rating item were highly variable (range 29–73%). Average scores of greater than 50% were obtained in four of six domains plus the general rating item. Relative to other domains, Rigour of Development and Editorial Independence had the greatest range in scores . The Scope and Purpose domain scores were consistently high across all the websites (72.6±11.2%), with the Applicability domain scoring the lowest (29.0±17.3%). Overall, NICE breast and Cancer Care Ontario (CCO) sarcoma guidelines achieved the highest scores across most domains, with the British Columbia Cancer Agency (BCCA) guidelines scoring lowest across most domains. Guidelines scoring well in one domain generally scored well across all the domains.Additionally, domain and overall rating scores for breast and sarcoma guidelines disseminated by the same website were generally consistent. Only 7 of 35 scores varied by more than 10%, and 4 of these were from NICE, in which the sarcoma guideline scored lower than the breast guideline.We attained mean scores of 5 or more (maximum score 7) on seven items: all questions in the Scope and Purpose domain (Items 1–3), clearly defining target users (Item 6) and all items in the Clarity of Presentation domain (Items 15–17). Scores of less than 3 were obtained for items referring to the process of seeking views and preferences of the target population, and providing descriptions of the strengths and limitations of the evidence informing the guidelines . Items relating to guideline implementation such as consideration of facilitators and barriers to application and resource implications of applying the recommendations also achieved scores of less than 3  (Table 4).The difference in mean domain scores for breast protocols combined and sarcoma protocols combined ranged from 1 to 6%. Therefore, we report the overall mean domain scores for breast and sarcoma protocols combined .There was a high degree of variability in the overall scores across the six domains and general rating item (31–71%). Average scores of greater than 50% were obtained for two of six domains, plus the general rating item. Relative to other domains, Rigour of Development and Editorial Independence had the greatest range in scores . Clarity of Presentation was the highest scoring domain across protocols (70.6±17.6%); with the Rigour of Development score being the lowest (30.8±20.0%). Overall, CCO and eviQ protocols achieved the highest scores across most domains, with OncologySTAT protocols scoring the lowest across most domains for both breast and sarcoma. Protocols scoring well in one domain generally scored well across all domains.We found little variation between domain scores for breast and sarcoma protocols disseminated by the same website. Only 3 of 35 scores yielded differences more than 10% with no difference of greater than 20%.Scores greater than 5 (maximum score 7) were obtained for two items in the Clarity of Presentation domain , and advice on putting recommendations into practice (Item 19). Scores of less than 3 were obtained for items addressing the process of seeking the views and preferences of the target population (Item 5), and five of the eight items in the Rigour of Development domain . Scores of less than 3 were also obtained for items such as consideration of the resource implications of applying the recommendations and recording/addressing the competing interests of development group members  .The overall intra-class correlation coefficient was 0.80 before arbitration of discrepant scores by the fourth independent reviewer and 0.85 thereafter, suggesting the overall variance between raters was minimal. This was also the case when considering guidelines/protocols and breast/sarcoma cancers separately (range: 0.75–0.83). As expected, we found a noticeable improvement in the intra-class correlations after arbitration of discrepant scores (range: 0.84–0.85).Our study is the first comprehensive evaluation of the quality of clinical guidelines and treatment protocols disseminated on websites designed for cancer clinicians. Using a psychometrically robust evaluation tool we identified areas of strength and deficiency, and distinguished between the quality of different oncology guidelines and protocols. Overall, the quality of oncology resources was modest.In general, we found little variation between breast and sarcoma resources with respect to combined domain scores and for resources disseminated by the same website. This finding is not surprising, and suggests the processes underpinning the development of oncology resources do not vary by cancer type. We found the greatest variability in domains addressing the processes used to locate and summarise evidence, and to formulate and update recommendations. Further, items addressing the way in which bias and competing interests are minimised during development were highly variable. Our findings provide clear guidance to resource developers as to the way in which they can improve their processes and/or the way in which they are communicated to end-users. Clearly, collaboration across international boundaries would be prudent so as to minimise duplication of effort and costs of developing these tools (From the perspective of oncology practice, it is difficult to ascertain whether the differences demonstrated in resource quality will have meaningful effects on the uptake and use of oncology guidelines and protocols, or whether the use of higher quality resources equates to better quality care and improved outcomes for patients. The premise of oncology guidelines and protocols is to reduce treatment variation, adverse events, and patient mortality . ResearcSystematic reviews in the area of prescriber behaviour change and computerised clinical support highlight repeatedly that the provision of clinical resources does not guarantee uptake  by proviOur study is not without limitations. We acknowledge that our evaluation was not systematic, rather websites were selected by a small group of content experts and we evaluated a relatively small sample of guidelines and protocols. As such, our evaluation may not be representative of all oncology guidelines/protocols disseminated online. Further, our evaluation group is based in one healthcare setting and does not have members representing all of the websites under evaluation. Finally, we note that the AGREE-II was not developed to evaluate protocol quality. However, our initial psychometric evaluation demonstrated that the tool's properties were robust for this type of assessment, which may serve as preliminary evidence that the AGREE-II can be used for protocol assessment research.Web-based information systems have revolutionised healthcare delivery and have the distinct advantage over paper-based systems because of their capacity to accommodate changes in best-practice evidence in real time. Given the increasing popularity of web-based tools in clinical practice, it is paramount we monitor and evaluate the quality of clinician-targeted resources disseminated online. It is unreasonable to expect individual practitioners to replicate the efforts detailed in this paper. As such we encourage continued evaluations of this kind, which provide a quick reference tool for oncology clinicians to scrutinise the resources they are using in their day-to-day practice. Further our research pinpoints where resource developers should direct their efforts to obtain high-quality guidelines and protocols.


The objective of this systematic review was to examine the benefits, harms and pharmacokinetic interactions arising from the co-administration of commonly used dietary supplements with cardiovascular drugs. Many patients on cardiovascular drugs take dietary supplements for presumed benefits and may be at risk for adverse supplement-drug interactions.The Allied and Complementary Medicine Database, the Cochrane Library, EMBASE, International Bibliographic Information on Dietary Supplements and MEDLINE were searched from the inception of the review to October 2011. Grey literature was also reviewed.Two reviewers independently screened records to identify studies comparing a supplement plus cardiovascular drug(s) with the drug(s) alone. Reviewers extracted data using standardized forms, assessed the study risk of bias, graded the strength of evidence and reported applicability.Evidence was obtained from 65 randomized clinical trials, 2 controlled clinical trials and 1 observational study. With only a few small studies available per supplement, evidence was insufficient for all predefined gradable clinical efficacy and harms outcomes, such as mortality and serious adverse events. One long-term pragmatic trial showed no benefit from co-administering vitamin E with aspirin on a composite cardiovascular outcome. Evidence for most intermediate outcomes was insufficient or of low strength, suggesting no effect. Incremental benefits were noted for triglyceridemia with omega-3 fatty acid added to statins; and there was an improvement in levels of high-density lipoprotein cholesterol with garlic supplementation when people also consumed nitratesEvidence of low-strength indicates benefits of omega-3 fatty acids  and garlic (plus nitrates or warfarin) on triglycerides and HDL-C, respectively. Safety concerns, however, persist. The American Heart Association estimates that more than 81 million (one in three) American adults have at least one form of cardiovascular disease (CVD) -4.Billions of dollars are spent annually in the US on complementary and alternative medicine, and a large portion of this expenditure is directly on dietary supplements . ApproxiWhile much research is available describing drug-drug interactions in various populations, the evidence is less well described for drug-supplement interactions or simply the effects of add-on supplementation, especially in populations with CVD. The aim of this extensive synthesis review is to examine the evidence for benefits, harms, pharmacokinetic and statistical interactions from co-administration of a set of commonly used dietary supplements with CV drugs.We followed a pre-specified and peer-reviewed study protocol. The Agency for Healthcare Research and Quality (AHRQ) commissioned the full evidence report, which is available online .Using a peer-reviewed strategy, the Allied and Complementary Medicine Database, the Cochrane Library, EMBASE, International Bibliographic Information on Dietary Supplements and MEDLINE, as well as the grey literature, were searched from study inception until October 2011.Echinacea, garlic, ginger, Ginkgo biloba, Panax ginseng, American ginseng (P. quinquefolius), hawthorn, oral magnesium, niacin (≤250 mg/day), omega-3 fatty acids or fish oils, red yeast rice extract, resveratrol, vitamin A, vitamin D with or without calcium, vitamin E or vitamin K as supplements. Finally, we included studies that employed CV drugs commonly used in outpatient settings in the US and Canada. Additional file A comparative study was eligible if it was published in English or German; other languages were excluded due to concerns with study quality  or appliOne reviewer screened all titles and abstracts for potential relevance, and a second verified exclusions at this level. Two independent reviewers assessed the full publication of any potentially relevant studies, with discrepancies resolved by consensus.Study characteristics, population, intervention, comparator and outcomes data were extracted using standardized forms. The extracted outcomes of interest were categorized into four groups: clinical, intermediate, harms and pharmacokinetic , half life of CV drug, maximum of peak concentration (Cmax), and amount of time that a drug is present at the maximum concentration (tmax)). The full list of outcomes considered for this review is presented in Additional file a priori through consultations with the Technical Expert Panel was graded Additional file A methodologist and a content expert graded the strength of the body of evidence per each outcome  based on the following four domains: overall risk of bias, consistency, directness and precision . Only a The strength of evidence was graded as insufficient when there was no evidence for an outcome, the direction of the estimates was inconsistent across studies, and/or the evidence from the contributing study/studies had an imprecise statistically non-significant pooled estimate  were wide enough to be compatible with either clinical benefit, true no difference or harm).All analyses compared the combination of a dietary supplement plus CV drug(s) with CV drug(s) alone or plus placebo or plus another dietary supplement.The decision to pool individual study results was based on the degree of similarity in methodological and clinical characteristics of studies under consideration. Meta-analysis was considered when studies were randomized trials that included similar populations, compared the same type of dietary supplement and CV medication in the intervention and control groups, and reported the identical outcome measures in the same statistical format  or geometric mean ratio (GMR)). The estimates of post-treatment MD for continuous outcomes and relative risk (RR) for binary outcomes (except for rare events) of individual studies were pooled using a random-effects model by DerSimonian and Laird . The cho2 statistic. We planned to explore clinical  and methodological factors  as potential sources of statistically significant heterogeneity (Chi-square statistic P < 0.10 and/or I2 > 50%).The degree of statistical heterogeneity across pooled studies was assessed by visual inspection of the forest plot and the generation of Cochran’s Q (α = 0.10) and the IWe followed the US Food and Drug Administration (FDA) guidance for analysis and interpretation of drug interaction pharmacokinetic studies; the two comparators are considered bioequivalent  if the lower and upper bounds of the 90% CI for the GMR were between 0.8 and 1.25 . Where aAll analyses were performed using Comprehensive Meta Analysis version 2.2.057, StatsDirect statistical software and R: A Language and Environment for Statistical Computing, Foundation for Statistical Computing -36.The AHRQ supported this study but had no role in formulating study questions, conducting the systematic review, or approving the manuscript for submission and publication.de novo synthesis of evidence. Most studies had a moderate risk of bias for the gradable outcomes. A paucity of studies precluded exploration of subgroup heterogeneity and how this may have affected outcomes. Statistical interactions between supplement(s) and drug(s) were generally not reported.In total, 32,314 records were screened for eligibility  [Here, we outline selected results for gradable outcomes Additional file dex.cfm) , selecteOverall, evidence for clinical, harms and pharmacokinetic outcomes was inconclusive (grade: insufficient). The majority of the reported evidence was based on intermediate efficacy outcomes (grade: insufficient to low).These results represent evidence on: clinical outcomes of effectiveness from 19 RCTs -55 Tabl and 3; hOverall, the majority of included RCTs were of moderate risk of bias with only 25% of the studies explicitly reporting adequate sequence generation and 9% reporting allocation concealment. Adherence to CV medication was reported for co-administration of coenzyme Q10 plus statins, omega-3 fatty acids plus statins, and vitamin E plus statins in five studies -40,43,52No evidence.Evidence from three RCTs for co-administration of ginseng and warfarin was inconclusive (grade: insufficient) -70.American ginseng (2 g/day from weeks 2 to 4) caused a statistically significant reduction in the warfarin AUC ) . The cliEvidence for the effect of coenzyme Q10 co-administered with angiotensin-converting enzyme inhibitors on all-cause mortality and quality of life in one study of mostly male patients with left ventricular dysfunction was inconclusive (grade: insufficient) . No diffLow grade evidence was available from one trial indicating no significant difference in high-density lipoprotein-cholesterol (HDL-C) for combination of coenzyme Q10 plus fenofibrate versus fenofibrate alone .Evidence from five RCTs for the combination of coenzyme Q10 and statins, fenofibrate or angiotensin-converting enzyme inhibitors was inconclusive (grade: insufficient) ,53,56-58No evidence.No evidence.Echinacea and warfarin was inconclusive (grade: low) [Evidence from one study for the combination of de: low) .∞, an increase in drug clearance and an apparent increase in volume of distribution ; 1.09 ; and 1.09 , respectively) [Results of one study showed no clinically important but a statistically significant decrease (grade: insufficient) in S-warfarin AUCctively) .No evidence.In one study , a combiEvidence in four RCTs for garlic co-administered with warfarin, nitrates, or statins plus aspirin in healthy men  or thosemax; grade: insufficient) [Evidence from two studies demonstrated neither clinically important   nor statficient)  interactGinkgo biloba plus antiplatelets (aspirin and/or pentoxifylline) on all-cause mortality (no deaths in either group) in South Asians with previous stroke [Insufficient evidence was found for the effect of s stroke .Ginkgo and acetylsalicylic acid, clopidogrel, ticlopidine, warfarin or cilostazol was inconclusive (grade: insufficient) [Evidence from five RCTs for the combination of ficient) -67.Seven studies provided insufficient evidence for harm for the co-administration with warfarin, digoxin, aspirin, aspirin and/or pentoxifylline, nitrates, cilostazol or clopidogrel, or ticlopidine ,63-67,98Ginkgo biloba and specific CV drugs  [max were either clinically not important or statistically non-significant (grade: insufficient).Three studies examined pharmacokinetic interaction of arfarin) ,66,98. SEvidence on all-cause mortality for healthy individuals and highly selected patients with dyslipidemia taking statins as an add-on therapy , and patThere is inconsistent evidence for a benefit when omega-3 fatty acids were added to conventional antiplatelet therapy and calcium channel antagonists on rates of acute myocardial infarction ,51. In tCo-administration with statins showed no benefit of lowering low density lipoprotein-cholesterol (LDL-C) Figure  41,43,5,74,81, tInsufficient evidence was available from 22 studies (21 RCTs and one retrospective cohort study) which examined omega-3 fatty acids plus statins ,96,103, Meta-analyses of studies comparing omega-3 fatty acids and statin combinations versus statins alone yielded inconclusive results for serious adverse events ), withdrawal due to adverse events ), elevated aspartate aminotransferase ) and elevated alanine transaminase ) (grade: insufficient) ,81,83,96max GMRs (grade: low). Observed changes in steady state β-hydroxysimvastatin arithmetic means of AUC, Cmax, tmaxclearance and half-life were not statistically significant (grade: insufficient).In three open-label RCTs of healthy adult volunteers (sample size range 24 to 50) ,83,96 taThe evidence for the effect of vitamin E plus aspirin on stroke and transient ischemic attacks in selected patients with previous neurologic deficit was inconclusive (grade: insufficient) . In one In one study of 30 elderly patients at high risk of CHD, addition of vitamin E to nifedipine significantly lowered total cholesterol, LDL-C (grade: low), triglycerides (grade: low) and systolic blood pressure   Tables , 3.Evidence from 10 RCTs for co-administration of vitamin E and aspirin, nifedipine, furosemide, or statins in participants who were healthy, or who had CHD or risk factors for CHD was inconclusive (grade: insufficient). Sample sizes were generally small, except for one study that recruited over 9,000 women .No evidence.Across all combinations of dietary supplements and CV drugs, the strength of evidence of the gradable outcomes of comparative efficacy or effectiveness was mostly graded as insufficient. Type II errors could not be excluded due to the low statistical power of mostly short-term efficacy trials, particularly with strict inclusion criteria excluding patients with uncontrolled comorbidities and acute ischemic events. In addition, most studies were short-term efficacy trials and thus unable to evaluate longer term effects from co-administration.Limited findings on intermediate outcomes were available and the majority of evidence was contributed by small RCTs with statistically non-significant results and broad CIs. This imprecision precluded ruling in or out important benefits or harms, thus the strength of evidence for several gradable intermediate outcomes was rated insufficient. Statistically significant effects were graded as low strength of evidence because of limitations in the internal validity of studies, surrogacy of outcomes, and often absent reproducibility in the direction of effect estimates Table . Forest With respect to harms data, for all supplement-drug combinations examined, the strength of evidence from single or heterogeneous studies for bleeding, serious adverse events, withdrawal due to adverse events, renal dysfunction, hepatotoxicity and prolongation of corrected QT interval was insufficient. This was due to either inconsistent effect estimates across studies (suggesting conflicting findings with no obvious explanation) or imprecise estimates .Evidence gleaned from an initial search yielding over 32,000 records identified a considerable knowledge gap regarding the safety and efficacy of combining dietary supplements with CV drugs.Among 168 records that addressed the relevant possibility of interaction, 63 studies contributed evidence for synthesis. With a few exceptions, there was insufficient evidence to draw any conclusions on particular interactions. In addition to an overall lack of evidence, the included studies were often underpowered to assess the predetermined clinically relevant outcomes set for this synthesis review. As well, many studies had important methodological limitations or were poorly generalizable to the relevant population. The strength of the identified evidence was frequently compromised by poor allocation concealment, and issues related to blinding, study reporting and potential conflict of interest. Drug interactions resulting in positive or negative outcomes likely occur, but the evidence available and identified in this review is insufficient to allow meaningful conclusions with confidence.Available evidence comes primarily from short-term trials of highly selected participants, with limited external validity. The strength of evidence was low at best, with poor grading resulting from risks of bias, small sample sizes, and the fact that evidence is largely generated from intermediate surrogate outcomes rather than primary clinical endpoints. While there are data from which we can derive a sense of lack of interactions in some cases, the small size of the trials made it difficult to impossible to ascertain the potential for true clinical interaction.Much of the pharmacokinetic research was conducted on healthy young adults; thus this evidence may not be applicable to populations with CVD and particularly for older patients taking CV drugs, due to possible differences in metabolism and the existence of comorbidities. The internal validity of most trials was compromised by flawed design, lack of appropriate allocation concealment and risk of bias. A formal assessment of statistical interaction was rarely undertaken. In the absence of corroborating pharmacokinetic evidence or assessment for statistical interaction, it is often impossible to determine whether a difference in outcome is due to true pharmacological interaction, or due to more independent additive, or possibly counteracting therapeutic effects.A principal limitation of the included trials was that they were small and susceptible to type II errors. A marginally reassuring corollary is that if there was a real, dramatic clinical impact due to an interaction then some clinical effect would likely have been evident despite being underpowered for smaller effect sizes. Of more concern are possible interactions that could arise through polypharmacy of prescription drugs, a situation all too common, in particular for the elderly population.With these caveats in mind, the following is a summary of the clearer signals from the evidence reviewed.Omega-3 fatty acids (2 to 4 g/day) from fish and/or supplements likely do not interfere with the efficacy of statin therapy or calcium channel blockers in the presence of antiplatelet agents, and may provide an independent benefit in resolving hypertriglyceridemia. Also, garlic (4 to 10g/day) may not interact negatively with nitrates and warfarin and may confer independent benefit in improving HDL-C.Interpretation of this report requires the reader to recognize that dietary supplements in the US are not regulated in the same manner as prescription drugs nor are manufacturers of dietary supplements held to the same standards with respect to providing evidence of efficacy and safety prior to marketing. Dietary supplements do not require FDA approval, nor are there any FDA regulations that require evidence of purity, quality or composition prior to marketing. This has resulted in a lack of standardization among products both from a single manufacturer and between manufacturers . The lacet al. focused on effects of natural health products on the metabolism of a broad range of conventional medicines [Ginkgo biloba and warfarin, and Ginkgo biloba and digoxin. Both reviews also identified a shift in AUC of the international normalized ratio when American ginseng was taken in conjunction with warfarin; however, we question the clinical significance of this finding.Recent systematic reviews related to the topic of dietary supplement-drug interactions do not address the same scope, are not comprehensive, do not grade the outcomes extracted, do not evaluate the quality of evidence, or involve different populations of interest. A 2005 systematic review by Mills edicines . Consistet al. reviewed interactions between dietary supplements and antiplatelet agents reported in clinical trials and case reports [Also in 2005, Desai  reports . With reet al. in 2005 and Skalli et al. in 2007 described evidence for drug-supplement interactions, but the majority of evidence was generated from case reports and small case series [Reviews published by Izzo e series ,108. Thee series . Their tA most obvious limitation of our review arose from the need to scope the work to a manageable yet relevant synthesis by restricting the number of dietary supplements to the sixteen that were considered. This subset of supplements was based on published North American usage surveys and a consensus selection process that included a Technical Experts Panel ,21-26. TThe greatest strengths of the present review are its broad search strategy and consideration of extensive literature, and a methodology that focused on the highest quality of evidence. We followed published guidance to pool data from studies, grade the strength of evidence, and assess applicability. Based upon preliminary searches we did not exclude German language literature, a language where most negative studies are published . In ordeWhile a plethora of strong recommendations was the hope, we revealed instead a glaring knowledge gap regarding interactions between some of the agents most commonly used for their presumed pharmacological effects for serious chronic disease.With the continuing and increasing burden of CVD, precise recommendations are needed to guide the use of dietary supplements in disease prevention and management. An ungrounded call for avoidance of dietary supplements in conjunction with pharmaceutical treatments may result in the avoidance of potentially beneficial supplements, or just as importantly might be readily ignored, leading to potential harm with negative interactions. Strategic investment to build research capacity to address the important knowledge gap in the area of dietary supplement-drug interactions should address relevant questions in appropriate populations according to disease, genetic makeup, age, and so on. While awaiting results of future, adequately powered interventional trials focusing on meaningful clinical outcomes, evidence from well-conducted prospective observational studies should be sought. Electronic health record linkages between databases of dietary supplement use and CV drug prescription may also add to the equipoise that has been so insufficiently addressed to date.AHRQ: Agency for Healthcare Research and Quality; AUC: area under the curve; CI: confidence interval; CHD: coronary heart disease; CV: cardiovascular; CVD: cardiovascular disease; FDA: Food and Drug Administration; GMR: geometric mean ratio; HDL-C: high density lipoprotein-cholesterol; INR: International Normalized Ratio; LDL-C: low density lipoprotein-cholesterol; MD: mean difference; OR: odds ratios; RCT: randomized clinical trials; RR: relative risk.The authors declare that they have no competing interests.SK and DS were involved in the conception and design, data interpretation, reviewing and revising the manuscript critically for important intellectual content, and its final approval. FY, KS, AT, ACT and MS analyzed and interpreted data, reviewed the draft and revised it critically for important intellectual content, and approved the manuscript. JT was involved in the conception and design, reviewed the draft and revised the manuscript critically for important intellectual content, and approved the manuscript. TCO, MAT and BS were involved in the conception and design, reviewed the draft and revised it critically for important intellectual content, and approved the manuscript. MTA was involved in the conception and design, data analysis and interpretation, drafting of the manuscript, and final approval of the manuscript. All authors read and approved the final manuscript.This project was funded under Contract No. HHSA290-2007-10059-I (EPCIII) from the AHRQ, US Department of Health and Human Services. The authors of this report are responsible for its content. Statements in the report should not be construed as endorsement by the AHRQ, National Institute of Health or the US Department of Health and Human Services.Table S1. Selected cardiovascular drugs for current review.Click here for fileTable S2. List of included outcomes.Click here for fileTable S3. a Priori outcomes for grading the strength of evidence.Click here for file


In patients with congenital heart disease (CHD), it is desirable to accurately measure peak velocity (Vmax). Unfortunately, phase-contrast MR (PCMR) tends to underestimate peak velocities. Fourier Velocity Encoding (FVE) can measure peak velocities in MRI, but is not commonly used due to long acquisition times.Therefore, we have developed a FVE sequence that combines spiral trajectories with parallel imaging (SENSE), partial-Fourier acquisition and a novel velocity-unwrap technique. The aim of this study is to validate this sequence.FVE sequence: FVE was performed using a spiral trajectory table . Spiral In-vitro: A pulsatile flow pump was connected to a tube phantom (13mm diameter) with a stenosis (6mm diameter). Peak velocity measurements using the following techniques were compared at 15 different flow rates; 1) US doppler, 2) low-resolution PCMR (lr-PCMR), 3) high-resolution PCMR (hr-PCMR), 4) FVE.In-vivo: 12 CHD patients  with stenoses were assessed. Peak velocity measurements were compared between; 1) lr-PCMR, 2) hr-PCMR, and 3) FVE.In-vitro: There were no statistically significant differences between Vmax measured using US and FVE table . HoweverFourier velocity encoding allows accurate assessment of peak velocities as it measures a velocity spectrum per pixel, rather than the average velocity. However this extra encoding takes time, which has reduced its clinical effectiveness. We have shown that it possible to achieve high resolution FVE within a short breath-hold by combining spiral trajectories, parallel imaging, partial Fourier and velocity-unwrap. This sequence was shown to be significantly more accurate than PCMR in-vitro, and also to provide higher peak velocities than PCMR in-vivo. Thus, the sequence should be able to replace Doppler echocardiography making CMR a true one-stop-shop in assessing congenital heart disease.JAS: EPSRC PhD+.VM: BHF.