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Background: Health systems guidance (HSG) are systematically developed statements that assist with decisions about options for addressing health systems challenges, including related changes in health systems arrangements. However, the development, appraisal, and reporting of HSG poses unique conceptual and methodological challenges related to the varied types of evidence that are relevant, the complexity of health systems, and the pre-eminence of contextual factors. To address this gap, we are conducting a program of research that aims to create a tool to support the appraisal of HSG and further enhance HSG development and reporting. The focus of this paper was to conduct a knowledge synthesis of the published and grey literatures to determine quality criteria (concepts) relevant for this process., Methods: We applied a critical interpretive synthesis (CIS) approach to knowledge synthesis that enabled an iterative, flexible, and dynamic analysis of diverse bodies of literature in order to generate a candidate list of concepts that will constitute the foundational components of the HSG tool. Using our review questions as compasses, we were able to guide the search strategy to look for papers based on their potential relevance to HSG appraisal, development, and reporting. The search strategy included various electronic databases and sources, subject-specific journals, conference abstracts, research reports, book chapters, unpublished data, dissertations, and policy documents. Screening the papers and data extraction was completed independently and in duplicate, and a narrative approach to data synthesis was executed., Results: We identified 43 papers that met eligibility criteria. No existing review was found on this topic, and no HSG appraisal tool was identified. Over one third of the authors implicitly or explicitly identified the need for a high-quality tool aimed to systematically evaluate HSG and contribute to its development/reporting. We identified 30 concepts that may be relevant to the appraisal of HSG and were able to cluster them into three meaningful domains: process principles, content, and context principles., Conclusions: Our study showed the role that the quality criteria play in the development, appraisal, and reporting of HSG and demonstrated the link and resonance within and between the various concepts in the three domains.

Background: Health system guidance (HSG) provides recommendations aimed to address health system challenges. However, there is a paucity of methods to direct, appraise, and report HSG. Earlier research identified 30 candidate criteria (concepts) that can be used to evaluate the quality of HSG and guide development and reporting requirements. The objective of this paper was to describe two studies aimed at evaluating the importance of these 30 criteria, design a draft HSG appraisal tool, and test its usability., Methods: This study involved a two-step survey process. In step 1, respondents rated the 30 concepts for appropriateness to, relevance to, and priority for health system decisions and HSG. This led to a draft tool. In step 2, respondents reviewed HSG documents, appraised them using the tool, and answered a series of questions. Descriptive analyses were computed., Results: Fifty participants were invited in step 1, and we had a response rate of 82 %. The mean response rates for each concept within each survey question were universally favorable. There was also an overall agreement about the need for a high-quality tool to systematically direct the development, appraisal, and reporting of HSG. Qualitative feedback and a consensus process by the team led to refinements to some of the concepts and the creation of a beta (draft) version of the HSG tool. In step 2, 35 participants were invited and we had a response rate of 74 %. Exploratory analyses showed that the quality of the HSGs reviewed varied as a function of the HSG item and the specific document assessed. A favorable consensus was reached with participants agreeing that the HSG items were easy to understand and easy to apply. Moreover, the overall agreement was high for the usability of the tool to systematically direct the development (85 %), appraisal (92 %), and reporting (81 %) of HSG. From this process, version 1.0 of the HSG appraisal tool was generated complete with 32 items (and their descriptions) and 4 domains., Conclusions: The final tool, named the Appraisal of Guidelines for Research and Evaluation for Health Systems (AGREE-HS) (version 1), defines expectations of HSG and facilitates informed decisions among policymakers on health system delivery, financial, and governance arrangements.

Background: Nerve repair may be effective in improving function following obstetrical brachial plexus injury. No previous review has directly compared nerve repair to nonoperative management for similar patients, and no previous analysis has been adequately powered to determine whether nerve repair reduces impairment., Methods: Electronic databases were searched (MEDLINE, Embase, CINAHL, and Cochrane Central). Eligible studies were randomized controlled trials, observational studies, and case series (n > 9); included patients younger than 2 years undergoing nerve repair or nonoperative management of obstetrical brachial plexus injury; and reported functional impairment. Two reviewers independently screened articles using objective a priori criteria. Bias was assessed for each study. Overall quality of evidence was evaluated for each outcome., Results: Among nine cohort studies including 222 patients, nerve repair significantly reduced functional impairment compared with nonoperative management (relative risk, 0.58; 95 percent CI, 0.43 to 0.79; p < 0.001; I = 0 percent; absolute risk reduction, 19 percent; number needed to treat, six). Findings are consistent with comparison of similar patients from case series. With operative management, no deaths were reported; major adverse events were reported in 1.5 percent, and minor adverse events were reported in 5.0 percent of cases. Among demographic (all severities) samples managed nonoperatively, residual impairment remains in 27 percent (19 to 36 percent)., Conclusions: Nerve repair reduces functional impairment in obstetrical brachial plexus injury. Nonoperative management in patients with a deficit at 3 months of age leads to a high proportion of functional impairment. Mortality is not a common risk of modern pediatric microsurgical nerve repair. Residual impairment with nonoperative management is underestimated in the reported literature., Clinical Question/level of Evidence: Therapeutic, IV.

Background: Health care professionals (HCPs) are able to make effective decisions regarding patient care through the use of systematically developed clinical practice guidelines (CPGs). These recommendations are especially important in a cancer health care context as patients are exposed to a multitude of interdisciplinary HCPs offering high-quality care throughout diagnosis, treatment, survivorship and palliative care. Although a large number of CPGs targeted towards cancer are widely disseminated, it is unknown whether implementation strategies targeting the use of these guidelines are effective in effecting HCP behaviour and patient outcomes in the cancer care context. The purpose of this systematic review will be to determine the effectiveness of different CPG dissemination and implementation interventions on HCPs' behaviour and patient outcomes in the cancer health care context., Methods/design: Five electronic databases (CINAHL, the Cochrane Controlled Trials Register, MEDLINE via Ovid, EMBASE via Ovid and PsycINFO via Ovid) will be searched to include all studies examining the dissemination and/or implementation of CPGs in a cancer care setting targeting all HCPs. CPG implementation strategies will be included if the CPGs were systematically developed (e.g. literature review/evidence-informed, expert panel, evidence appraisal). The studies will be limited to randomized controlled trials, controlled clinical trials and quasi-experimental (interrupted time series, controlled before-and-after designs) studies. Two independent reviewers will assess articles for eligibility, data extraction and quality appraisal., Discussion: The aim of this review is to inform cancer care health care professionals and policymakers about evidence-based implementation strategies that will allow for effective use of CPGs., Systematic Review Registration: PROSPERO CRD42015019331.

Background: Practice guideline (PG) implementability refers to PG features that promote their use. While there are tools and resources to promote PG implementability, none are based on an evidence-informed and multidisciplinary perspective. Our objectives were to (i) create a comprehensive and evidence-informed model of PG implementability, (ii) seek support for the model from the international PG community, (iii) map existing implementability tools on to the model, (iv) prioritize areas for further investigation, and (v) describe how the model can be used by PG developers, users, and researchers., Methods: A mixed methods approach was used. Using our completed realist review of the literature of seven different disciplines as the foundation, an iterative consensus process was used to create the beta version of the model. This was followed by (i) a survey of international stakeholders (guideline developers and users) to gather feedback and to refine the model, (ii) a content analysis comparing the model to existing PG tools, and (iii) a strategy to prioritize areas of the model for further research by members of the research team., Results: The Guideline Implementability for Decision Excellence Model (GUIDE-M) is comprised of 3 core tactics, 7 domains, 9 subdomains, 44 attributes, and 40 subattributes and elements. Feedback on the beta version was received from 248 stakeholders from 34 countries. The model was rated as logical, relevant, and appropriate. Seven PG tools were selected and compared to the GUIDE-M: very few tools targeted the Contextualization and Deliberations domain. Also, fewer of the tools addressed PG appraisal than PG development and reporting functions. These findings informed the research priorities identified by the team., Conclusions: The GUIDE-M provides an evidence-informed international and multidisciplinary conceptualization of PG implementability. The model can be used by PG developers to help them create more implementable recommendations, by clinicians and other users to help them be better consumers of PGs, and by the research community to identify priorities for further investigation.

Regular screening using guaiac fecal occult blood test (gFOBT) reduces mortality from colorectal cancer (CRC). The objective of this study was to determine whether the addition of a gFOBT kit to a second mailed invitation compared to a second mailed invitation alone increases CRC screening among eligible persons who did not respond to an initial mailed invitation. We conducted a cluster randomized controlled trial, with the physician as the unit of randomization. Participants were persons who had been invited but who had not responded to an invitation for CRC screening in an earlier pilot project. The intervention group received a mailed gFOBT kit and second mailed CRC screening invitation (n = 2,008) while the control group received a second mailed CRC screening invitation alone (n = 1,586). The primary outcome was the uptake of gFOBT within 6 months of the second mailing. We found that the uptake of gFOBT was more than twice as high in the intervention group (20.1%) compared to the control group (9.6%). The absolute difference between the two groups was 10.5% (95% CI: 7.5-13.4%, p ≤ 0.0001). In a subsequent adjusted analysis, participants in the intervention group were twice as likely to complete the test as those in the control group (OR = 2.1; 95% CI: 1.6-2.6). These findings suggest that directly mailed gFOBT kits increase CRC screening participation among previous nonresponders to a mailed invitation and that approximately 10 gFOBT kits would have to be sent by mail in order to screen 1 additional person. (ClinicalTrials.gov: NCT01629004)., (© 2014 UICC.)

Background: Continuous escalation in methodological and procedural rigor for evidence-based processes in guideline development is associated with increasing costs and production delays that threaten sustainability. While health research methodologists are appropriately responsible for promoting increasing rigor in guideline development, guideline sponsors are responsible for funding such processes., Discussion: This paper acknowledges that other stakeholders in addition to methodologists should be more involved in negotiating trade-offs between methodological procedures and efficiency in guideline production to produce guidelines that are 'good enough' to be trustworthy and affordable under specific circumstances. The argument for reasonable methodological compromise to meet practical circumstances is consistent with current implicit methodological practice. This paper proposes a conceptual tool as a framework to be used by different stakeholders in negotiating, and explicitly reporting, reasonable compromises for trustworthy as well as cost-worthy guidelines. The framework helps fill a transparency gap in how methodological choices in guideline development are made. The principle, 'when good is good enough' can serve as a basis for this approach. The conceptual tool 'Efficiency-Validity Methodological Continuum' acknowledges trade-offs between validity and efficiency in evidence-based guideline development and allows for negotiation, guided by methodologists, of reasonable methodological compromises among stakeholders. Collaboration among guideline stakeholders in the development process is necessary if evidence-based guideline development is to be sustainable.

Objectives: Despite early and continuous treatment many patients with phenylketonuria (PKU) still experience neurocognitive problems. Most problems have been observed in the domain of executive functioning (EF). For regular monitoring of EF, the use of the Behavior Rating Inventory of Executive Function (BRIEF) has been proposed. The aim of this study was to investigate whether the BRIEF is indeed a useful screening instrument in monitoring of adults with PKU., Study Design: Adult PKU patients (n = 55; mean age 28.3 ± 6.2 years) filled out the BRIEF-A (higher scores=poorer EF) and performed computerized tasks measuring executive functions (inhibition, cognitive flexibility, and working memory). The outcome of the BRIEF-A questionnaire was compared with the neurocognitive outcome as measured by three tasks from the Amsterdam Neuropsychological Tasks (ANT)., Results: Forty-two percent of the PKU patients scored in the borderline/clinical range of the BRIEF-A. Six of the 55 patients (11%) scored >1 SD above the normative mean, mostly on the Metacognition Index. With respect to ANT measurements, patients mainly showed deficits in inhibitory control (34-36%) and cognitive flexibility (31-40%) as compared to the general Dutch population. No significant correlations between the two methods were found, which was confirmed with the Bland-Altman approach where no agreement between the two methods was observed. Only with respect to inhibitory control, patients scored significantly worse on both BRIEF-A and ANT classifications. No other associations between classification according to the BRIEF-A and classifications according to the ANT tasks were found., Conclusions: Patients reporting EF problems in daily life are not necessarily those that present with core EF deficits. The results of this study suggest that regular self-administration of the BRIEF-A is not a sufficient way to monitor EF in adult PKU patients., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objective: Providers and patients are most likely to use and benefit from guidelines accompanied by implementation support. Guidelines published in 2007 and earlier assessed with the Appraisal of Guidelines, Research and Evaluation (AGREE) instrument scored poorly for applicability, which reflects the inclusion of implementation instructions or tools. The purpose of this study was to examine the applicability of guidelines published in 2008 or later and identify factors associated with applicability., Design: Systematic review of studies that used AGREE to assess guidelines published in 2008 or later., Data Sources: MEDLINE and EMBASE were searched from 2008 to July 2014, and the reference lists of eligible items. Two individuals independently screened results for English language studies that reviewed guidelines using AGREE and reported all domain scores, and extracted data. Descriptive statistics were calculated across all domains. Multilevel regression analysis with a mixed effects model identified factors associated with applicability., Results: Of 245 search results, 53 were retrieved as potentially relevant and 20 studies were eligible for review. The mean and median domain scores for applicability across 137 guidelines published in 2008 or later were 43.6% and 42.0% (IQR 21.8-63.0%), respectively. Applicability scored lower than all other domains, and did not markedly improve compared with guidelines published in 2007 or earlier. Country (UK) and type of developer (disease-specific foundation, non-profit healthcare system) appeared to be associated with applicability when assessed with AGREE II (not original AGREE)., Conclusions: Despite increasing recognition of the need for implementation tools, guidelines continue to lack such resources. To improve healthcare delivery and associated outcomes, further research is needed to establish the type of implementation tools needed and desired by healthcare providers and consumers, and methods for developing high-quality tools., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Background: Research shows that guidelines featuring implementation tools (GItools) are more likely to be used than those without GItools, however few guidelines offer GItools and guidance on developing GItools is lacking. The objective of this study was to identify common processes and considerations for developing GItools., Methods: Interviews were conducted with developers of 4 types of GItools (implementation, patient engagement, point-of-care decision-making and evaluation) accompanying guidelines on various topics created in 2008 or later identified in the National Guideline Clearinghouse. Participants were asked to describe the GItool development process and related considerations. A descriptive qualitative approach was used to collect and analyze data., Results: Interviews were conducted with 26 GItool developers in 9 countries. Participants largely agreed on 11 broad steps, each with several tasks and considerations. Response variations identified issues lacking uniform approaches that may require further research including timing of GItool development relative to guideline development; decisions about GItool type, format and content; and whether and how to engage stakeholders. Although developers possessed few dedicated resources, they relied on partnerships to develop, implement and evaluate GItools., Interpretation: GItool developers employed fairly uniform and rigorous processes for developing GItools. By supporting GItool development, the GItool methods identified here may improve guideline implementation and use.

Objective: Guidelines are meant to facilitate evidence-based clinical decision-making but vary in methodological rigor and quality of reporting. We assessed the quality of guidelines published in major pediatric surgery journals., Methods: A MEDLINE search of 4 key pediatric surgery journals was performed. Included studies had guidelines, clinical practice guidelines, and consensus statements as a subject heading or keyword. Evaluations of guidelines were excluded. Eligible guidelines were assessed by three reviewers using the Appraisal of Guidelines for Research and Evaluation (AGREE II) Instrument., Results: Our search identified ten guidelines for review. Agreement for study selection was excellent [K = 0.81 (95 % CI 0.63-0.99)]. The mean AGREE II score for individual guidelines was 18 % (SD 5.7 %). The best-scored quality domains were "scope and purpose" [mean score 49 % (SD 8.7 %)] and "clarity of presentation" [mean score 40 % (SD 18.7 %)]. The poorest score was for "editorial independence" [mean score 2 % (SD 3.7 %)]., Conclusions: The overall quality of guidelines in pediatric surgery, using AGREE II, is poor and may lead to inappropriate clinical decisions. Increased awareness of proper reporting and the methodological requirements for guideline development are needed to optimize the potential of guideline recommendations to improve practice., Level of Evidence: n/a (Quality Appraisal).

Background: Collaboration among researchers (clinician, non-clinician) and decision makers (managers, policy-makers, clinicians), referred to as integrated knowledge translation (IKT), enhances the relevance and use of research, leading to improved decision-making, policies, practice, and health care outcomes. However IKT is not widely practiced due to numerous challenges. This research explored how context influenced IKT as a means of identifying how IKT could be strengthened., Methods: This research investigated IKT in three health services programs for colon cancer screening, prostate cancer diagnosis, and the treatment of pancreatic cancer. Qualitative methods were used to explore contextual factors that influenced how IKT occurred, and its impact. Data were collected between September 1, 2012 and May 15, 2013 from relevant documents, observation of meetings, and interviews with researchers and decision-makers, analyzed using qualitative methods, and integrated., Results: Data were analyzed from 39 documents, observation of 6 meetings, and 36 interviews. IKT included interaction at meetings, joint undertaking of research, and development of guidelines. IKT was most prevalent in one program with leadership, clear goals, dedicated funding and other infrastructural resources, and an embedded researcher responsible for, and actively engaged in IKT. This program achieved a variety of social, research and health service outcomes despite mixed individual views about the value of IKT and the absence of a programmatic culture of IKT. Participants noted numerous challenges including lack of time and incentives, and recommendations to support IKT. A conceptual framework of factors that influence IKT and associated outcomes was generated, and can be used by others to plan or evaluate IKT., Conclusions: The findings can be applied by researchers, clinicians, managers or policy-makers to plan or improve collaborative decision-making for health services planning, delivery, evaluation or quality improvement. Further research is needed to explore whether these findings are widespread, and further understand how IKT can be optimized.

Background: The original AGREE (Appraisal of Guidelines for REsearch and Evaluation) Instrument was published in 2003, and its revision, the AGREE II, in 2009. Together, they filled an important gap in the guideline and quality of care fields. Ten years later, the AGREE Enterprise reflects on a trajectory of projects and international collaboration that have contributed to advancing the science and quality of practice guidelines and the uptake of AGREE/AGREE II., Findings: The AGREE Enterprise has undertaken activities to improve the tool and to develop resources to support its use. Since 2003, the uptake and adoption of AGREE by the international community has been swift and broad. A total of 33 language translations of the original AGREE Instrument and the current AGREE II are available and were initiated by the international community. A recent scan of the published literature identified over 600 articles that referenced the AGREE tools. The AGREE tools have been widely received and applied, with several organizations having incorporated the AGREE as part of their formal practice guideline programs. Since its redevelopment in 2010, the AGREE Enterprise website (www.agreetrust.org) continues to experience steady increases in visitors per month and currently has over 10,000 registered users., Conclusions: The AGREE Enterprise has contributed to the advancements of guidelines through research activities and international participation by scientific and user communities. As we enter a new decade, we look forward to ongoing collaborations and contributing to further advancements to improve quality of care and health care systems.

Background: Guidelines are the foundation for healthcare planning, delivery and quality improvement but are not consistently implemented. Few guidelines are accompanied by guideline implementation tools (GItools). Users have requested GItools, and developers have requested guidance on how to develop GItools. First it is necessary to characterize GItools. The purpose of this research was to generate a framework of desirable features of GItools., Methods: Items representing desirable GItool features were generated by a cross-sectional survey of the international guideline community. Items were confirmed by 31 guideline developers, implementers and researchers in a two-round Delphi survey administered on the Internet. The resulting GItool framework was applied with a sample of GItools accompanying guidelines identified in the National Guideline Clearinghouse., Results: The cross-sectional survey was completed by 96 respondents from Australia, Canada, the United Kingdom, the United States, The Netherlands, and various other countries. Seven of nine items were rated by the majority as desirable. A total of 31 panelists from 10 countries including Australia, Canada, Germany, New Zealand, Peru, Saudi Arabia, Spain, the United Kingdom, and the United States took part in a two-round Delphi survey. Ten items achieved consensus as desirable GItool features in round #1, and two additional items in round #2. A total of 13 GItools for Resource Planning, Implementation and Evaluation were identified among 149 guidelines on a variety of clinical topics (8.7%). Many GItools did not possess features considered desirable., Conclusions: Inclusion of higher quality GItools in guidelines is needed to support user adoption of guidelines. The GItool framework can serve as the basis for evaluating and adapting existing GItools, or developing new GItools. Further research is needed to validate the framework, develop and implement instruments by which developers can apply the framework, and specify which guidelines should be accompanied by GItools.

Purpose of Review: This review presents recent basic and clinical developments in familial combined hyperlipidemia (FCHL)., Recent Findings: A variety of experiments have contributed to the elucidation of this complex disease. They consist of dynamic and gene expression studies in adipocytes, confirming the role of dysfunctional adipose tissue in the pathogenesis of FCHL and identifying potential new pathways, such as complement activation. Whole exome sequencing and classical linkage studies in FCHL pedigrees, some conducted with new traits (e.g. plasma proprotein convertase subtilisin/kexin type 9 [PCSK9] and phospholipid transfer protein activity), have revealed new genes of interest, among which SLC25A40 and LASS4. Finally, gene expression studies in liver biopsies and liver cell culture experiments have gained further insight in the role of upstream stimulatory factor 1, one of the most replicated genes in FCHL, in its pathogenesis.On the basis of these observations and recent phase II clinical trials, PCSK9 antagonizing is the most promising lipid-lowering therapy to be added to our current arsenal of statins and fibrates in FCHL treatment., Summary: Ongoing basic research provides a steady growth in our knowledge on the genes that are involved in FCHL as well as their metabolic function(s). This field of research may be enhanced when data are expanded and integrated for systems biology approaches. Our growing insights in the cause of FCHL allow for better, targeted treatment of dyslipidemia and prevention of cardiovascular complications.

Homozygous carriers of the apolipoprotein ε2 allele are at risk of type III hyperlipidaemia, but do not necessarily develop this lipid disorder. In the present study, we have investigated the role of circulating PCSK9 (pro-protein convertase subtilisin kexin type 9), an important regulator of LDL (low-density lipoprotein) receptor expression, in the development of this hyperlipidaemic phenotype. In an observational study, plasma PCSK9 was measured in homozygous carriers of apolipoprotein ε2 (ε2/ε2; n=12), normal controls (n=72) and hypertriglyceridaemic patients with FCHL (familial combined hyperlipidaemia; n=38), who served as a hyperlipidaemic reference group. Cholesterol, triacylglycerols (triglycerides) and apolipoprotein B content in VLDL (very-low-density lipoprotein) and LDL particles was determined by ultracentrifugation in ε2/ε2 and FCHL patients. Median circulating PCSK9 levels did not differ between ε2/ε2 carriers compared with controls and hypertriglyceridaemic FCHL patients (84.5 compared with 82.0 and 84.9 ng/ml; P=0.2 and 0.6 respectively). Circulating PCSK9 was associated with total cholesterol and triacylglycerols levels in ε2/ε2 carriers (P<0.05). These associations were stronger in ε2/ε2 carriers when compared with controls (P values for interaction=0.01 and 0.02 respectively). A direct comparison with FCHL patients demonstrated a similar discrepancy for the association with plasma triacylglycerols and also VLDL-apolipoprotein B, cholesterol and triacylglycerols (P value for interaction=0.01, 0.01, 0.03 and 0.03 respectively). Plasma PCSK9 is associated with type III hyperlipidaemia. Its strong relationship with plasma triacylglycerols and total cholesterol distinguishes ε2/ε2 carriers from controls and another type of dyslipidaemia, which provides valuable information regarding the pathogenesis of this complex dyslipidaemia. Furthermore, these results suggest that patients with type III hyperlipidaemia may benefit from PCSK9-antagonizing therapy.

Introduction: Practice pattern data demonstrate regional variation and lower than expected rates of adherence to practice guideline (PG) recommendations for the treatment of stage II/IIIA resected and stage IIIA/IIIB unresected non-small cell lung cancer (NSCLC) patients in Ontario, Canada. This study sought to understand how clinical decisions are made for the treatment of these patients and the role of PGs., Methods: Surveys and key informant interviews were undertaken with clinicians and administrators., Results: Participants reported favorable ratings for PGs and the evidentiary bases underpinning them. The majority of participants agreed more patients should have received treatment and that regional variation is problematic. Participants estimated that up to 30% of patients are not good candidates for treatment and up to 20% of patients refuse treatment. The most common barrier to implementing PGs was the lack of organizational support by clinical administrative leadership. There was concern that the trial results underpinning the PG recommendations were not generalizable to the typical patients seen in clinic. The qualitative analysis yielded five themes related to physicians' decision making: the unique patient, the unique physician, the family, the clinical team, and the clinical evidence. A dynamic interplay between these factors exists., Conclusion: Our study demonstrates the challenges inherent in (i) the complexity of clinical decision making; (ii) how quality of care problems are perceived and operationalized; and (iii) the clinical appropriateness and utility of PG recommendations. We argue that systematic and rigorous methodologies to help decision makers mitigate or negotiate these challenges are warranted.

Background: Inter-professional collaborative care (ICC) for cancer leads to multiple system, organizational, professional, and patient benefits, but is limited by numerous challenges. Empirical research on interventions that promote or enable ICC is sparse so guidance on how to achieve ICC is lacking. Research shows that ICC for diagnosis could be improved. Diagnostic assessment programs (DAPs) appear to be a promising model for enabling ICC. The purpose of this study was to explore how DAP structure and function enable ICC, and whether that may be associated with organizational and clinical outcomes., Methods: A case study approach will be used to explore ICC among eight DAPs that vary by type of cancer (lung, breast), academic status, and geographic region. To describe DAP function and outcomes, and gather information that will enable costing, recommendations expressed in DAP standards and clinical guidelines will be assessed through retrospective observational study. Data will be acquired from databases maintained by participating DAPs and the provincial cancer agency, and confirmed by and supplemented with review of medical records. We will conduct a pilot study to explore the feasibility of estimating the incremental cost-effectiveness ratio using person-level data from medical records and other sources. Interviews will be conducted with health professionals, staff, and referring physicians from each DAP to learn about barriers and facilitators of ICC. Qualitative methods based on a grounded approach will be used to guide sampling, data collection and analysis., Discussion: Findings may reveal opportunities for unique structures, interventions or tools that enable ICC that could be developed, implemented, and evaluated through future research. This information will serve as a formative needs assessment to identify the nature of ongoing or required improvements, which can be directly used by our decision maker collaborators, and as a framework by policy makers, cancer system managers, and DAP managers elsewhere to strategically plan for and implement diagnostic cancer services.

Background and Aims: Two recent independent studies showed that patients with familial combined hyperlipidemia (FCHL) have elevated plasma levels of proprotein convertase subtilisin kexin type 9 (PCSK9) and markers of cholesterol synthesis. Both PCSK9 expression and cholesterol synthesis are downstream effects of hepatic activation of sterol regulatory element binding protein 2 (SREBP2). The present study was conducted to study the relationship between plasma PCSK9 and markers of cholesterol synthesis in FCHL., Methods and Results: Markers of cholesterol synthesis (squalene, desmosterol, lathosterol), cholesterol absorption (campesterol, sitosterol, cholestanol) and PCSK9 were measured in plasma of FCHL patients (n = 103) and their normolipidemic relatives (NLR; n = 240). Plasma PCSK9, lathosterol and desmosterol levels were higher in FCHL patients than their NLR (p < 0.001, age and sex adjusted). Heritability calculations demonstrated that 35% of the variance in PCSK9 levels could be explained by additive genetic effects (p < 0.001). Significant age- and sex-adjusted correlations were observed for the relationship between PCSK9 and lathosterol, both unadjusted and adjusted for cholesterol, in the overall FCHL population (both p < 0.001). Multivariate regression analyses, with PCSK9 as the dependent variable, showed that the regression coefficient for FCHL status decreased by 25% (from 0.8 to 0.6) when lathosterol was included. Nevertheless, FCHL status remained an independent contributor to plasma PCSK9 (p < 0.001)., Conclusions: The present study confirms the previously reported high and heritable PCSK9 levels in FCHL patients. Furthermore, we now show that high PCSK9 levels are, in part, explained by plasma lathosterol, suggesting that SREBP2 activation partly accounts for elevated PCSK9 levels in FCHL., (Copyright © 2012 Elsevier B.V. All rights reserved.)

This article presents a new Dutch multicenter study ("PKU-COBESO") into cognitive and behavioral sequelae of early and continuously treated Phenylketonuria (PKU) patients. Part of the study sample will consist of young adult PKU patients who have participated in a large neuropsychological study approximately 10 years ago, when they were 7-to-15-year-olds (Huijbregts et al., 2002 [1]). Their neurocognitive development will be mapped in association with their earlier and continued metabolic history, taking into account possible changes in, for instance, medication. A second part of the sample will consist of PKU patients between the ages of 7 and approximately 40 years (i.e., born in or after 1974, when neonatal screening was introduced in The Netherlands), who have not participated in the earlier neuropsychological study. Again, their cognitive functioning will be related to their metabolic history. With respect to aspects of cognition, there will be an emphasis on executive functioning. The concept of executive functioning will however be extended with further emphasis on the impact of cognitive deficits on the daily lives of PKU patients, aspects of social cognition, social functioning, and behavior/mental health (i.e., COgnition, BEhavior, SOcial functioning: COBESO). In addition to a description of the PKU-COBESO study, some preliminary results with respect to mental health and social functioning will be presented in this article. Thirty adult PKU patients (mean age 27.8, SD 6.4) and 23 PKU patients under the age of 18 years (mean age 11.0, SD 3.3) were compared to 14 (mean age 26.9 years, SD 5.9) and 7 matched controls (mean age 10.5, SD 2.6) respectively, with respect to their scores on the Adult Self-Report or Child Behavior Checklist (measuring mental health problems) and the Social Skills Checklist or Social Skills Rating System (measuring social skills). Whereas there were very few significant group differences (except for mental health problems in the internalizing spectrum for adult PKU patients), possibly due to the small control groups, several significant associations between mental health problems and Phe levels were observed for the PKU patients. Childhood Phe levels and internalizing problems for adult PKU patients were related; concurrent Phe was associated with both internalizing and externalizing behavioral problems for those under the age of 18. These preliminary results underline the importance of early dietary adherence., (© 2013.)

Background: Dysfunctional adipose tissue plays an important role in the etiology of the metabolic syndrome, type 2 diabetes, and dyslipidemia. However, the molecular mechanisms underlying adipocyte dysfunction are incompletely understood., Aim: The aim of the study was to identify differentially regulated pathways in sc adipocytes of dyslipidemic subjects., Methods: Whole-genome expression profiling was conducted on sc adipocytes from a discovery group of nine marginally overweight subjects with familial combined hyperlipidemia (FCHL) and nine controls of comparable body sizes as well as two independent confirmation groups. In this study, FCHL served as a model of familial insulin resistance and dyslipidemia, in the absence of frank obesity., Results: Functional analyses and gene set enrichment analysis using the Kyoto Encyclopedia of Genes and Genomes or a custom pathway database identified the complement system and complement regulators as one of the top up-regulated pathways in FCHL [false discovery rate (FDR) < 1E-30]. Higher adipocyte complement expression in FCHL was confirmed in the appropriate confirmation group. Higher complement gene expression was associated with lower adipocyte insulin receptor substrate-1 expression as marker of adipocyte insulin resistance, independent of age, sex, or disease status, and this association was corroborated in the two confirmation groups. Additionally, complement gene expression was associated with triglycerides in the discovery set and with triglycerides and/or waist circumference in the confirmation groups. Complement pathway up-regulation did not appear to be driven by hypertriglyceridemia because a 40% pharmacological reduction in triglycerides did not affect complement expression., Conclusions: These findings point to an up-regulation of a complement-related transcriptome in sc adipocytes under metabolically stressed conditions, even in the absence of overt obesity. Such up-regulation may subsequently influence downstream processes, including macrophage infiltration into adipose tissue and adipocyte insulin resistance.

Purpose: The objectives of this article are (1) to examine the similarities and differences between comparative effectiveness research (CER) and evidence-based medicine (EBM); (2) to describe the implications of CER for systematic review methodologies in oncology; and (3) to address the transition from systematic reviews to guideline development and the implications of CER in this process., Method: An analysis of the principles and methods of CER was undertaken in light of EBM, systematic reviews, and guidelines., Results and Conclusion: There is considerable overlap between the principles and methods of the two paradigms. The focus on best care options in the context of routine practice is a more central tenet of the CER paradigm. Thus, its value is not that it is the first paradigm to recognize the importance of a patient-focused approach in the research community, but rather, given the attention it has garnered, the CER paradigm may be precisely the reminder and push required to: one, influence how systematic questions are framed so that a more patient-relevant perspective is achieved; two, broaden the types of study designs that are valued and to include those, such as pragmatic trials and observational studies, that are better able to answer effectiveness questions; three, accelerate the development and application of statistical methods that enable indirect comparisons of cancer care options; and four, create clinical practice guidelines that are better positioned to improve quality of care and system performance. Over time, we will see if the CER paradigm lives up to its potential.

Objective: We conducted a systematic review and bibliometric network analysis (SeBriNA) of rituximab for non-Hodgkin's lymphoma., Study Design and Setting: We searched three primary data sources (1997-2003) for five document types: original research, reviews, guidelines, editorials, and media reports. We conducted cumulative meta-analysis on three outcomes (mortality, tumor response, safety) and used GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) to classify evidence quality. Direct citation relationships between original research documents and other documents were analyzed and visually represented., Results: Of 6,798 documents, 757 met inclusion criteria. The 317 original research documents represented 209 study clusters and 8,483 evaluated patients. Of 209 study clusters, 2.9% were randomized controlled trials (RCTs) and reported data on outcomes of interest. The quality of evidence was moderate. We identified 1,571 direct citations to the 317 original research documents. The first RCT reporting relevant outcomes appeared in 2000, whereas the first guidelines appeared in 1999. Of 212 media reports, 92% cited no original research., Conclusions: Of 757 rituximab documents, RCTs of comparisons and outcomes represented <3% of original research. In contrast, review articles, guidelines, editorials, and media reports each outnumbered the relevant original research. The SeBriNA review facilitated the analysis, contextualization, and interpretation of these complex relationships., (Copyright © 2012 Elsevier Inc. All rights reserved.)

The American Society of Clinical Oncology (ASCO) guidelines program employs a systematic review-based methodology to produce evidence-based guidelines. This is consistent with the stance of the Institute of Medicine on guideline development, which is that high-quality evidence syntheses form the basis for recommendation development. In the absence of high-quality evidence, recommendation development becomes more complex. One option is to provide no recommendations or withdraw a guideline topic. However, it is often the areas of greatest uncertainty in which the evidentiary base is incomplete, and thus, guidelines are needed most. To provide recommendations in such circumstances, an explicit methodology is needed to ensure that a credible process is undertaken, and rigorous, reliable advice is provided. In 2010, the ASCO Board of Directors approved development of guideline recommendations using consensus methodology. A modified Delphi approach to recommendation development, based on the best available data identified in a systematic review, was piloted with an ASCO guideline. Consensus was achieved through the rating of a series of recommendations by a large group of clinicians, including academic and community-based content and methodology experts. A prespecified threshold of agreement was determined to indicate when consensus was achieved. Consensus was defined as agreement by ≥ 75% of raters. The formal consensus methodology used by ASCO enabled development of guideline recommendations on a challenging clinical issue based on limited evidence using a rigorous, transparent, and explicit method. This methodology is proposed for development of future ASCO guidelines on topics for which limited evidence is available.

Background: Guidelines are important tools that inform healthcare delivery based on best available research evidence. Guideline use is in part based on quality of the guidelines, which includes advice for implementation and has been shown to vary. Others hypothesized this is due to limited instructions in guideline development manuals. The purpose of this study was to examine manual instructions for implementation advice., Methods: We used a directed and summative content analysis approach based on an established framework of guideline implementability. Six manuals identified by another research group were examined to enumerate implementability domains and elements., Results: Manuals were similar in content but lacked sufficient detail in particular domains. Most frequently this was Accomodation, which includes information that would help guideline users anticipate and/or overcome organizational and system level barriers. In more than one manual, information was also lacking for Communicability, information that would educate patients or facilitate their involvement in shared decision making, and Applicability, or clinical parameters to help clinicians tailor recommendations for individual patients., Discussion: Most manuals that direct guideline development lack complete information about incorporating implementation advice. These findings can be used by those who developed the manuals to consider expanding their content in these domains. It can also be used by guideline developers as they plan the content and implementation of their guidelines so that the two are integrated. New approaches for guideline development and implementation may need to be developed. Use of guidelines might be improved if they included implementation advice, but this must be evaluated through ongoing research.

The existence of metformin-induced lactic acidosis has been questioned, in particular in the absence of specific risk factors such as impaired renal function. This report describes the presence of lactic acidosis in a patient with normal kidney function and normal doses of metformin. Subsequent positive rechallenge with metformin confirms causality., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Background: Modifying the format and content of guidelines may facilitate their use and lead to improved quality of care. We reviewed the medical literature to identify features desired by different users and associated with guideline use to develop a framework of implementability and found that most guidelines do not contain these elements. Further research is needed to develop and evaluate implementability tools., Methods: We are launching the Guideline Implementability Research and Application Network (GIRAnet) to enable the development and testing of implementability tools in three domains: Resource Implications, Implementation, and Evaluation. Partners include the Guidelines International Network (G-I-N) and its member guideline developers, implementers, and researchers. In phase one, international guidelines will be examined to identify and describe exemplar tools. Indication-specific and generic tools will populate a searchable repository. In phase two, qualitative analysis of cognitive interviews will be used to understand how developers can best integrate implementability tools in guidelines and how health professionals use them for interpreting and applying guidelines. In phase three, a small-scale pilot test will assess the impact of implementability tools based on quantitative analysis of chart-based behavioural outcomes and qualitative analysis of interviews with participants. The findings will be used to plan a more comprehensive future evaluation of implementability tools., Discussion: Infrastructure funding to establish GIRAnet will be leveraged with the in-kind contributions of collaborating national and international guideline developers to advance our knowledge of implementation practice and science. Needs assessment and evaluation of GIRAnet will provide a greater understanding of how to develop and sustain such knowledge-exchange networks. Ultimately, by facilitating use of guidelines, this research may lead to improved delivery and outcomes of patient care.

Background: Effective implementation strategies are needed to optimize advancements in the fields of cancer diagnosis, treatment, survivorship, and end-of-life care. We conducted a review of systematic reviews to better understand the evidentiary base of implementation strategies in cancer control., Methods: Using three databases, we conducted a search and identified English-language systematic reviews published between 2005 and 2010 that targeted consumer, professional, organizational, regulatory, or financial interventions, tested exclusively or partially in a cancer context (primary focus); generic or non-cancer-specific reviews were also considered. Data were extracted, appraised, and analyzed by members of the research team, and research ideas to advance the field were proposed., Results: Thirty-four systematic reviews providing 41 summaries of evidence on 19 unique interventions comprised the evidence base. AMSTAR quality ratings ranged between 2 and 10. Team members rated most of the interventions as promising and in need of further research, and 64 research ideas were identified., Conclusions: While many interventions show promise of effectiveness in the cancer-control context, few reviews were able to conclude definitively in favor of or against a specific intervention. We discuss the complexity of implementation research and offer suggestions to advance the science in this area.

The aim of the present study was to investigate the relationship between circulating PCSK9 (proprotein convertase subtilisin kexin type 9) and FCHL (familial combined hyperlipidaemia) and, when positive, to determine the strength of its heritability. Plasma PCSK9 levels were measured in FCHL patients (n=45), NL (normolipidaemic) relatives (n=139) and their spouses (n=72). In addition, 11 FCHL patients were treated with atorvastatin to study the response in PCSK9 levels. PCSK9 levels were higher in FCHL patients compared with NL relatives and spouses: 96.1 compared with 78.7 and 82.0 ng/ml (P=0.004 and P=0.002 respectively). PCSK9 was significantly associated with both TAG (triacylglycerol) and apolipoprotein B levels (P<0.001). The latter relationship was accounted for by LDL (low-density lipoprotein)-apolipoprotein B (r=0.31, P=0.02), not by VLDL (very-low-density lipoprotein)-apolipoprotein B (r=0.09, P=0.49) in a subgroup of subjects (n=59). Heritability calculations for PCSK9 using SOLAR and FCOR software yielded estimates of 67-84% respectively (P<0.0001). PCSK9 increased from 122 to 150 ng/ml in 11 FCHL patients treated with atorvastatin (40 mg) once daily for 8 weeks (P=0.018). In conclusion, plasma PCSK9 is a heritable trait associated with both FCHL diagnostic hallmarks. These results, combined with the significant rise in PCSK9 levels after statin therapy, warrant further studies in order to unravel the exact role of PCSK9 in the pathogenesis and treatment of this highly prevalent genetic dyslipidaemia.

Background: Appropriate screening may reduce the mortality and morbidity of colorectal, breast, and cervical cancers. Several high-quality systematic reviews and practice guidelines exist to inform the most effective screening options. However, effective implementation strategies are warranted if the full benefits of screening are to be realized. We developed an implementation guideline to answer the question: What interventions have been shown to increase the uptake of cancer screening by individuals, specifically for breast, cervical, and colorectal cancers?, Methods: A guideline panel was established as part of Cancer Care Ontario's Program in Evidence-based Care, and a systematic review of the published literature was conducted. It yielded three foundational systematic reviews and an existing guidance document. We conducted updates of these reviews and searched the literature published between 2004 and 2010. A draft guideline was written that went through two rounds of review. Revisions were made resulting in a final set of guideline recommendations., Results: Sixty-six new studies reflecting 74 comparisons met eligibility criteria. They were generally of poor to moderate quality. Using these and the foundational documents, the panel developed a draft guideline. The draft report was well received in the two rounds of review with mean quality scores above four (on a five-point scale) for each of the items. For most of the interventions considered, there was insufficient evidence to support or refute their effectiveness. However, client reminders, reduction of structural barriers, and provision of provider assessment and feedback were recommended interventions to increase screening for at least two of three cancer sites studied. The final guidelines also provide advice on how the recommendations can be used and future areas for research., Conclusion: Using established guideline development methodologies and the AGREE II as our methodological frameworks, we developed an implementation guideline to advise on interventions to increase the rate of breast, cervical and colorectal cancer screening. While advancements have been made in these areas of implementation science, more investigations are warranted.

Background: Appropriate screening may reduce the mortality and morbidity of colorectal, breast, and cervical cancers. However, effective implementation strategies are warranted if the full benefits of screening are to be realized. As part of a larger agenda to create an implementation guideline, we conducted a systematic review to evaluate interventions designed to increase the rate of breast, cervical, and colorectal cancer (CRC) screening. The interventions considered were: client reminders, client incentives, mass media, small media, group education, one-on-one education, reduction in structural barriers, reduction in out-of-pocket costs, provider assessment and feedback interventions, and provider incentives. Our primary outcome, screening completion, was calculated as the overall median post-intervention absolute percentage point (PP) change in completed screening tests., Methods: Our first step was to conduct an iterative scoping review in the research area. This yielded three relevant high-quality systematic reviews. Serving as our evidentiary foundation, we conducted a formal update. Randomized controlled trials and cluster randomized controlled trials, published between 2004 and 2010, were searched in MEDLINE, EMBASE and PSYCHinfo., Results: The update yielded 66 studies new eligible studies with 74 comparisons. The new studies ranged considerably in quality. Client reminders, small media, and provider audit and feedback appear to be effective interventions to increase the uptake of screening for three cancers. One-on-one education and reduction of structural barriers also appears effective, but their roles with CRC and cervical screening, respectively, are less established. More study is required to assess client incentives, mass media, group education, reduction of out-of-pocket costs, and provider incentive interventions., Conclusion: The new evidence generally aligns with the evidence and conclusions from the original systematic reviews. This review served as the evidentiary foundation for an implementation guideline. Poor reporting, lack of precision and consistency in defining operational elements, and insufficient consideration of context and differences among populations are areas for additional research.

Introduction: Self-audit involves self-collection of personal performance data, reflection on gaps between performance and standards, and development and implementation of learning or quality improvement plans by individual care providers. It appears to stimulate learning and quality improvement, but few physicians engage in self-audit. The purpose of this study was to identify how self-audit has been operationalized; factors influencing self-audit conduct and outcomes, including program design; and issues warranting further research., Methods: A systematic review of quantitative and qualitative studies was undertaken. Two individuals independently reviewed searches of indexed literature databases, tables of contents, and references of eligible studies. Data were extracted and tabulated to describe the nature and impact of self-audit programs., Results: Six studies evaluated the impact of self-audit programs. No program was based on a model or theory that informed its design. All studies showed improved compliance with care delivery guidelines and/or improved patient outcomes, although these findings were largely self-reported. Programs varied so features associated with benefit could not be identified., Discussion: Overall there is a need for guidance on all aspects of self-audit for both participants and leaders. This guidance would be useful to educators, professional associations, and medical certification bodies to plan, develop, implement, evaluate, and support self-audit programs. Further research should aim at developing training programs and tools that address and evaluate a variety of competencies across different disciplines using more rigorous research designs, including both quantitative and qualitative approaches., (Copyright © 2011 The Alliance for Continuing Medical Education, the Society for Academic Continuing Medical Education, and the Council on CME, Association for Hospital Medical Education.)

Background: Practice guidelines (PGs) are systematically developed statements intended to assist in patient and practitioner decisions. The AGREE II is the revised tool for PG development, reporting, and evaluation, comprised of 23 items, two global rating scores, and a new User's Manual. In this study, we sought to develop, execute, and evaluate the impact of two internet interventions designed to accelerate the capacity of stakeholders to use the AGREE II., Methods: Participants were randomized to one of three training conditions. 'Tutorial'--participants proceeded through the online tutorial with a virtual coach and reviewed a PDF copy of the AGREE II. 'Tutorial + Practice Exercise'--in addition to the Tutorial, participants also appraised a 'practice' PG. For the practice PG appraisal, participants received feedback on how their scores compared to expert norms and formative feedback if scores fell outside the predefined range. 'AGREE II User's Manual PDF (control condition)'--participants reviewed a PDF copy of the AGREE II only. All participants evaluated a test PG using the AGREE II. Outcomes of interest were learners' performance, satisfaction, self-efficacy, mental effort, time-on-task, and perceptions of AGREE II., Results: No differences emerged between training conditions on any of the outcome measures., Conclusions: We believe these results can be explained by better than anticipated performance of the AGREE II PDF materials (control condition) or the participants' level of health methodology and PG experience rather than the failure of the online training interventions. Some data suggest the online tools may be useful for trainees new to this field; however, this requires further study.

Objective: Type 2 diabetes mellitus (T2DM) is associated with elevated plasma apolipoprotein B and triglycerides levels, reduced HDL cholesterol and the presence of small-dense LDL particles. The present study was conducted to investigate the role of plasma proprotein convertase subtilisin kexin type 9 (PCSK9) levels, a regulator of LDL-receptor expression, in the occurrence of diabetic dyslipidemia., Methods: Plasma PCSK9 was measured in a cohort of subjects with normal glucose metabolism (NGM; n=288), impaired glucose metabolism (IGM; n=121) and type 2 diabetes mellitus (T2DM; n=139) to study whether its relation with plasma apolipoprotein B, triglycerides, total cholesterol, non-HDL cholesterol, LDL cholesterol and HDL cholesterol differed by levels of glucose metabolism status., Results: Plasma PCSK9 levels were not different between the three groups (82, 82 and 80 ng/mL in NGM, IGM and T2DM, respectively). PCSK9 was positively associated with total cholesterol, non-HDL cholesterol, LDL cholesterol, apolipoprotein B and triglycerides levels in all subgroups. The regression slopes for the associations with non-HDL cholesterol were steeper among individuals with T2DM than with NGM (β = 0.016 versus β=0.009, p-interaction=0.05). Similar results were obtained for the relation with apolipoprotein B (β = 0.004 versus β = 0.002, p-interaction=0.09)., Conclusions: Although glucose metabolism status per se is not associated with plasma PCSK9 levels, the presence of T2DM may modify the relation between plasma PCSK9 and non-HDL cholesterol and apolipoprotein B. These observations should be regarded as hypothesis generating for further studies aimed at elucidating the role of PCSK9 in the pathogenesis and treatment of diabetic dyslipidemia., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Purpose: In-the-field projects aiming to improve quality in cancer control provide a valuable complement to health services and knowledge translation (kt) research studies. The present paper describes the methods used to develop the Knowledge Translation for Cancer Control in Canada: A Casebook and its results., Methods: Nominations for in-the-field projects were accepted from individuals and organizations across Canada. The nominations had to demonstrate that a specific cancer control problem was identified; that a deliberate and organized effort was developed and implemented to address the identified problem; and that an evaluation-formal or informal-was used to assess the effort. A selection of nominated cases were chosen for more comprehensive analysis., Results: Thirty nominations were received. Most tackled problems related to treatment or diagnosis. Challenges related to breast, gastrointestinal, and genitourinary cancer were most common among the disease-specific projects, and most projects were regional in scope, with strategies targeting organizational solutions. Of the 30 nominations, 19 were chosen for further analysis. Of those 19, 5 were influenced by a kt model or theory, and 16 reported formal evaluation strategies. Surveys were the most common evaluation method, and process outcomes and clinical surrogate outcomes were the most frequently cited. Financial and administrative challenges were most often cited as key barriers. The key lessons learned concerned the need for a collaborative high-functioning team, project management, and support., Conclusions: The casebook provides tangible examples of in-the-field efforts to improve cancer control and provides practical direction for other individuals and institutions facing similar challenges. We discuss the interface between field projects and research projects in the kt arena and how mutual learning can help to optimize the value of each approach.

The Inventory of Cancer Guidelines (ICG) was designed to mitigate challenges associated with inconsistencies in the quality of cancer guidelines, keeping guidelines current and the duplication of effort in guideline development. The ICG is a searchable database of quality-appraised guidelines in cancer control that also includes designations of guidelines in progress, those in need of an update and those currently being updated. From a clinical perspective, the majority of the completed guidelines target breast, lung, colorectal and prostate cancers, and focus on the treatment stage of the cancer continuum. There is considerable variability in guideline quality both within and across guideline developers, as measured by the Appraisal of Guidelines for Research and Evaluation II. Quality domains of applicability and editorial independence are the guideline quality domains that score the poorest. While the ability to inform on the status of cancer control guidelines is important, the real potential of the ICG is in its ability to leverage positive change in the guideline enterprise. Pilot projects are underway to use data from the ICG to tailor audit and feedback interventions for guideline developers and to pursue collaborative updating and guideline adaptation initiatives, using the ICG as the platform from which these partnerships can evolve.

Background: Guidelines continue to be underutilized, and a variety of strategies to improve their use have been suboptimal. Modifying guideline features represents an alternative, but untested way to promote their use. The purpose of this study was to identify and define features that facilitate guideline use, and examine whether and how they are included in current guidelines., Methods: A guideline implementability framework was developed by reviewing the implementation science literature. We then examined whether guidelines included these, or additional implementability elements. Data were extracted from publicly available high quality guidelines reflecting primary and institutional care, reviewed independently by two individuals, who through discussion resolved conflicts, then by the research team., Results: The final implementability framework included 22 elements organized in the domains of adaptability, usability, validity, applicability, communicability, accommodation, implementation, and evaluation. Data were extracted from 20 guidelines on the management of diabetes, hypertension, leg ulcer, and heart failure. Most contained a large volume of graded, narrative evidence, and tables featuring complementary clinical information. Few contained additional features that could improve guideline use. These included alternate versions for different users and purposes, summaries of evidence and recommendations, information to facilitate interaction with and involvement of patients, details of resource implications, and instructions on how to locally promote and monitor guideline use. There were no consistent trends by guideline topic., Conclusions: Numerous opportunities were identified by which guidelines could be modified to support various types of decision making by different users. New governance structures may be required to accommodate development of guidelines with these features. Further research is needed to validate the proposed framework of guideline implementability, develop methods for preparing this information, and evaluate how inclusion of this information influences guideline use.

Background: Patient involvement in healthcare represents the means by which to achieve a healthcare system that is responsive to patient needs and values. Characterization and evaluation of strategies for involving patients in their healthcare may benefit from a knowledge translation (KT) approach. The purpose of this knowledge synthesis is to develop a conceptual framework for patient-mediated KT interventions., Methods: A preliminary conceptual framework for patient-mediated KT interventions was compiled to describe intended purpose, recipients, delivery context, intervention, and outcomes. A realist review will be conducted in consultation with stakeholders from the arthritis and cancer fields to explore how these interventions work, for whom, and in what contexts. To identify patient-mediated KT interventions in these fields, we will search MEDLINE, the Cochrane Library, and EMBASE from 1995 to 2010; scan references of all eligible studies; and examine five years of tables of contents for journals likely to publish quantitative or qualitative studies that focus on developing, implementing, or evaluating patient-mediated KT interventions. Screening and data collection will be performed independently by two individuals., Conclusions: The conceptual framework of patient-mediated KT options and outcomes could be used by healthcare providers, managers, educationalists, patient advocates, and policy makers to guide program planning, service delivery, and quality improvement and by us and other researchers to evaluate existing interventions or develop new interventions. By raising awareness of options for involving patients in improving their own care, outcomes based on using a KT approach may lead to greater patient-centred care delivery and improved healthcare outcomes.

Purpose of Review: Familial combined hyperlipidemia (FCHL) and type 2 diabetes mellitus (T2DM) are prevalent entities that share many features of the metabolic syndrome. Recent findings suggest that FCHL and T2DM are less distinct than initially anticipated, which could offer new insights for their therapeutic approach., Recent Findings: Genetic association studies have provided evidence for a common genetic background (upstream transcription factor 1, activating transcription factor 6, transcription factor 7-like 2 and hepatocyte nuclear factor 4 alpha) between FCHL and T2DM. The metabolic overlap can be illustrated by the presence of ectopic fat accumulation and insulin resistance (muscle, adipose tissue and liver). We have shown that FCHL patients are at increased risk to develop T2DM. This indicates that both entities are not static, but instead the former is able to migrate to the latter as insulin resistance progresses. Given these new findings, it can be anticipated that FCHL patients could also benefit from insulin-sensitizing therapy such as pioglitazone and metformin. Indeed, pilot studies have demonstrated that pioglitazone might be advantageous in FCHL patients., Summary: Recent studies suggest that FCHL patients have an increased risk to develop T2DM, which has important clinical implications. Further studies are necessary to evaluate whether FCHL patients can be protected from new-onset T2DM and premature cardiovascular events with insulin-sensitizing therapy.

Background: We undertook research to improve the AGREE instrument, a tool used to evaluate guidelines. We tested a new seven-point scale, evaluated the usefulness of the original items in the instrument, investigated evidence to support shorter, tailored versions of the tool, and identified areas for improvement., Method: We report on one component of a larger study that used a mixed design with four factors (user type, clinical topic, guideline and condition). For the analysis reported in this article, we asked participants to read a guideline and use the AGREE items to evaluate it based on a seven-point scale, to complete three outcome measures related to adoption of the guideline, and to provide feedback on the instrument's usefulness and how to improve it., Results: Guideline developers gave lower-quality ratings than did clinicians or policy-makers. Five of six domains were significant predictors of participants' outcome measures (p < 0.05). All domains and items were rated as useful by stakeholders (mean scores > 4.0) with no significant differences by user type (p > 0.05). Internal consistency ranged between 0.64 and 0.89. Inter-rater reliability was satisfactory. We received feedback on how to improve the instrument., Interpretation: Quality ratings of the AGREE domains were significant predictors of outcome measures associated with guideline adoption: guideline endorsements, overall intentions to use guidelines, and overall quality of guidelines. All AGREE items were assessed as useful in determining whether a participant would use a guideline. No clusters of items were found more useful by some users than others. The measurement properties of the seven-point scale were promising. These data contributed to the refinements and release of the AGREE II.

Background: We established a program of research to improve the development, reporting and evaluation of practice guidelines. We assessed the construct validity of the items and user's manual in the beta version of the AGREE II., Methods: We designed guideline excerpts reflecting high-and low-quality guideline content for 21 of the 23 items in the tool. We designed two study packages so that one low-quality and one high-quality version of each item were randomly assigned to each package. We randomly assigned 30 participants to one of the two packages. Participants reviewed and rated the guideline content according to the instructions of the user's manual and completed a survey assessing the manual., Results: In all cases, content designed to be of high quality was rated higher than low-quality content; in 18 of 21 cases, the differences were significant (p < 0.05). The manual was rated by participants as appropriate, easy to use, and helpful in differentiating guidelines of varying quality, with all scores above the mid-point of the seven-point scale. Considerable feedback was offered on how the items and manual of the beta-AGREE II could be improved., Interpretation: The validity of the items was established and the user's manual was rated as highly useful by users. We used these results and those of our study presented in part 1 to modify the items and user's manual. We recommend AGREE II (available at www.agreetrust.org) as the revised standard for guideline development, reporting and evaluation.

Background: Self-administered surveys are an essential methodological tool for health services and knowledge translation research, and engaging end-users of the research is critical. However, few documented accounts of the efforts invested in recruitment of multiple different stakeholders to one health services research study exist. Here, we highlight the challenges of recruiting key stakeholders (policy-makers, clinicians, guideline developers) to a Canadian Institutes of Health Research (CIHR) funded health services research (HSR) study aimed to develop an updated and refined version of a guideline appraisal tool, the AGREE., Methods: Using evidence-based methods of recruitment, our goal was to recruit 192 individuals: 80 international guideline developers, 80 Canadian clinicians and 32 Canadian policy/decision-makers. We calculated the participation rate and the recruitment efficiency., Results: We mailed 873 invitation letters. Of 838 approached, our participation rate was 29%(240) and recruitment efficiency, 19%(156). One policy-maker manager did not allow policy staff to participate in the study., Conclusions: Based on the results from this study, we suggest that future studies aiming to engage similar stakeholders in HSR over sample by at least 5 times to achieve their target sample size and allow for participant withdrawals. We need continued efforts to communicate the value of research between researchers and end-users of research (policy-makers, clinicians, and other researchers), integration of participatory research strategies, and promotion of the value of end-user involvement in research. Future research to understand methods of improving recruitment efficiency and engaging key stakeholders in HSR is warranted.

Background: Practice guidelines (PGs) are systematically developed statements intended to assist in patient, practitioner, and policy decisions. The AGREE II is the revised and updated standard tool for guideline development, reporting and evaluation. It is comprised of 23 items and a user's Manual. The AGREE II is ready for use., Objectives: To develop, execute, and evaluate the impact of two internet-based educational interventions designed to accelerate the capacity of stakeholders to use the AGREE II: a multimedia didactic tutorial with a virtual coach, and a higher intensity training program including both the didactic tutorial and an interactive practice exercise component., Methods: Participants (clinicians, developers, and policy makers) will be randomly assigned to one of three conditions. Condition one, didactic tutorial -- participants will go through the on-line AGREE II tutorial supported by a virtual coach and review of the AGREE II prior to appraising the test PG. Condition two, tutorial + practice -- following the multimedia didactic tutorial with a virtual coach, participants will review the on-line AGREE II independently and use it to appraise a practice PG. Upon entering their AGREE II score for the practice PG, participants will be given immediate feedback on how their score compares to expert norms. If their score falls outside a predefined range, the participant will receive a series of hints to guide the appraisal process. Participants will receive an overall summary of their performance appraising the PG compared to expert norms. Condition three, control arm -- participants will receive a PDF copy of the AGREE II for review and to appraise the test PG on-line. All participants will then rate one of ten test PGs with the AGREE II. The outcomes of interest are learners' performance, satisfaction, self-efficacy, mental effort, and time-on-task; comparisons will be made across each of the test groups., Discussion: Our research will test innovative educational interventions of various intensities and instructional design to promote the adoption of AGREE II and to identify those strategies that are most effective for training. The results will facilitate international capacity to apply the AGREE II accurately and with confidence and to enhance the overall guideline enterprise.

Background: The current study was conducted to investigate whether patients with familial combined hyperlipidaemia (FCHL ) are predisposed to the development of type 2 diabetes mellitus (T2DM)., Methods: A cohort of 56 FCHL patients and 54 spouses was followed over time with a five-year interval. Diagnosis of T2DM was based on fasting glucose levels or use of antidiabetic medication. Baseline body mass index, waist circumference, blood pressure, use of antihypertensive and lipid-lowering medication, plasma cholesterol, triglycerides, apolipoprotein B, glucose, insulin and alanine aminontransferase (ALAT) levels were determined as potential predictors of new onset T2DM., Results: Baseline prevalence of T2DM was 2% in spouses and 9% in FCHL patients, and 4 and 20%, respectively, after five-year follow-up. The incidence of T2DM was significantly higher in FCHL patients (2 vs 14%; OR 9.1; 95% CI 1.0 to 81.4; p=0.04; age and sex adjusted). Of all baseline variables, only plasma insulin levels (not glucose) significantly predicted the development of T2DM (p=0.04)., Conclusion: The present study is the first to present incidence numbers of T2DM in FCHL and demonstrates that FCHL patients, as compared with healthy controls, are predisposed to the development of T2DM. This is - at least in part - accounted for by an increased insulin resistance.