Infographic summaries for clinical practice guidelines: results from user testing of the BMJ Rapid Recommendations in primary care.

OBJECTIVES: Infographics have the potential to enhance knowledge translation and implementation of clinical practice guidelines at the point of care. They can provide a synoptic view of recommendations, their rationale and supporting evidence. They should be understandable and easy to use. Little evaluation of these infographics regarding user experience has taken place. We explored general practitioners' experiences with five selected BMJ Rapid Recommendation infographics suited for primary care. METHODS: An iterative, qualitative user testing design was applied on two consecutive groups of 10 general practitioners for five selected infographics. The physicians used the infographics before clinical encounters and we performed hybrid think-aloud interviews afterwards. 20 interviews were analysed using the Qualitative Analysis Guide of Leuven. RESULTS: Many clinicians reported that the infographics were simple and rewarding to use, time-efficient and easy to understand. They were perceived as innovative and their knowledge basis as trustworthy and supportive for decision-making. The interactive, expandable format was preferred over a static version as general practitioners focused mainly on the core message. Rapid access through the electronic health record was highly desirable. The main issues were about the use of complex scales and terminology. Understanding terminology related to evidence appraisal as well as the interpretation of statistics and unfamiliar scales remained difficult, despite the infographics. CONCLUSIONS: General practitioners perceive infographics as useful tools for guideline translation and implementation in primary care. They offer information in an enjoyable and user friendly format and are used mainly for rapid, tailored and just in time information retrieval. We recommend future infographic producers to provide information as concise as possible, carefully define the core message and explore ways to enhance the understandability of statistics and difficult concepts related to evidence appraisal. TRIAL REGISTRATION NUMBER: MP011977.

How do network meta-analyses address intransitivity when assessing certainty of evidence: a systematic survey.

OBJECTIVES: To describe how systematic reviews with network meta-analyses (NMAs) that used the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) NMA approach addressed intransitivity when assessing certainty of evidence. DESIGN: Systematic survey. DATA SOURCES: Medline, Embase and Cochrane Database of Systematic Reviews from September 2014 to October 2022. ELIGIBILITY CRITERIA: Systematic reviews of randomised controlled trials with aggregate data NMAs that used the GRADE NMA approach for assessing certainty of evidence. DATA EXTRACTION AND SYNTHESIS: We documented how reviewers described methods for addressing intransitivity when assessing certainty of evidence, how often they rated down for intransitivity and their explanations for rating down. RESULTS: Of the 268 eligible systematic reviews, 44.8% (120/268) mentioned intransitivity when describing methods for assessing the certainty of evidence. Of these, 28.3% (34/120) considered effect modifiers and from this subset, 67.6% (23/34) specified the effect modifiers; however, no systematic review noted how they chose the effect modifiers. 15.0% (18/120) mentioned looking for differences between the direct comparisons that inform the indirect estimate. No review specified a threshold for difference in effect modifiers between the direct comparisons that would lead to rating down for intransitivity. Reviewers noted rating down indirect evidence for intransitivity in 33.1% of systematic reviews, and noted intransitivity for network estimates in 23.0% of reviews. Authors provided an explanation for rating down for intransitivity in 59.6% (31/52) of the cases in which they rated down. Of the 31 in which they provided an explanation, 74.2% (23/31) noted they detected differences in effect modifiers and 67.7% (21/31) specified in what effect modifiers they detected differences. CONCLUSIONS: A third of systematic reviews with NMAs using the GRADE approach rated down for intransitivity. Limitations in reporting of methods to address intransitivity proved considerable. Whether the problem is that reviewers neglected to address rating down for transitivity at all, or whether they did consider but not report, is not clear. At minimum systematic reviews with NMAs need to improve their reporting practices regarding intransitivity; it may well be that they need to improve their practice in transitivity assessment. How to best address intransitivity may remain unclear for many reviewers thus additional GRADE guidance providing practical instructions for addressing intransitivity may be desirable.

Culture-based prescribing to improve mental health: a scoping review protocol.

OBJECTIVE: The objective of this review is to investigate what is known about culture-based prescribing to improve mental health and well-being. INTRODUCTION: Culture-based prescribing, where a person is referred by a clinical professional to an arts or cultural activity aimed at improving mental health and well-being, is increasingly used as a community-based source of support. Although culture-based prescribing seems promising, the field is heterogeneous with respect to definition, underlying hypotheses, and cultural activity. This hampers its further development and implementation. INCLUSION CRITERIA: We will consider publications that report on or explore culture-based prescribing to improve mental health and well-being for adults with symptoms related to mental health conditions who are seeking care from any clinical professional. METHODS: We will search 8 electronic literature databases for published or unpublished reports on culture-based prescribing, without date limits. We will also search for gray literature and screen reference lists of relevant reviews. No language restrictions will be applied during the screening process, but for data extraction, we will only extract studies in languages our team has proficiency in. The screening and data extraction will be performed by 2 reviewers, independently. Data analysis will be descriptive, with results tabulated separately for each subquestion. The results will be complemented with a narrative summary. REVIEW REGISTRATION: Open Science Framework https://osf.io/ndbqj.

PCSK9 inhibitors and ezetimibe with or without statin therapy for cardiovascular risk reduction: a systematic review and network meta-analysis.

OBJECTIVE: To compare the impact of ezetimibe and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors on cardiovascular outcomes in adults taking maximally tolerated statin therapy or who are statin intolerant. DESIGN: Network meta-analysis. DATA SOURCES: Medline, EMBASE, and Cochrane Library up to 31 December 2020. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Randomised controlled trials of ezetimibe and PCSK9 inhibitors with ≥500 patients and follow-up of ≥6 months. MAIN OUTCOME MEASURES: We performed frequentist fixed-effects network meta-analysis and GRADE (grading of recommendations, assessment, development, and evaluation) to assess certainty of evidence. Results included relative risks (RR) and absolute risks per 1000 patients treated for five years for non-fatal myocardial infarction (MI), non-fatal stroke, all-cause mortality, and cardiovascular mortality. We estimated absolute risk differences assuming constant RR (estimated from network meta-analysis) across different baseline therapies and cardiovascular risk thresholds; the PREDICT risk calculator estimated cardiovascular risk in primary and secondary prevention. Patients were categorised at low to very high cardiovascular risk. A guideline panel and systematic review authors established the minimal important differences (MID) of 12 per 1000 for MI and 10 per 1000 for stroke. RESULTS: We identified 14 trials assessing ezetimibe and PCSK9 inhibitors among 83 660 adults using statins. Adding ezetimibe to statins reduced MI (RR 0.87 (95% confidence interval 0.80 to 0.94)) and stroke (RR 0.82 (0.71 to 0.96)) but not all-cause mortality (RR 0.99 (0.92 to 1.06)) or cardiovascular mortality (RR 0.97 (0.87 to 1.09)). Similarly, adding PCSK9 inhibitor to statins reduced MI (0.81 (0.76 to 0.87)) and stroke (0.74 (0.64 to 0.85)) but not all-cause (0.95 (0.87 to 1.03)) or cardiovascular mortality (0.95 (0.87 to 1.03)). Among adults with very high cardiovascular risk, adding PCSK9 inhibitor was likely to reduce MI (16 per 1000) and stroke (21 per 1000) (moderate to high certainty); whereas adding ezetimibe was likely to reduce stroke (14 per 1000), but the reduction of MI (11 per 1000) (moderate certainty) did not reach MID. Adding ezetimibe to PCSK9 inhibitor and statin may reduce stroke (11 per 1000), but the reduction of MI (9 per 1000) (low certainty) did not reach MID. Adding PCSK9 inhibitors to statins and ezetimibe may reduce MI (14 per 1000) and stroke (17 per 1000) (low certainty). Among adults with high cardiovascular risk, adding PCSK9 inhibitor probably reduced MI (12 per 1000) and stroke (16 per 1000) (moderate certainty); adding ezetimibe probably reduced stroke (11 per 1000), but the reduction in MI did not achieve MID (8 per 1000) (moderate certainty). Adding ezetimibe to PCSK9 inhibitor and statins did not reduce outcomes beyond MID, while adding PCSK9 inhibitor to ezetimibe and statins may reduce stroke (13 per 1000). These effects were consistent in statin-intolerant patients. Among moderate and low cardiovascular risk groups, adding PCSK9 inhibitor or ezetimibe to statins yielded little or no benefit for MI and stroke. CONCLUSIONS: Ezetimibe or PCSK9 inhibitors may reduce non-fatal MI and stroke in adults at very high or high cardiovascular risk who are receiving maximally tolerated statin therapy or are statin-intolerant, but not in those with moderate and low cardiovascular risk.

PCSK9 inhibitors and ezetimibe for the reduction of cardiovascular events: a clinical practice guideline with risk-stratified recommendations.

CLINICAL QUESTION: In adults with low density lipoprotein (LDL) cholesterol levels >1.8 mmol/L (>70 mg/dL) who are already taking the maximum dose of statins or are intolerant to statins, should another lipid-lowering drug be added, either a proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitor or ezetimibe, to reduce the risk of major cardiovascular events? If so, which drug is preferred? Having decided to use one, should we add the other lipid-lowering drug? CURRENT PRACTICE: Most guidelines emphasise LDL cholesterol targets in their recommendations for prescribing PCSK9 inhibitors and/or ezetimibe in adults at high risk of experiencing a major adverse cardiovascular event. However, to achieve these goals in very high risk patients with statins alone is almost impossible, so physicians are increasingly considering other lipid-lowering drugs solely for achieving LDL cholesterol treatment goals rather than for achieving important absolute cardiovascular risk reduction. Most guidelines do not systematically assess the cardiovascular benefits of adding PCSK9 inhibitors and/or ezetimibe for all risk groups across primary and secondary prevention, nor do they report, in accordance with explicit judgments of assumed patients' values and preferences, absolute benefits and harms and potential treatment burdens. RECOMMENDATIONS: The guideline panel provided mostly weak recommendations, which means we rely on shared decision making when applying these recommendations. For adults already using statins, the panel suggests adding a second lipid-lowering drug in people at very high and high cardiovascular risk but recommends against adding it in people at low cardiovascular risk. For adults who are intolerant to statins, the panel recommends using a lipid-lowering drug in people at very high and high cardiovascular risk but against adding it in those at low cardiovascular risk. When choosing to add another lipid-lowering drug, the panel suggests ezetimibe in preference to PCSK9 inhibitors. The panel suggests further adding a PCSK9 inhibitor to ezetimibe for adults already taking statins at very high risk and those at very high and high risk who are intolerant to statins. HOW THIS GUIDELINE WAS CREATED: An international panel including patients, clinicians, and methodologists produced these recommendations following standards for trustworthy guidelines and using the GRADE approach. The panel identified four risk groups of patients (low, moderate, high, and very high cardiovascular risk) and primarily applied an individual patient perspective in moving from evidence to recommendations, though societal issues were a secondary consideration. The panel considered the balance of benefits and harms and burdens of starting a PCSK9 inhibitor and/or ezetimibe, making assumptions of adults' average values and preferences. Interactive evidence summaries and decision aids accompany multi-layered recommendations, developed in an online authoring and publication platform (www.magicapp.org) that also allows re-use and adaptation. THE EVIDENCE: A linked systematic review and network meta-analysis (14 trials including 83 660 participants) of benefits found that PCSK9 inhibitors or ezetimibe probably reduce myocardial infarctions and stroke in patients with very high and high cardiovascular risk, with no impact on mortality (moderate to high certainty evidence), but not in those with moderate and low cardiovascular risk. PCSK9 inhibitors may have similar effects to ezetimibe on reducing non-fatal myocardial infarction or stroke (low certainty evidence). These relative benefits were consistent, but their absolute magnitude varied based on cardiovascular risk in individual patients (for example, for 1000 people treated with PCSK9 inhibitors in addition to statins over five years, benefits ranged from 2 fewer strokes in the lowest risk to 21 fewer in the highest risk). Two systematic reviews on harms found no important adverse events for these drugs (moderate to high certainty evidence). PCSK9 inhibitors require injections that sometimes result in injection site reactions (best estimate 15 more per 1000 in a 5 year timeframe), representing a burden and harm that may matter to patients. The MATCH-IT decision support tool allows you to interact with the evidence and your patients across the alternative options: https://magicevidence.org/match-it/220504dist-lipid-lowering-drugs/. UNDERSTANDING THE RECOMMENDATIONS: The stratification into four cardiovascular risk groups means that, to use the recommendations, physicians need to identify their patient's risk first. We therefore suggest, specific to various geographical regions, using some reliable risk calculators that estimate patients' cardiovascular risk based on a mix of known risk factors. The largely weak recommendations concerning the addition of ezetimibe or PCSK9 inhibitors reflect what the panel considered to be a close balance between small reductions in stroke and myocardial infarctions weighed against the burdens and limited harms.Because of the anticipated large variability of patients' values and preferences, well informed choices warrant shared decision making. Interactive evidence summaries and decision aids linked to the recommendations can facilitate such shared decisions. The strong recommendations against adding another drug in people at low cardiovascular risk reflect what the panel considered to be a burden without important benefits. The strong recommendation for adding either ezetimibe or PCSK9 inhibitors in people at high and very high cardiovascular risk reflect a clear benefit.The panel recognised the key uncertainty in the evidence concerning patient values and preferences, namely that what most people consider important reductions in cardiovascular risks, weighed against burdens and harms, remains unclear. Finally, availability and costs will influence decisions when healthcare systems, clinicians, or people consider adding ezetimibe or PCSK9 inhibitors.

A Tool to Assess the Trustworthiness of Evidence-Based Point-of-Care Information for Health Care Professionals (CAPOCI): Design and Validation Study.

BACKGROUND: User-friendly information at the point of care for health care professionals should be well structured, rapidly accessible, comprehensive, and trustworthy. The reliability of information and the associated methodological process must be clear. There is no standard tool to evaluate the trustworthiness of such point-of-care (POC) information. OBJECTIVE: We aim to develop and validate a new tool for assessment of trustworthiness of evidence-based POC resources to enhance the quality of POC resources and facilitate evidence-based practice. METHODS: We designed the Critical Appraisal of Point-of-Care Information (CAPOCI) tool based on the criteria important for assessment of trustworthiness of POC information, reported in a previously published review. A group of health care professionals and methodologists (the authors of this paper) defined criteria for the CAPOCI tool in an iterative process of discussion and pilot testing until consensus was reached. In the next step, all criteria were subject to content validation with a Delphi study. We invited an international panel of 10 experts to rate their agreement with the relevance and wording of the criteria and to give feedback. Consensus was reached when 70% of the experts agreed. When no consensus was reached, we reformulated the criteria based on the experts' comments for a next round of the Delphi study. This process was repeated until consensus was reached for each criterion. In a last step, the interrater reliability of the CAPOCI tool was calculated with a 2-tailed Kendall tau correlation coefficient to quantify the agreement between 2 users who piloted the CAPOCI tool on 5 POC resources. Two scoring systems were tested: a 3-point ordinal scale and a 7-point Likert scale. RESULTS: After validation, the CAPOCI tool was designed with 11 criteria that focused on methodological quality and author-related information. The criteria assess authorship, literature search, use of preappraised evidence, critical appraisal of evidence, expert opinions, peer review, timeliness and updating, conflict of interest, and commercial support. Interrater agreement showed substantial agreement between 2 users for scoring with the 3-point ordinal scale (τ=.621, P<.01) and scoring with the 7-point Likert scale (τ=.677, P<.01). CONCLUSIONS: The CAPOCI tool may support validation teams in the assessment of trustworthiness of POC resources. It may also provide guidance for producers of POC resources.

Tools to Assess the Trustworthiness of Evidence-Based Point-of-Care Information for Health Care Professionals: Systematic Review.

BACKGROUND: User-friendly information at the point of care should be well structured, rapidly accessible, and comprehensive. Also, this information should be trustworthy, as it will be used by health care practitioners to practice evidence-based medicine. Therefore, a standard, validated tool to evaluate the trustworthiness of such point-of-care information resources is needed. OBJECTIVE: This systematic review sought to search for tools to assess the trustworthiness of point-of-care resources and to describe and analyze the content of these tools. METHODS: A systematic search was performed on three sources: (1) we searched online for initiatives that worked off of the trustworthiness of medical information; (2) we searched Medline (PubMed) until June 2019 for relevant literature; and (3) we scanned reference lists and lists of citing papers via Web of Science for each retrieved paper. We included all studies, reports, websites, or methodologies that reported on tools that assessed the trustworthiness of medical information for professionals. From the selected studies, we extracted information on the general characteristics of the tools. As no standard, risk-of-bias assessment instruments are available for these types of studies, we described how each tool was developed, including any assessments on reliability and validity. We analyzed the criteria used in the different tools and divided them into five categories: (1) author-related information; (2) evidence-based methodology; (3) website quality; (4) website design and usability; and (5) website interactivity. The percentage of tools in compliance with these categories and the different criteria were calculated. RESULTS: Included in this review was a total of 17 tools, all published between 1997 and 2018. The tools were developed for different purposes, from a general quality assessment of medical information to very detailed analyses, all specifically for point-of-care resources. However, the development process of the tools was poorly described. Overall, seven tools had a scoring system implemented, two were assessed for reliability only, and two other tools were assessed for both validity and reliability. The content analysis showed that all the tools assessed criteria related to an evidence-based methodology: 82% of the tools assessed author-related information, 71% assessed criteria related to website quality, 71% assessed criteria related to website design and usability, and 47% of the tools assessed criteria related to website interactivity. There was significant variability in criteria used, as some were very detailed while others were more broadly defined. CONCLUSIONS: The 17 included tools encompass a variety of items important for the assessment of the trustworthiness of point-of-care information. Overall, two tools were assessed for both reliability and validity, but they lacked some essential criteria for the assessment of the trustworthiness of medical information for use at the point-of-care. Currently, a standard, validated tool does not exist. The results of this review may contribute to the development of such an instrument, which may enhance the quality of point-of-care information in the long term. TRIAL REGISTRATION: PROSPERO CRD42019122565; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=122565.

Bupropion for attention deficit hyperactivity disorder (ADHD) in adults.

BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is a prevalent neurobiological condition, characterised by behavioral and cognitive symptoms such as inattention, impulsivity and/or excessive activity. The syndrome is commonly accompanied by psychiatric comorbidities and is associated with educational and occupational underachievement.Although psychostimulant medications are the mainstay of treatment for ADHD, not all adults respond optimally to, or can tolerate, these medicines. Thus, alternative non-stimulant treatment approaches for ADHD have been explored. One of these alternatives is bupropion, an aminoketone antidepressant and non-competitive antagonism of nicotinic acetylcholine receptors. Bupropion is registered for the treatment of depression and smoking cessation, but is also used off-label to treat ADHD. OBJECTIVES: To assess the effects and safety of bupropion for the treatment of adults with ADHD. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, and seven other databases in February 2017. We also searched three trials registers and three online theses portals. In addition, we checked references of included studies and contacted study authors to identify potentially relevant studies that were missed by our search. SELECTION CRITERIA: We included all randomised controlled trials (RCTs) that evaluated the effects (including adverse effects) of bupropion compared to placebo in adults with ADHD. DATA COLLECTION AND ANALYSIS: Two review authors (WV, GB) independently screened records and extracted data using a data extraction sheet that we tested in a pilot study. We extracted all relevant data on study characteristics and results. We assessed risks of bias using the Cochrane 'Risk of bias' tool, and assessed the overall quality of evidence using the GRADE approach. We used a fixed-effect model to pool the results across studies. MAIN RESULTS: We included six studies with a total of 438 participants. Five studies were conducted in the USA, and one in Iran. All studies evaluated a long-acting version of bupropion, with the dosage ranging from 150 mg up to 450 mg daily. Study intervention length varied from six to 10 weeks. Four studies explicitly excluded participants with psychiatric comorbidity and one study included only participants with opioid dependency. Four studies were funded by industry, but the impact of this on study results is unknown. Two studies were publicly funded and in one of these studies, the lead author was a consultant for several pharmaceutical companies and also received investigator-driven funding from two companies, however none of these companies manufacture bupropion. We judged none of the studies to be free of bias because for most risk of bias domains the study reports failed to provide sufficient details. Using the GRADE approach, we rated the overall quality of evidence as low. We downgraded the quality of the evidence because of serious risk of bias and serious imprecision due to small sample sizes.We found low-quality evidence that bupropion decreased the severity of ADHD symptoms (standardised mean difference -0.50, 95% confidence interval (CI) -0.86 to -0.15, 3 studies, 129 participants), and increased the proportion of participants achieving clinical improvement (risk ratio (RR) 1.50, 95% CI 1.13 to 1.99, 4 studies, 315 participants), and reporting an improvement on the Clinical Global Impression - Improvement scale (RR 1.78, 95% CI 1.27 to 2.50, 5 studies, 337 participants). There was low-quality evidence that the proportion of participants who withdrew due to any adverse effect was similar in the bupropion and placebo groups (RR 1.20, 95% CI 0.35 to 4.10, 3 studies, 253 participants). The results were very similar when using a random-effects model and when we analysed only studies that excluded participants with a psychiatric comorbidity. AUTHORS' CONCLUSIONS: The findings of this review, which compared bupropion to placebo for adult ADHD, indicate a possible benefit of bupropion. We found low-quality evidence that bupropion decreased the severity of ADHD symptoms and moderately increased the proportion of participants achieving a significant clinical improvement in ADHD symptoms. Furthermore, we found low-quality evidence that the tolerability of bupropion is similar to that of placebo. In the pharmacological treatment of adults with ADHD, extended- or sustained-release bupropion may be an alternative to stimulants. The low-quality evidence indicates uncertainty with respect to the pooled effect estimates. Further research is very likely to change these estimates. More research is needed to reach more definite conclusions as well as clarifying the optimal target population for this medicine. Treatment response remains to be reported in a DSM5-diagnosed population. There is also a lack of knowledge on long-term outcomes.

Home- and Community-Based Occupational Therapy Improves Functioning in Frail Older People: A Systematic Review.

OBJECTIVES: The objective is to assess the effectiveness of occupational therapy to improve performance in daily living activities in community-dwelling physically frail older people. DESIGN: We conducted a systematic review and meta-analysis. We included randomized controlled trials reporting on occupational therapy as intervention, or as part of a multidisciplinary approach. This systematic review was carried out in accordance with the Cochrane methods of systematic reviews of interventions. MEASUREMENTS: Meta-analyses were performed to pool results across studies using the standardized mean difference. The primary outcome measures were mobility, functioning in daily living activities, and social participation. Secondary outcome measures were fear of falling, cognition, disability, and number of falling persons. RESULTS: Nine studies met the inclusion criteria. Overall, the studies were of reasonable quality with low risk of bias. There was a significant increase in all primary outcomes. The pooled result for functioning in daily living activities was a standardized mean difference of -0.30 (95% CI -0.50 to -0.11; P = .002), for social participation -0.44 (95% CI -0.69, -0.19; P = .0007) and for mobility -0.45 (95% CI -0.78 to -0.12; P = .007). All secondary outcomes showed positive trends, with fear of falling being significant. No adverse effects of occupational therapy were found. CONCLUSION: There is strong evidence that occupational therapy improves functioning in community-dwelling physically frail older people.

Patient-reported and proxy-reported outcome measures for the assessment of health-related quality of life among patients receiving enteral feeding: a systematic review protocol.

REVIEW QUESTION/OBJECTIVE: The objective is to systematically review the psychometric properties and the clinical utility of patient-reported outcome measures (PROMs) and proxy-reported outcome measures that assess health-related quality of life (HRQoL) among patients receiving enteral feeding to make recommendations for use in clinical practice and research. The purpose of this systematic review is to evaluate the psychometric properties and the clinical utility of:The research question is: What are the psychometric properties and the clinical utility of these measures? We will summarize evidence on the following properties: validity (content validity, criterion-related validity, construct validity, floor and ceiling effects), reliability (reproducibility and internal consistency) and responsiveness and clinical utility (interpretability and feasibility to complete the PROM and the proxy-reported outcome measure).

Development and Validation of Quality Indicators on Continuing Care for Patients With AUD: A Delphi Study.

AIMS: To develop indicators to assess quality of continuing care for persons with alcohol use disorder (AUD). METHODS: A guideline-based RAND-modified Delphi method was used to develop and validate indicators regarding the process and outcome of continuing care. We systematically searched for evidence-based guidelines and existing quality indicators. A multidisciplinary expert panel prioritized recommendations using a written questionnaire followed by a group discussion. Important recommendations were then translated to quality indicators. The panel subsequently selected indicators that were measurable and applicable in Belgium. In a final round the indicators face-validity was assessed. RESULTS: We extracted 69 recommendations from 06 guidelines and 17 relevant quality indicators. Of all, 13 indicators remained after 03 written rounds and 02 group discussions. CONCLUSIONS: This study describes a systematic approach to develop and validate quality indicators for continuing care for AUD. The final set of selected indicators consisted of 10 process and 03 outcome indicators. As the level of evidence of effective continuing care components is very low further development of the indicators is recommended. SHORT SUMMARY: This study describes a systematic approach to develop and validate quality indicators for continuing care for AUD. The proposed set of indicators consisted of 10 process and 03 outcome indicators. As the level of evidence of effective continuing care components is very low further development of the indicators is recommended.

The uniqueness of the human dentition as forensic evidence: a systematic review on the technological methodology.

The uniqueness of human dentition is routinely approached as identification evidence in forensic odontology. Specifically in bitemark and human identification cases, positive identifications are obtained under the hypothesis that two individuals do not have the same dental features. The present study compiles methodological information from articles on the uniqueness of human dentition to support investigations into the mentioned hypothesis. In April 2014, three electronic library databases (SciELO®, MEDLINE®/PubMed®, and LILACS®) were systematically searched. In parallel, reference lists of relevant studies were also screened. From the obtained articles (n = 1235), 13 full-text articles were considered eligible. They were examined according to the studied parameters: the sample size, the number of examined teeth, the registration technique for data collection, the methods for data analysis, and the study outcomes. Six combinations of studied data were detected: (1) dental shape, size, angulation, and position (n = 1); (2) dental shape, size, and angulation (n = 4); (3) dental shape and size (n = 5); (4) dental angulation and position (n = 2); (5) dental shape and angulation (n = 1); and (6) dental shape (n = 1). The sample size ranged between 10 and 1099 human dentitions. Ten articles examined the six anterior teeth, while three articles examined more teeth. Four articles exclusively addressed three-dimensional (3D) data registration, while six articles used two-dimensional (2D) imaging. In three articles, both imaging registrations were combined. Most articles (n = 9) explored the data using landmark placement. The other articles (n = 4) comprised digital comparison of superimposed dental contours. Although there were large methodological variations within the investigated articles, the uniqueness of human dentition remains unproved.

Do randomized clinical trials with inadequate blinding report enhanced placebo effects for intervention groups and nocebo effects for placebo groups?

BACKGROUND: Studies suggest that expectations powerfully shape clinical outcomes. For subjective outcomes in adequately blinded trials, health improvements are substantial and largely explained by non-specific factors.The objective of this study was to investigate if unblinding in randomized controlled trials (RCTs) is associated with enhanced placebo effects for intervention groups and nocebo effects for placebo groups. For these effects, a secondary objective was to explore potential moderating factors. METHODS: We included RCTs that investigated the efficacy of phosphodiesterase-5 (PDE-5) inhibitors for male erectile dysfunction by comparing one PDE-5 inhibitor to placebo. In addition, to be included studies must have reported scores for change from baseline, or baseline and final International Index of Erectile Functioning-Erectile Functioning domain score (IIEF-EF), and be published in either English, French, Dutch, or German.We searched for both published and unpublished relevant trials using PUBMED, EMBASE, the Cochrane Central Register of Controlled Trials, a clinical trials register (clinicaltrials.gov) and the Food and Drug Administration clinical reviews through March 2012.We evaluated the blinding status of trials with the Cochrane Risk of Bias Tool, using the domains of allocation sequence concealment, blinding of participants, healthcare providers and outcome assessors. Across these four domains, studies that scored low risk of bias were judged to be adequately blinded and studies that scored unclear or high risk of bias were judged to be inadequately blinded. RESULTS: We included 110 studies (205 journal publications and 2 unpublished sources) that involved 23,877 participants; 93 (85%), 51 (46%), 93 (85%) and 93 (85%) studies were assessed with an unclear risk of bias for allocation concealment, blinding of participant, blinding of caregiver and blinding of outcome assessor, respectively. None of the studies reported testing of blinding.None of the 205 journal publications provided sufficient details to assess allocation concealment, blinding of participants, caregivers and outcome assessors. After contacting authors for additional information, we judged five studies to be adequately (n = 1,202) and 16 to be inadequately (n = 3,006) blinded. The IIEF-EF score for placebo groups in adequately blinded trials versus inadequately blinded trials was 1.92 points (95% CI, 0.64 to 3.20) versus 1.56 (95% CI, 0.93 to 2.20), respectively. The IIEF-EF score for intervention groups in adequately blinded trials versus inadequately blinded trials was 9.40 (95% CI, 6.96 to 11.83) versus 8.33 (95% CI, 7.29 to 9.37), respectively. In a secondary analysis, prior experience with the drug affected the scores; in placebo groups with participants naïve to the intervention the score was 2.89 (95% CI, 2.33 to 3.45) versus -0.11 (95% CI, -2.06 to 1.84) with participants having prior experience. In the intervention groups, these scores were 7.99 (95% CI, 6.85 to 9.14) versus 8.33 (95% CI, 7.51 to 9.16), respectively.Unblinding lowered placebo scores (creating a nocebo effect) by 19% (0.33 points; 95% CI, -0.96 to 1.62). Unblinding lowered intervention scores by 11% (1.0; 95% CI, -1.35 to 3.47). The results provided no conclusive evidence for nocebo or enhanced placebo effects. Patients taking a PDE-5 inhibitor for the first time experience a larger placebo effect that accounts for 35% of the total effect. CONCLUSIONS: Given the overall poor reporting of blinding in clinical trial reports and the small number of trials that could be rated as adequately or inadequately blinded, we could not draw any robust conclusions about the existence or absence of nocebo and enhanced placebo effects. A large placebo effect was found for patients taking PDE-5 inhibitors for the first time. It was not clear if previous exposure to the drug impacted trial blinding.We found clear evidence that studies assessing a subjective continuous outcome fail to report on measures taken to secure double blinding. Although we observed a trend for the presence of a nocebo effect, there was insufficient evidence to quantify its impact on expectations. RCTs with patients with no prior experience with PDE-5 inhibitors reported larger placebo effects and possibly these studies were better blinded. Future research should further investigate the factors that contribute to blinding and their impact on health outcomes in randomized trials of subjectively assessed conditions. This research is part of a PhD project and has no external funding. The authors have no competing interests to declare.

A systematic review on micronutrient intake adequacy in adult minority populations residing in Europe: the need for action.

This systematic review evaluated micronutrient intake inadequacy of ten micronutrients for adult ethnic minority populations residing in Europe. Pubmed was searched for studies, related references were checked and experts consulted. Ten studies were identified and six were included in the final analysis representing Albanian, Roma, Sub-Saharan African, South Asian and African-Caribbean minority groups. The Estimated Average Requirement cut point was applied to estimate inadequate intake. With the exception of a sub-Saharan African study, of seven micronutrients analysed, inadequate intakes were markedly elevated (>50 % of the population in most cases) in both genders for folate, vitamin B(12), calcium and iron (the latter in females only). A pressing need exists for intake adequacy studies with sound methodologies addressing ethnic minority groups in Europe. These populations constitute a vulnerable population for inadequate intakes and results substantiate the need for further investigation, interventions and policy measures to reduce their nutritional risk.

Micronutrient intake and status in Central and Eastern Europe compared with other European countries, results from the EURRECA network.

OBJECTIVE: To compare micronutrient intakes and status in Central and Eastern Europe (CEE) with those in other European countries and with reference values. DESIGN: Review of the micronutrient intake/status data from open access and grey literature sources from CEE. SETTING: Micronutrients studied were folate, iodine, Fe, vitamin B12 and Zn (for intake and status) and Ca, Cu, Se, vitamin C and vitamin D (for intake). Intake data were based on validated dietary assessment methods; mean intakes were compared with average nutrient requirements set by the Nordic countries or the US Institute of Medicine. Nutritional status was assessed using the status biomarkers and cut-off levels recommended primarily by the WHO. SUBJECTS: For all population groups in CEE, the mean intake and mean/median status levels were compared between countries and regions: CEE, Scandinavia, Western Europe and Mediterranean. RESULTS: Mean micronutrient intakes of adults in the CEE region were in the same range as those from other European regions, with exception of Ca (lower in CEE). CEE children and adolescents had poorer iodine status, and intakes of Ca, folate and vitamin D were below the reference values. CONCLUSIONS: CEE countries are lacking comparable studies on micronutrient intake/status across all age ranges, especially in children. Available evidence showed no differences in micronutrient intake/status in CEE populations in comparison with other European regions, except for Ca intake in adults and iodine and Fe status in children. The identified knowledge gaps urge further research on micronutrient intake/status of CEE populations to make a basis for evidence-based nutrition policy.

Do randomized clinical trials with inadequate blinding report enhanced placebo effects for intervention groups and nocebo effects for placebo groups? A protocol for a meta-epidemiological study of PDE-5 inhibitors.

BACKGROUND: Patients' expectations of treatment effects may contribute to positive (placebo) and negative (nocebo) outcomes. The effect of patient expectations may be pronounced in subjectively assessed conditions, such as male erectile dysfunction. The aim of this project is to examine the magnitude of expectancy in trials of phosphodiesterase-5 inhibitors. We hypothesize that randomized controlled trials with inadequate blinding will report enhanced placebo effects for intervention groups and nocebo effects for placebo groups, compared with adequately blinded studies. METHODS/DESIGN: We will quantify the magnitude of expectancy by comparing the effect estimates of trials with inadequate and adequate blinding. Blinding will be assessed using four domains from the Cochrane 'risk-of-bias' tool: allocation concealment; blinding of patient; caregiver; and outcome assessor. Our secondary aim is to identify factors that can modify expectations, such as prior experience with the intervention and drug side effects.We will perform an electronic search using a combination of controlled vocabulary and free text words in the following databases: MEDLINE, EMBASE, CENTRAL, and a clinical trials register. We will include randomized controlled trials, with either parallel or crossover design, that compare one phosphodiesterase-5 inhibitor with a placebo. The study's primary aim should be to investigate the efficacy of phosphodiesterase-5 inhibitors for treating male erectile dysfunction. Screening will take place at two levels: abstracts and titles, followed by full text reports. Two reviewers will independently extract data on the primary outcome and assess risk of bias.We will meta-analyze treatment effects, if appropriate, to assess the magnitude of enhanced placebo effects and nocebo effects in intervention and placebo groups, respectively. We will explore possible mediators of placebo and nocebo effects with subgroup and meta-regression analyses. DISCUSSION: Treatments may confer significant costs and risk of adverse effects; it is important, therefore, to determine whether the effects of treatments are larger than expectancy alone. If treatment expectations can be used in a non-deceptive way to produce clinically advantageous outcomes, then it may be possible to incorporate such mechanisms into evidence-based healthcare decision-making.

Epidemiology of chronic pain in denmark and sweden.

Introduction. Estimates on the epidemiology of chronic pain vary widely throughout Europe. It is unclear whether this variation reflects true differences between populations or methodological factors. Information on the epidemiology of chronic pain can support decision makers in allocating adequate health care resources. Methods. In order to obtain epidemiological data on chronic pain in Denmark and Sweden, we conducted a literature review of epidemiological data primarily on chronic noncancer pain, prioritising studies of highest quality, recency, and validity by conducting a systematic search for relevant studies. Following quality assessment, data were summarised and assigned to the research questions. Results. The prevalence of moderate to severe noncancer pain was estimated at 16% in Denmark and 18% in Sweden. Chronic pain impacts negatively on perceived health status, quality of life and is associated with increased cost. Despite using pain medications, a large proportion of chronic pain sufferers have inadequate pain control. There was a lack of high-quality and low-bias studies with clear inclusion criteria. Conclusions. In both Denmark and Sweden, chronic pain is a common health problem which is potentially undertreated and warrants attention of health care workers, policy makers and researchers. Future research should utilise clear reporting guidelines to assist decision and policy makers, in this important area.

Incidence and preventability of adverse events requiring intensive care admission: a systematic review.

RATIONALE, AIMS AND OBJECTIVES: Adverse events are unintended patient injuries or complications that arise from health care management resulting in death, disability or prolonged hospital stay. Adverse events that require critical care are a considerable financial burden to the health care system, but also their global impact on patients and society is probably underestimated. The objectives of this systematic review were to synthesize the best available evidence regarding the estimates of the incidence and preventability of adverse events that necessitate intensive care admission, to determine the type and consequences [mortality, length of intensive care unit (ICU) stay and costs] of these adverse events. METHODS: MEDLINE (from 1966 to present), EMBASE (from 1974 to present) and CENTRAL (version 1-2010) were searched for studies reporting on unplanned admissions on ICUs. Several other sources were searched for additional studies. Only quantitative studies that used chart review for the detection of adverse events requiring intensive care admission were considered for eligibility. For the purposes of this systematic review, ICUs were defined as specialized hospital facilities which provide continuous monitoring and intensive care for acutely ill patients. Studies that were published in the English, Dutch, German, French or Spanish language were eligible for inclusion. Two reviewers independently extracted data and assessed the methodological quality of the included studies. RESULTS: A total of 27 studies were reviewed. Meta-analysis of the data was not appropriate because of methodological and statistical heterogeneity between studies; therefore, results are presented in a descriptive way. The percentage of surgical and medical adverse events that required ICU admission ranged from 1.1% to 37.2%. ICU readmissions varied from 0% to 18.3%. Preventability of the adverse events varied from 17% to 76.5%. Preventable adverse events are further synthesized by type of event. Consequences of the adverse events included a mean length of ICU stay that ranged from 1.5 days to 10.4 days for the patient's first stay in ICU and mortality percentages between 0% and 58%. CONCLUSIONS: Adverse events are an important reason for (re)admission to the ICU and a considerable proportion of these are preventable. It was not possible to estimate an overall incidence and preventability rate of these events as we found considerable heterogeneity. To decrease adverse events that necessitate ICU admission, several systems are recommended such as early detection of patients with clinical instability on general wards and the implementation of rapid response teams. Step-down or intermediate care units could be a useful strategy for patients who require monitoring to avoid ICU readmissions. However, the effectiveness of such systems needs to be investigated.

Genetic evidence supporting the association of protease and protease inhibitor genes with inflammatory bowel disease: a systematic review.

As part of the European research consortium IBDase, we addressed the role of proteases and protease inhibitors (P/PIs) in inflammatory bowel disease (IBD), characterized by chronic mucosal inflammation of the gastrointestinal tract, which affects 2.2 million people in Europe and 1.4 million people in North America. We systematically reviewed all published genetic studies on populations of European ancestry (67 studies on Crohn's disease [CD] and 37 studies on ulcerative colitis [UC]) to identify critical genomic regions associated with IBD. We developed a computer algorithm to map the 807 P/PI genes with exact genomic locations listed in the MEROPS database of peptidases onto these critical regions and to rank P/PI genes according to the accumulated evidence for their association with CD and UC. 82 P/PI genes (75 coding for proteases and 7 coding for protease inhibitors) were retained for CD based on the accumulated evidence. The cylindromatosis/turban tumor syndrome gene (CYLD) on chromosome 16 ranked highest, followed by acylaminoacyl-peptidase (APEH), dystroglycan (DAG1), macrophage-stimulating protein (MST1) and ubiquitin-specific peptidase 4 (USP4), all located on chromosome 3. For UC, 18 P/PI genes were retained (14 proteases and 4 protease inhibitors), with a considerably lower amount of accumulated evidence. The ranking of P/PI genes as established in this systematic review is currently used to guide validation studies of candidate P/PI genes, and their functional characterization in interdisciplinary mechanistic studies in vitro and in vivo as part of IBDase. The approach used here overcomes some of the problems encountered when subjectively selecting genes for further evaluation and could be applied to any complex disease and gene family.