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Presenting continuous outcomes in Summary of Findings tables presents particular challenges to interpretation. When each study uses the same outcome measure, and the units of that measure are intuitively interpretable (e.g., duration of hospitalization, duration of symptoms), presenting differences in means is usually desirable. When the natural units of the outcome measure are not easily interpretable, choosing a threshold to create a binary outcome and presenting relative and absolute effects become a more attractive alternative. When studies use different measures of the same construct, calculating summary measures requires converting to the same units of measurement for each study. The longest standing and most widely used approach is to divide the difference in means in each study by its standard deviation and present pooled results in standard deviation units (standardized mean difference). Disadvantages of this approach include vulnerability to varying degrees of heterogeneity in the underlying populations and difficulties in interpretation. Alternatives include presenting results in the units of the most popular or interpretable measure, converting to dichotomous measures and presenting relative and absolute effects, presenting the ratio of the means of intervention and control groups, and presenting the results in minimally important difference units. We outline the merits and limitations of each alternative and provide guidance for meta-analysts and guideline developers.

Zusammenfassung In diesem Artikel beschreiben wir, wie Uberlegungen zum Ressourcenverbrauch in die Erarbeitung von Empfehlungen nach dem GRADE-Ansatz einbezogen werden konnen. Wir fokussieren dabei auf die Probleme bei der Einschatzung der Vertrauenswurdigkeit der Effektschatzer (Qualitat der Evidenz) und wie der Ressourcenverbrauch in die Evidenzprofile und die Summary-of-Findings-(SoF)-Tabellen einbezogen werden kann. GRADE empfiehlt, relevante Unterschiede im Ressourcenverbrauch zwischen alternativen Behandlungsstrategien zusammen mit anderen wichtigen Endpunkten im Evidenzprofil und der SoF-Tabelle aufzufuhren. Wichtige Schritte bei der Berucksichtigung des Ressourcenverbrauchs bei der Erarbeitung von Empfehlungen nach GRADE sind die Identifikation des Ressourcenverbrauchs, der zwischen alternativen Behandlungen differiert und fur Entscheidungstrager potenziell wichtig ist, die Identifikation von Evidenz fur Unterschiede im Ressourcenverbrauch, die Einschatzung der Vertrauenswurdigkeit von Effektschatzern unter Anwendung derselben Kriterien wie fur klinische Endpunkte und die Bewertung des Ressourcenverbrauchs in monetaren Einheiten (Kosten) fur das spezifische Setting, fur das die Empfehlungen gelten sollen. Kernaussagen: • GRADE (Grading of Recommendations Assessment, Development, and Evaluation) bietet einen transparenten, strukturierten Prozess zur Einbeziehung des Ressourcenverbrauchs bei der Formulierung von Empfehlungen in der Gesundheitsversorgung. • Wichtige Unterschiede im Ressourcenverbrauch sollten zusammen mit anderen wichtigen Endpunkten in Evidenzprofilen und Summary-of-Findings (SoF)-Tabellen dokumentiert werden. • Wichtige Schritte bei der Berucksichtigung des Ressourcenverbrauchs sind die Identifikation von potenziell fur Entscheidungstrager relevanter Ressourcennutzung, die Bewertung der Vertrauenswurdigkeit von Effektschatzern fur relevanten Ressourcenverbrauch und die Ermittlung der Kosten des Ressourcenverbrauchs fur das spezifische Setting, fur das die Empfehlungen formuliert werden.

Zusammenfassung Der haufigste Grund fur das Heraufstufen der Qualitat von Evidenz ist das Vorliegen eines grosen Effekts. Der GRADE-Ansatz empfiehlt das Heraufstufen der Qualitat der Evidenz um eine Stufe, wenn methodisch prazise durchgefuhrte Beobachtungsstudien eine mehr als zweifache Reduktion oder einen mehr als zweifachen Anstieg des Risikos zeigen, und das Heraufstufen um zwei Stufen, wenn das Relative Risiko kleiner als 0,2 bzw. groser als 5 ist. Autoren von systematischen Ubersichtsarbeiten und Entwickler von Leitlinien konnen ebenfalls ein Heraufstufen der Qualitat in Erwagung ziehen, wenn eine Dosis-Wirkungs-Beziehung vorliegt oder wenn alle plausiblen Confounder oder Verzerrungen den gezeigten Behandlungseffekt eher reduzieren bzw. einen scheinbaren Effekt erzeugen wurden, wahrend die vorhandenen Ergebnisse keinen Effekt zeigen. Andere Uberlegungen beziehen sich auf die Schnelligkeit, mit der sich ein Effekt einstellt, den zugrunde liegenden Verlauf der Erkrankung und das Vorliegen von indirekter Evidenz. Kernaussagen •GRADE umfasst drei Kriterien fur das Heraufstufen der Qualitat von Evidenz, die insbesondere fur Beobachtungsstudien relevant sind. •Das Heraufstufen um eine oder sogar zwei Stufen ist moglich, wenn Effekte in Beobachtungsstudien ausreichend gros sind, insbesondere wenn sie innerhalb einer kurzen Zeitperiode auftreten. •Eine Dosis-Wirkungs-Beziehung oder die Uberlegung, dass plausible Confounder die Schlusse bezuglich des Behandlungseffekts weiter unterstutzen wurden, konnen ebenfalls zum Heraufstufen der Qualitat der Evidenz fuhren.

GRADE requires guideline developers to make an overall rating of confidence in estimates of effect (quality of evidence-high, moderate, low, or very low) for each important or critical outcome. GRADE suggests, for each outcome, the initial separate consideration of five domains of reasons for rating down the confidence in effect estimates, thereby allowing systematic review authors and guideline developers to arrive at an outcome-specific rating of confidence. Although this rating system represents discrete steps on an ordinal scale, it is helpful to view confidence in estimates as a continuum, and the final rating of confidence may differ from that suggested by separate consideration of each domain. An overall rating of confidence in estimates of effect is only relevant in settings when recommendations are being made. In general, it is based on the critical outcome that provides the lowest confidence.

Summary of Findings (SoF) tables present, for each of the seven (or fewer) most important outcomes, the following: the number of studies and number of participants; the confidence in effect estimates (quality of evidence); and the best estimates of relative and absolute effects. Potentially challenging choices in preparing SoF tables include using direct evidence (which may have very few events) or indirect evidence (from a surrogate) as the best evidence for a treatment effect. If a surrogate is chosen, it must be labeled as substituting for the corresponding patient-important outcome. Another such choice is presenting evidence from low-quality randomised trials or high-quality observational studies. When in doubt, a reasonable approach is to present both sets of evidence; if the two bodies of evidence have similar quality but discrepant results, one would rate down further for inconsistency. For binary outcomes, relative risks (RRs) are the preferred measure of relative effect and, in most instances, are applied to the baseline or control group risks to generate absolute risks. Ideally, the baseline risks come from observational studies including representative patients and identifying easily measured prognostic factors that define groups at differing risk. In the absence of such studies, relevant randomised trials provide estimates of baseline risk. When confidence intervals (CIs) around the relative effect include no difference, one may simply state in the absolute risk column that results fail to show a difference, omit the point estimate and report only the CIs, or add a comment emphasizing the uncertainty associated with the point estimate. KEY STATEMENTS: Summary of Findings (SoF) tables provide succinct; easily digestible presentations of confidence in effect estimates (quality of evidence) and magnitude of effects. SoF tables should present the seven (or fewer) most important outcomes. These outcomes must always be patient-important outcomes and never be surrogates, although surrogates can be used to estimate effects on patient-important outcomes. SoF tables should present the highest quality evidence. When the quality of two bodies of evidence (e.g., randomised trials and observational studies) is similar, SoF tables may include summaries from both. SoF tables should include both relative and absolute effect measures, and separate estimates of absolute effect for identifiable patient groups with substantially different baseline or control group risks.

Background Pruritus is not the most prevalent but one of the most puzzling symptoms in palliative care patients. It can cause considerable discomfort and has a major impact on patients’ quality of life. In the field of palliative care, pruritus is a symptom occurring in patients with disparate underlying diseases and based on different pathologic mechanisms but ending in the same phenomenon. The pathogenesis of pruritus is complex and not fully elucidated. Thus, it is still very difficult to treat pruritus effectively. Evidence-based treatment approaches are needed. Objectives The objective was to evaluate the efficacy of different pharmacological treatments for preventing or treating pruritus in adult palliative care patients. Search methods A systematic literature search up to January 2012 was performed and it was updated in August 2012. The following databases were searched: The Cochrane Library (CENTRAL, DARE, CDSR) (2012, issue 8 of 12); MEDLINE (1950 to August 2012); EMBASE (1980 to August 2012) and three other databases. In addition, we searched trials registries and checked the reference lists of all relevant studies, key textbooks, reviews, and websites, and contacted investigators and specialists in pruritus and palliative care regarding unpublished data. Selection criteria We included randomised controlled trials assessing the effects of different pharmacological treatments on preventing or treating pruritus in palliative care patients. Data collection and analysis Two review authors independently assessed identified titles and abstracts. Three independent review authors performed assessment of all potentially relevant studies, data extraction, assessment of risk of bias and methodological quality. Results were summarised descriptively according to the different pharmacological interventions and the type of underlying pruritus. Where possible, results were presented in meta-analyses. Main results In total, 38 reports comprising 40 studies and 1286 participants were included in the review. Altogether, 30 different treatments for pruritus in four different patient groups were included. The findings of this review indicated that the treatment of pruritus for palliative care patients is challenging and requires an individualistic approach. Results showed that effective therapeutic choices have to be guided by the pathophysiology of the pruritus. Various forms of pruritus occur, especially in the field of palliative care, and sometimes the origin of the pruritus is difficult to determine. Therefore, identifying the underlying cause of pruritus is of prime importance in order to develop tailored treatment plans, even if in palliative care the treatment is focused towards the symptom and not necessarily the underlying disease. Results show that in palliative care patients with pruritus of different natures, treatment with the drug paroxetine, a selective serotonin reuptake inhibitor, may be beneficial. For patients suffering from pruritus associated with HIV infection, indomethacin was described as the most effective drug, although the evidence was weak. For patients suffering from chronic kidney disease-associated pruritus, gabapentin may be an option. An alternative treatment for this patient group seems to be the κ-opioid receptor agonist nalfurafine, which has shown significant amelioration of pruritus and acceptable adverse effects. As they have exhibited a low incidence of adverse effects, rifampicin and flumecinol may be recommended for patients with cholestatic pruritus. The opioid antagonist naltrexone has been shown to offer a therapeutic alternative for patients suffering from uraemic or cholestatic pruritus. However, these drugs are often inappropriate in the palliative population because of the risk of reducing analgesia when giving high doses of naltrexone. Authors' conclusions The findings of this review indicate that the number of systemic and topical drugs used for the different subforms of pruritus is increasing. Different interventions have been shown to be effective in the treatment of pruritus of different origins. Nevertheless, an optimal therapy for pruritus is constrained due to the limited understanding of crucial itch mediators and receptors in the various subforms of itch. Ideal antipruritic therapies are still lacking, especially for palliative care patients. This systematic review also indicates that there is insufficient evidence to give any concrete recommendations regarding treatment of pruritus in palliative care patients. Due to the very small sample sizes and poor methodological quality of the majority of studies that were included, the results of this review need to be interpreted with caution. Furthermore, the generalizability is questionable. Additional studies, and particularly carefully designed treatment trials, are needed to provide valid evidence for adequate treatment of pruritus in palliative care patients.

X-linked inhibitor of apoptosis (XIAP) deficiency caused by mutations in BIRC4 was initially described in patients with X-linked lymphoproliferative syndrome (XLP) who had no mutations in SH2D1A. In the initial reports, EBV-associated hemophagocytic lymphohistiocytosis (HLH) was the predominant clinical phenotype. Among 25 symptomatic patients diagnosed with XIAP deficiency, we identified 17 patients who initially presented with manifestations other than HLH. These included Crohn-like bowel disease (n=6), severe infectious mononucleosis (n=4), isolated splenomegaly (n=3), uveitis (n=1), periodic fever (n=1), fistulating skin abscesses (n=1) and severe Giardia enteritis (n=1). Subsequent manifestations included celiac-like disease, antibody deficiency, splenomegaly and partial HLH. Screening by flow cytometry identified 14 of 17 patients in our cohort. However, neither genotype nor protein expression nor results from cell death studies were clearly associated with the clinical phenotype. Only mutation analysis can reliably identify affected patients. XIAP deficiency must be considered in a wide range of clinical presentations.

Background Unilateral ureteric-pelvic junction obstruction (UPJO) is the most common cause of obstructive uropathy and may lead to renal impairment and loss of renal function. The current diagnostic approach with renal imaging cannot reliably determine which newborns and infants less than two years of age have a significant obstruction and are at risk for permanent kidney damage. There is therefore no consensus on optimal therapeutic management of unilateral UPJO. Objectives To assess the effects of surgical versus non-surgical treatment options for newborns and infants less than two years of age with unilateral UPJO. Search methods We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 6, 2016), MEDLINE/Ovid, and EMBASE/Ovid databases from their inception to 13 June 2016. We searched the reference lists of potentially relevant studies without using any language restriction. We also searched the following trial registers for relevant registered studies: www.clinicaltrials.gov/; ISRCTN registry (controlled-trials.com/); www.trialscentral.org/; apps.who.int/trialsearch/; www.drks.de/; and www.anzctr.org.au/trialSearch.aspx. Selection criteria We selected randomised and quasi-randomised controlled trials comparing surgical with non-surgical interventions for the treatment of unilateral UPJO. Data collection and analysis Two review authors independently assessed study eligibility and risk of bias of included studies and extracted data. In case of disagreements we consulted a third review author. The data reported in the two included studies did not allow us to perform a meta-analysis. Main results We found only two studies at high risk of bias that were eligible for inclusion in this review. The total sample size, including both trials, was small (n = 107 participants less than six months of age from the UK and USA), and not all prespecified outcome measures were assessed. Reported measures only accounted for the short-term follow-ups. The mean split renal function was not statistically different between the surgical and non-surgical group at the six-month or one-year time point (very low-quality evidence). The surgical group showed a significantly less obstructed drainage pattern and a lower urinary tract dilatation than the non-surgical group (very low-quality evidence). Transfer from the non-surgical group to the surgical group was reported for about one out of five participants. Split renal function after secondary surgical intervention was reported with variable results, but most of the participants reverted to pre-deteriorated values. The studies either provided no or insufficient data on the following outcome measures: postoperative complications, UPJO-associated clinical symptoms, costs of interventions, radiation exposure, quality of life, and adverse effects. Authors' conclusions We found limited evidence assessing the benefits and harms of surgical compared to non-surgical treatment options for newborns and infants less than two years of age with unilateral UPJO. The majority of participants in the non-surgical treatment group did not experience any significant deterioration of split renal function, and only about 20% of them underwent secondary surgical intervention, with minor risk of permanent deteriorated split renal function. The study follow-up period was too short to assess the long-term effects on split renal function in both treatment groups. We need further randomised controlled trials with sufficient statistical power and an adequate follow-up period to determine the optimal therapy for newborns and infants less than two years of age with unilateral UPJO.

Objectives: The aim of this paper is to describe a conceptual framework for how to consider health equity in the Grading Recommendations Assessment and Development Evidence (GRADE) guideline development process. Study Design and Setting: Consensus-based guidance developed by the GRADE working group members and other methodologists. Results: We developed consensus-based guidance to help address health equity when rating the certainty of synthesized evidence (i.e., quality of evidence). When health inequity is determined to be a concern by stakeholders, we propose five methods for explicitly assessing health equity: (1) include health equity as an 'outcome; (2) consider patient-important outcomes relevant to health equity; (3) assess differences in the relative effect size of the treatment; (4) assess differences in baseline risk and the differing impacts on absolute effects; and (5) assess indirectness of evidence to disadvantaged populations and/or settings. Conclusion: The most important priority for research on health inequity and guidelines is to identify and document examples where health equity has been considered explicitly in guidelines. Although there is a weak scientific evidence base for assessing health equity, this should not discourage the explicit consideration of how guidelines and recommendations affect the most vulnerable members of society. (C) 2017 The Authors. Published by Elsevier Inc.

Background Little is known about publication agreements between industry and academic investigators in trial protocols and the consistency of these agreements with corresponding statements in publications. We aimed to investigate (i) the existence and types of publication agreements in trial protocols, (ii) the completeness and consistency of the reporting of these agreements in subsequent publications, and (iii) the frequency of co-authorship by industry employees. Methods and Findings We used a retrospective cohort of randomized clinical trials (RCTs) based on archived protocols approved by six research ethics committees between 13 January 2000 and 25 November 2003. Only RCTs with industry involvement were eligible. We investigated the documentation of publication agreements in RCT protocols and statements in corresponding journal publications. Of 647 eligible RCT protocols, 456 (70.5%) mentioned an agreement regarding publication of results. Of these 456, 393 (86.2%) documented an industry partner’s right to disapprove or at least review proposed manuscripts; 39 (8.6%) agreements were without constraints of publication. The remaining 24 (5.3%) protocols referred to separate agreement documents not accessible to us. Of those 432 protocols with an accessible publication agreement, 268 (62.0%) trials were published. Most agreements documented in the protocol were not reported in the subsequent publication (197/268 [73.5%]). Of 71 agreements reported in publications, 52 (73.2%) were concordant with those documented in the protocol. In 14 of 37 (37.8%) publications in which statements suggested unrestricted publication rights, at least one co-author was an industry employee. In 25 protocol-publication pairs, author statements in publications suggested no constraints, but 18 corresponding protocols documented restricting agreements. Conclusions Publication agreements constraining academic authors’ independence are common. Journal articles seldom report on publication agreements, and, if they do, statements can be discrepant with the trial protocol., In a document analysis of trial protocols and publications, Erik von Elm and colleagues investigate the potential impact of publication agreements between industry sponsors and academic investigators., Author Summary Why Was This Study Done? Many randomized trials are designed and sponsored by for-profit companies that contract academic investigators to recruit and manage patients. Clinical research under these circumstances is a business transaction that bears the potential for conflicts of interest, in particular with respect to trial publication. Besides evidence from a small sample, it was unclear how often trial protocols included publication agreements between industry and academic investigators, whether these agreements constrained the investigators’ publication rights, and how consistent such agreements stated in trial protocols were with those reported in corresponding publications. What Did the Researchers Do and Find? We investigated publication agreements in 647 randomized trial protocols approved in 2000–2003 by six research ethics committees in Switzerland, Canada, and Germany, and in 388 corresponding journal publications. Seventy percent of protocols mentioned an agreement on publication rights between industry and academic investigators; in 86% of those agreements, industry retained the right to disapprove or at least review manuscripts before publication. Seventy-four percent of agreements documented in protocols were not mentioned in corresponding journal articles. What Do These Findings Mean? Publication agreements constraining academic investigators’ independence are incompletely reported in publications; this may compromise the scientific evidence base established by randomized clinical trials. More transparency on publication constraints is warranted. Half of the included journal articles were published before 2008, leaving open the possibility that these findings do not reflect current reporting practice.

Objectives This article introduces the rationale and methods for explicitly considering health equity in the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology for development of clinical, public health, and health system guidelines. Study Design and Setting We searched for guideline methodology articles, conceptual articles about health equity, and examples of guidelines that considered health equity explicitly. We held three meetings with GRADE Working Group members and invited comments from the GRADE Working Group listserve. Results We developed three articles on incorporating equity considerations into the overall approach to guideline development, rating certainty, and assembling the evidence base and evidence to decision and/or recommendation. Conclusion Clinical and public health guidelines have a role to play in promoting health equity by explicitly considering equity in the process of guideline development.

Objectives: The current format of summary of findings (SoFs) tables for presenting effect estimates and associated quality of evidence improve understanding and assist users finding key information in systematic reviews. Users of SoF tables have demanded alternative formats to express findings from systematic reviews. Study Design and Setting: We conducted a randomized controlled trial among systematic review users to compare the relative merits of a new format with the current formats of SoF tables regarding understanding, accessibility of information, satisfaction, and preference. Our primary goal was to show that the new format is not inferior to the current format. Results: Of 390 potentially eligible subjects, 290 were randomized. Of seven items testing understanding, three showed similar results, two showed small differences favoring the new format, and two (understanding risk difference and quality of the evidence associated with a treatment effect) showed large differences favoring the new format [63% (95% confidence interval {CU}: 55, 71) and 62% (95% CI: 52, 71) more correct answers, respectively]. Respondents rated information in the alternative format as more accessible overall and preferred the new format over the current format. Conclusions: While providing at least similar levels of understanding for some items and increased understanding for others, users prefer the new format of SoF tables. (C) 2016 Elsevier Inc. All rights reserved.

OBJECTIVES Randomized clinical trials that enroll patients in critical or emergency care (acute care) setting are challenging because of narrow time windows for recruitment and the inability of many patients to provide informed consent. To assess the extent that recruitment challenges lead to randomized clinical trial discontinuation, we compared the discontinuation of acute care and nonacute care randomized clinical trials. DESIGN Retrospective cohort of 894 randomized clinical trials approved by six institutional review boards in Switzerland, Germany, and Canada between 2000 and 2003. SETTING Randomized clinical trials involving patients in an acute or nonacute care setting. SUBJECTS AND INTERVENTIONS We recorded trial characteristics, self-reported trial discontinuation, and self-reported reasons for discontinuation from protocols, corresponding publications, institutional review board files, and a survey of investigators. MEASUREMENTS AND MAIN RESULTS Of 894 randomized clinical trials, 64 (7%) were acute care randomized clinical trials (29 critical care and 35 emergency care). Compared with the 830 nonacute care randomized clinical trials, acute care randomized clinical trials were more frequently discontinued (28 of 64, 44% vs 221 of 830, 27%; p = 0.004). Slow recruitment was the most frequent reason for discontinuation, both in acute care (13 of 64, 20%) and in nonacute care randomized clinical trials (7 of 64, 11%). Logistic regression analyses suggested the acute care setting as an independent risk factor for randomized clinical trial discontinuation specifically as a result of slow recruitment (odds ratio, 4.00; 95% CI, 1.72-9.31) after adjusting for other established risk factors, including nonindustry sponsorship and small sample size. CONCLUSIONS Acute care randomized clinical trials are more vulnerable to premature discontinuation than nonacute care randomized clinical trials and have an approximately four-fold higher risk of discontinuation due to slow recruitment. These results highlight the need for strategies to reliably prevent and resolve slow patient recruitment in randomized clinical trials conducted in the critical and emergency care setting.

In the GRADE approach, randomised trials start as high-quality evidence and observational studies as low-quality evidence, but both can be rated down if most of the relevant evidence comes from studies that suffer from a high risk of bias. Well-established limitations of randomised trials include failure to conceal allocation, failure to blind, loss to follow-up, and failure to appropriately consider the intention-to-treat principle. More recently, recognised limitations include stopping early for apparent benefit and selective reporting of outcomes according to the results. Key limitations of observational studies include use of inappropriate controls and failure to adequately adjust for prognostic imbalance. Risk of bias may vary across outcomes (e.g., loss to follow-up may be far less for all-cause mortality than for quality of life), a consideration that many systematic reviews ignore. In deciding whether to rate down for risk of bias - whether for randomised trials or observational studies-authors should not take an approach that averages across studies. Rather, for any individual outcome, when there are some studies with a high risk, and some with a low risk of bias, they should consider including only the studies with a lower risk of bias.

In the GRADE approach, randomized trials are classified as high quality evidence and observational studies as low quality evidence but both can be rated down if a body of evidence is associated with a high risk of publication bias. Even when individual studies included in best-evidence summaries have a low risk of bias, publication bias can result in substantial overestimates of effect. Authors should suspect publication bias when available evidence comes from a number of small studies most of which have been commercially funded. A number of approaches based on examination of the pattern of data are available to help assess publication bias. The most popular of these is the funnel plot; all, however, have substantial limitations. Publication bias is likely frequent, and caution in the face of early results, particularly with small sample size and number of events, is warranted.

Direct evidence comes from research that directly compares the interventions in which we are interested when applied to the populations in which we are interested and measures outcomes important to patients. Evidence can be indirect in one of four ways. First, patients may differ from those of interest (the term applicability is often used for this form of indirectness). Second, the intervention tested may differ from the intervention of interest. Decisions regarding indirectness of patients and interventions depend on an understanding of whether biological or social factors are sufficiently different that one might expect substantial differences in the magnitude of effect. Third, outcomes may differ from those of primary interest - for instance, surrogate outcomes that are not themselves important, but measured in the presumption that changes in the surrogate reflect changes in an outcome important to patients. A fourth type of indirectness, which is conceptually different from the first three, occurs when clinicians must choose between interventions that have not been tested in head to head comparisons. Making comparisons between treatments under these circumstances requires specific statistical methods and will be rated down in quality by one or two levels depending on the extent of differences between the patient populations, co-interventions, measurements of the outcome, and the methods of the trials of the candidate interventions against some other comparator.

This article is the first of a series providing guidance for the use of the GRADE system of rating quality of evidence and grading strength of recommendations in systematic reviews, health technology assessments, and clinical practice guidelines addressing alternative management options. The GRADE process begins with asking an explicit question, including specification of all important outcomes. After the evidence has been collected and summarised, GRADE provides explicit criteria for rating the quality of evidence that include study design, risk of bias, imprecision, inconsistency, indirectness, and magnitude of effect. Recommendations are characterised as strong or weak (alternative terms: conditional or discretionary) according to the quality of the supporting evidence and the balance between desirable and undesirable consequences of the alternative management options. GRADE suggests summarising evidence in succinct, transparent, and informative Summary of Findings tables that show the quality of evidence and the magnitude of relative and absolute effects for each important outcome and/or as evidence profiles that provide, in addition, detailed information about the reason for the quality of evidence rating. Subsequent articles in this series will address GRADE's approach to formulating questions, assessing quality of evidence, and developing recommendations.

GRADE requires a clear specification of the relevant setting, population, intervention, and comparator. It also requires specification of all important outcomes - whether evidence from research studies is, or is not, available. For a particular management question, the population, intervention, and outcome should be sufficiently similar across studies so that a similar magnitude of effect is plausible. Guideline developers should specify the relative importance of the outcomes before gathering the evidence and again when evidence summaries are complete. In considering the importance of a surrogate outcome, authors should rate the importance of the patient-important outcome for which the surrogate is a substitute and subsequently rate down the quality of evidence for indirectness of outcome.

GRADE suggests that examination of 95% confidence intervals (CIs) provides the optimal primary approach to decisions regarding imprecision. For practice guidelines, rating down the quality of evidence (i.e., confidence in estimates of effect) is required when clinical action would differ if the upper versus the lower boundary of the CI represented the truth. An exception to this rule occurs when an effect is large, and consideration of CIs alone suggests a robust effect, but the total sample size is not large and the number of events is small. Under these circumstances, one should consider rating down for imprecision. To inform this decision, one can calculate the number of patients required for an adequately powered individual trial (termed the "optimal information size" or OIS). For continuous variables, we suggest a similar process, initially considering the upper and lower limits of the CI, and subsequently calculating an OIS. Systematic reviews require a somewhat different approach. If the 95% CI excludes a relative risk (RR) of 1.0 and the total number of events or patients exceeds the OIS criterion, precision is adequate. If the 95% CI includes appreciable benefit or harm (we suggest a RR of under 0.75 or over 1.25 as a rough guide) rating down for imprecision may be appropriate even if OIS criteria are met.

This article deals with inconsistency of relative, rather than absolute, treatment effects in binary/dichotomous outcomes. A body of evidence is not rated up in quality if studies yield consistent results, but may be rated down in quality if inconsistent. Criteria for evaluating consistency include similarity of point estimates, extent of overlap of confidence intervals, and statistical criteria including tests of heterogeneity and I(2). To explore heterogeneity, systematic review authors should generate and test a small number of a priori hypotheses related to patients, interventions, outcomes, and methodology. When inconsistency is large and unexplained, rating down quality for inconsistency is appropriate, particularly if some studies suggest substantial benefit, and others no effect or harm (rather than only large versus small effects). Apparent subgroup effects may be spurious. Credibility is increased if subgroup effects are based on a small number of a priori hypotheses with a specified direction; subgroup comparisons come from within rather than between studies; tests of interaction generate low p-values; and have a biological rationale.

Zusammenfassung Dieser Artikel stellt den GRADE-Ansatz zur Bewertung der Qualitat der Evidenz vor. GRADE definiert vier Kategorien der Qualitat der Evidenz – hoch, moderat, niedrig und sehr niedrig – die auf einen Evidenzkorper angewendet werden und nicht auf einzelne Studien. Im Kontext von systematischen Ubersichtsarbeiten spiegelt die Qualitat unser Vertrauen wider, dass die ermittelten Effektschatzer korrekt sind. Im Kontext von Empfehlungen spiegelt die Qualitat unser Vertrauen wider, dass die Effektschatzer adaquat sind, um eine bestimmte Empfehlung zu unterstutzen. Randomisierte kontrollierte Studien beginnen als Evidenz hoher Qualitat, Beobachtungsstudien als Evidenz niedriger Qualitat. „Qualitat“ innerhalb des GRADE-Ansatzes bedeutet mehr als nur das Bias-Risiko der einzelnen Studien und kann auch durch fehlende Prazision, Inkonsistenz (Heterogenitat), Indirektheit (indirekte Studienergebnisse) und Publikationsbias beeintrachtigt werden. Zusatzlich konnen mehrere Faktoren unser Vertrauen in den Effektschatzer vergrosern. GRADE liefert einen systematischen Ansatz, um jeden dieser Faktoren zu berucksichtigen und zu berichten. GRADE trennt den Prozess der Bewertung der Qualitat der Evidenz vom Prozess der Entwicklung von Empfehlungen, wobei die Einschatzung der Starke einer Empfehlung nicht nur von der Qualitat der Evidenz abhangt.

BACKGROUND Acute graft-versus-host disease (aGvHD) is a major cause of morbidity and mortality after haematopoietic stem cell transplantation (HSCT) occurring in 8% to 59% of the recipients. Currently, the therapeutic mainstay for aGvHD is corticosteroids. However, there is no established standard treatment for steroid-refractory aGvHD. Extracorporeal photopheresis (ECP) is a type of immunomodulatory method amongst different therapeutic options that involves ex vivo collection of peripheral mononuclear cells, exposure to the photoactive agent 8-methoxypsoralen and ultraviolet-A radiation, and re-infusion of these treated blood cells to the patient. The mechanisms of action of ECP are not completely understood. This is an updated version of a Cochrane review first published in 2014. OBJECTIVES To evaluate the effectiveness and safety of ECP for the management of aGvHD in children and adolescents after HSCT. SEARCH METHODS We searched the Cochrane Register of Controlled Trials (CENTRAL) (Issue 9, 2015), MEDLINE (PubMed) and EMBASE (Ovid) databases from their inception to 23 September 2015. We searched the reference lists of potentially relevant studies without any language restrictions. We searched eight trial registers and four conference proceedings on 29 September 2015. SELECTION CRITERIA Randomised controlled trials (RCTs) comparing ECP with or without standard treatment versus standard treatment alone in paediatric patients with aGvHD after HSCT. DATA COLLECTION AND ANALYSIS Two review authors independently performed the study selection. We resolved disagreement in the selection of trials by consultation with a third review author. MAIN RESULTS We identified no additional studies in the 2015 review update, in total leading to no studies meeting the criteria for inclusion in this review. AUTHORS' CONCLUSIONS The efficacy of ECP in the treatment of aGvHD in paediatric patients after HSCT is unknown and its use should be restricted within the context of RCTs. Such studies should address a comparison of ECP alone or in combination with standard treatment versus standard treatment alone. The 2015 review update brought about no additions to these conclusions.

GRADE suggests that examination of 95% confidence intervals (CIs) provides the optimal primary approach to decisions regarding imprecision. For practice guidelines, rating down the quality of evidence (i.e., confidence in estimates of effect) is required if clinical action would differ if the upper versus the lower boundary of the CI represented the truth. An exception to this rule occurs when an effect is large, and consideration of CIs alone suggests a robust effect, but the total sample size is not large and the number of events is small. Under these circumstances, one should consider rating down for imprecision. To inform this decision, one can calculate the number of patients required for an adequately powered individual trial (termed the "optimal information size" [OIS]). For continuous variables, we suggest a similar process, initially considering the upper and lower limits of the CI, and subsequently calculating an OIS. Systematic reviews require a somewhat different approach. If the 95% CI excludes a relative risk (RR) of 1.0, and the total number of events or patients exceeds the OIS criterion, precision is adequate. If the 95% CI includes appreciable benefit or harm (we suggest an RR of under 0.75 or over 1.25 as a rough guide) rating down for imprecision may be appropriate even if OIS criteria are met.

In the GRADE approach, randomized trials start as high-quality evidence and observational studies as low-quality evidence, but both can be rated down if a body of evidence is associated with a high risk of publication bias. Even when individual studies included in best-evidence summaries have a low risk of bias, publication bias can result in substantial overestimates of effect. Authors should suspect publication bias when available evidence comes from a number of small studies, most of which have been commercially funded. A number of approaches based on examination of the pattern of data are available to help assess publication bias. The most popular of these is the funnel plot; all, however, have substantial limitations. Publication bias is likely frequent, and caution in the face of early results, particularly with small sample size and number of events, is warranted.

In the interest of patients evidence-based healthcare should be provided and is increasingly being demanded worldwide. In the daily medical practice however, healthcare based on proven scientific findings has not yet become firmly established. There are several causes for this. Problems occur at the level of knowledge generation, knowledge transfer from research into practice and also at the individual level of the treating healthcare professional. Nowadays, with a rapidly growing amount of knowledge it is almost impossible for the individual to quickly filter out the relevant facts. This article aims to shed light on the various aspects of the process of knowledge transfer from a clinical trial to evidence-based guidelines. It will make the reader aware of potential problems during this process and show some feasible approaches to solving them. Wherever possible, the field of anesthesiology will be used as the reference point. Evidence-based information sources will be presented and advice on how to use them will be given.

This article introduces the approach of GRADE to rating quality of evidence. GRADE specifies four categories-high, moderate, low, and very low-that are applied to a body of evidence, not to individual studies. In the context of a systematic review, quality reflects our confidence that the estimates of the effect are correct. In the context of recommendations, quality reflects our confidence that the effect estimates are adequate to support a particular recommendation. Randomized trials begin as high-quality evidence, observational studies as low quality. "Quality" as used in GRADE means more than risk of bias and so may also be compromised by imprecision, inconsistency, indirectness of study results, and publication bias. In addition, several factors can increase our confidence in an estimate of effect. GRADE provides a systematic approach for considering and reporting each of these factors. GRADE separates the process of assessing quality of evidence from the process of making recommendations. Judgments about the strength of a recommendation depend on more than just the quality of evidence.

In the GRADE approach, randomized trials start as high-quality evidence and observational studies as low-quality evidence, but both can be rated down if most of the relevant evidence comes from studies that suffer from a high risk of bias. Well-established limitations of randomized trials include failure to conceal allocation, failure to blind, loss to follow-up, and failure to appropriately consider the intention-to-treat principle. More recently recognized limitations include stopping early for apparent benefit and selective reporting of outcomes according to the results. Key limitations of observational studies include use of inappropriate controls and failure to adequately adjust for prognostic imbalance. Risk of bias may vary across outcomes (e.g., loss to follow-up may be far less for all-cause mortality than for quality of life), a consideration that many systematic reviews ignore. In deciding whether to rate down for risk of bias--whether for randomized trials or observational studies--authors should not take an approach that averages across studies. Rather, for any individual outcome, when there are some studies with a high risk, and some with a low risk of bias, they should consider including only the studies with a lower risk of bias.

This article is the first of a series providing guidance for use of the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system of rating quality of evidence and grading strength of recommendations in systematic reviews, health technology assessments (HTAs), and clinical practice guidelines addressing alternative management options. The GRADE process begins with asking an explicit question, including specification of all important outcomes. After the evidence is collected and summarized, GRADE provides explicit criteria for rating the quality of evidence that include study design, risk of bias, imprecision, inconsistency, indirectness, and magnitude of effect. Recommendations are characterized as strong or weak (alternative terms conditional or discretionary) according to the quality of the supporting evidence and the balance between desirable and undesirable consequences of the alternative management options. GRADE suggests summarizing evidence in succinct, transparent, and informative summary of findings tables that show the quality of evidence and the magnitude of relative and absolute effects for each important outcome and/or as evidence profiles that provide, in addition, detailed information about the reason for the quality of evidence rating. Subsequent articles in this series will address GRADE's approach to formulating questions, assessing quality of evidence, and developing recommendations.

This is the third and last article in the series about the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to grading the quality of evidence and the strength of recommendations in clinical practice guidelines and its application in the field of allergy. We describe the factors that influence the strength of recommendations about the use of diagnostic, preventive and therapeutic interventions: the balance of desirable and undesirable consequences, the quality of a body of evidence related to a decision, patients' values and preferences, and considerations of resource use. We provide examples from two recently developed guidelines in the field of allergy that applied the GRADE approach. The main advantages of this approach are the focus on patient important outcomes, explicit consideration of patients' values and preferences, the systematic approach to collecting the evidence, the clear separation of the concepts of quality of evidence and strength of recommendations, and transparent reporting of the decision process. The focus on transparency facilitates understanding and implementation and should empower patients, clinicians and other health care professionals to make informed choices.

In Germany and Central Europe, congenital disorders leading to secondary hemochromatosis are rare. The majority of these patients are treated in peripheral medical institutions. As a consequence, the experience of each institution in the treatment of secondary hemochromatosis in patients with congenital anemia is limited. Recent developments concerning new chelating agents, their combination for intensified chelation and new possibilities to diagnose and monitor iron overload have important consequences for the management of patients with secondary hemochromatosis and increase its complexity enormously. Therefore, the development of a guideline for rational and efficient diagnostics and treatment was necessary. The new guideline was developed within a formal consensus process and finally approved by a consensus conference with participants from both the pediatric and adult German hematology societies (GPOH and DGHO). Apart from general information and recommendations, the guideline contains 9 consensus statements on diagnostics (iron status, siderotic complications, chelator side-effects), the start of chelation, indications for intensified chelation, iron elimination in specific disorders, and iron elimination after stem cell transplantation. Here, these consensus statements are presented and discussed in detail. For the complete text of the guideline, please visit the AWMF homepage at http://www.leitlinien.net .

Resumen Los médicos no disponen del tiempo ni de los recursos para considerar la evidencia subyacente en las innumerables decisiones que tienen que tomar diariamente. En consecuencia, dependen de las recomendaciones de las guías de práctica clínica. Los paneles de las guías deben considerar todos los criterios relevantes que influyen en una decisión o recomendación de manera estructurada, explícita y transparente, y proporcionar a los médicos recomendaciones factibles. En este artículo describiremos los marcos de la evidencia a la decisión (EtD) para las recomendaciones de práctica clínica. La estructura general de un marco EtD para recomendaciones clínicas es similar a la de los marcos EtD para otras recomendaciones y decisiones, e incluye la formulación de la pregunta, la evaluación de los distintos criterios y las conclusiones. Las recomendaciones clínicas requieren que los criterios se consideren de forma diferente, dependiendo de si se adopta una perspectiva individual o poblacional. Por ejemplo, desde la perspectiva individual, los gastos personales son un aspecto importante a considerar, mientras que desde la perspectiva poblacional son más importantes el uso de recursos (no solo los gastos personales) y el coste-efectividad. Son también importantes desde la perspectiva poblacional la equidad, la aceptabilidad y la factibilidad, mientras que la importancia de estos criterios suele ser limitada en el caso de la perspectiva individual. Los subgrupos específicos para los cuales pueden necesitarse recomendaciones deben estar claramente identificados y considerados con relación a cada criterio, porque los juicios pueden variar entre subgrupos. El siguiente artículo es una traducción del artículo original publicado en British Medical Journal. Los marcos EtD se utilizan actualmente en el Programa de Guías de Práctica Clínica en el Sistema Nacional de Salud, coordinado por GuíaSalud.

Constipation and other gastrointestinal symptoms are frequent adverse effects of either short-term postoperative or chronic opioid therapy. The review authors have identified 23 studies to evaluate the efficacy of micro-opioid antagonists for the prevention and treatment of these complications. The data on safety and efficacy of the traditional antagonists naloxone and nalbuphine are insufficient. The results of studies with the newer, peripherally-acting antagonists alvimopan and methylnaltrexone are promising. Methylnaltrexone resulted in four studies with healthy probands in a significant shortening of the gastrointestinal transit time (-52 min). In the postoperative setting, five studies showed a significant improvement of the hazard ratios for different outcomes (e. g., bowel movement, tolerance of solid food) in the alvimopan group. Future studies will be needed to show whether these results can be reproduced in different patient groups on a larger scale. Also, with regard to other pharmacological (e. g., lactulose) and non-pharmacological interventions, the role of the above-mentioned not yet approved medications needs to be defined.

Objectives To evaluate efficacy and safety of gonadotropin-releasing hormone (GnRH) antagonists compared to standard androgen suppression therapy for advanced prostate cancer. Setting The international review team included methodologists of the German Cochrane Centre and clinical experts. Participants We searched CENTRAL, MEDLINE, Web of Science, EMBASE, trial registries and conference books for randomised controlled trials (RCT) for effectiveness data analysis, and randomised or non-randomised controlled studies (non-RCT) for safety data analysis (March 2015). Two authors independently screened identified articles, extracted data, evaluated risk of bias and rated quality of evidence according to GRADE. Results 13 studies (10 RCTs, 3 non-RCTs) were included. No study reported cancer-specific survival or clinical progression. There were no differences in overall mortality (RR 1.35, 95% CI 0.63 to 2.93), treatment failure (RR 0.91, 95% CI 0.70 to 1.17) or prostate-specific antigen progression (RR 0.83, 95% CI 0.64 to 1.06). While there was no difference in quality of life related to urinary symptoms, improved quality of life regarding prostate symptoms, measured with the International Prostate Symptom Score (IPSS), with the use of GnRH antagonists compared with the use of standard androgen suppression therapy (mean score difference −0.40, 95% CI −0.94 to 0.14, and −1.84, 95% CI −3.00 to −0.69, respectively) was found. Quality of evidence for all assessed outcomes was rated low according to GRADE. The risk for injection-site events was increased, but cardiovascular events may occur less often by using GnRH antagonist. Available evidence is hampered by risk of bias, selective reporting and limited follow-up. Conclusions There is currently insufficient evidence to make firm conclusive statements on the efficacy of GnRH antagonist compared to standard androgen suppression therapy for advanced prostate cancer. There is need for further high-quality research on GnRH antagonists with long-term follow-up. Trial registration number CRD42012002751.

Background Inhaled steroids have been studied for both prevention and treatment of bronchopulmonary dysplasia (BPD). Results have been inconsistent. Recently, a large randomized controlled trial (RCT) has been reported. Methods/design We will perform a comprehensive systematic literature search for randomized and quasi-randomized controlled trials that studied the efficacy and safety of inhaled corticosteroids administered to preterm infants (22–36 weeks) for either the prevention or treatment of BPD diagnosed by both clinical and physiological outcome criteria. We will assess potential risk of bias for each RCT meeting our selection criteria using the Cochrane risk of bias tool for RCTs. The primary outcome of interest will be mortality or BPD or both at 28 days postnatal age or 36 weeks postmenstrual age. Pooled estimates will be calculated using RevMan software with a random effects model as primary analysis. We will assess the quality of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Discussion Meta-analytic estimates of eligible RCTs, potentially including a new large RCT, may significantly influence neonatal practice in the prevention and treatment of respiratory problems in preterm infants. Systematic review registration PROSPEROCRD42015019628

Controversy exists about residual symptoms after pharmacological treatment of Lyme neuroborreliosis. Reports of disabling long-term sequels lead to concerns in patients and health care providers. We systematically reviewed the available evidence from studies reporting treatment of Lyme neuroborreliosis to assess the prevalence and spectrum of residual symptoms after treatment. A literature search was performed in three databases and three clinical trial registers to find eligible studies reporting on residual symptoms in patients after pharmacological treatment of LNB. Diagnosis must have been performed according to consensus-derived case definitions. No restrictions regarding study design or language were set. Symptom prevalence was pooled using a random-effects model. Forty-four eligible clinical trials and studies were found: 8 RCTs, 17 cohort studies, 2 case-control studies, and 17 case series. The follow-up period in the eligible studies ranged from 7 days to 20 years. The weighted mean proportion of residual symptoms was 28 % (95 % CI 23-34 %, n = 34 studies) for the latest reported time point. Prevalence of residual symptoms was statistically significantly higher in studies using the "possible" case definition (p = 0.0048). Cranial neuropathy, pain, paresis, cognitive disturbances, headache, and fatigue were statistically significantly lower in studies using the "probable/definite" case definition. LNB patients may experience residual symptoms after treatment with a prevalence of approximately 28 %. The prevalence and spectrum of residual symptoms differ according to the applied case definition. Symptoms like fatigue are not reported in studies using the "probable/definite" case definition. As the "possible" case definition is more unspecific, patients with other conditions may be included. Reports of debilitating fatigue and cognitive impairment after LNB, a "post-Lyme syndrome", could therefore be an artifact of unspecific case definitions in single studies.

OBJECTIVES To suggest approaches for guideline developers on how to assess a methodologist's expertise with Grading of Recommendations Assessment, Development and Evaluation (GRADE) methods and tasks and to provide a set of minimum skills and experience required to perform specific tasks related to guideline development using GRADE. STUDY DESIGN AND SETTING We used an iterative and consensus-based process involving individuals with in-depth experience with GRADE. We considered four main tasks: (1) development of key questions; (2) assessment of the certainty of effect estimates; (3) development of recommendations; and (4) teaching GRADE. RESULTS There are three basic approaches to determine a methodologist's skill set. First, self-report of knowledge, skills, and experience with a standardized "GRADE curriculum vitae (CV)" focused on each of the GRADE-related tasks; second, demonstration of skills using worked examples; third, a formal evaluation using a written or oral test. We suggest that the GRADE CV is likely to be useful and feasible to implement. We also suggest minimum training including attendance at one or more full-day workshops and familiarity with the main GRADE publications and the GRADE handbook. CONCLUSIONS The selection of a GRADE methodologist must be a thoughtful, reasoned decision, informed by the criteria suggested in this article and tailored to the specific project. Our suggested approaches need further pilot testing and validation.

Background Systematic reviews represent one of the most important tools for knowledge translation but users often struggle with understanding and interpreting their results. GRADE Summary-of-Findings tables have been developed to display results of systematic reviews in a concise and transparent manner. The current format of the Summary-of-Findings tables for presenting risks and quality of evidence improves understanding and assists users with finding key information from the systematic review. However, it has been suggested that additional methods to present risks and display results in the Summary-of-Findings tables are needed. Methods/Design We will conduct a non-inferiority parallel-armed randomized controlled trial to determine whether an alternative format to present risks and display Summary-of-Findings tables is not inferior compared to the current standard format. We will measure participant understanding, accessibility of the information, satisfaction, and preference for both formats. We will invite systematic review users to participate (that is clinicians, guideline developers, and researchers). The data collection process will be undertaken using the online 'Survey Monkey' system. For the primary outcome understanding, non-inferiority of the alternative format (Table A) to the current standard format (Table C) of Summary-of-Findings tables will be claimed if the upper limit of a 1-sided 95% confidence interval (for the difference of proportion of participants answering correctly a given question) excluded a difference in favor of the current format of more than 10%. Discussion This study represents an effort to provide systematic reviewers with additional options to display review results using Summary-of-Findings tables. In this way, review authors will have a variety of methods to present risks and more flexibility to choose the most appropriate table features to display (that is optional columns, risks expressions, complementary methods to display continuous outcomes, and so on). Trials registration NCT02022631 (21 December 2013)

Copyright © 2015 Wolters Kluwer Health Inc. All rights reserved. Objective: To investigate the prevalence of discontinuation and nonpublication of surgical versus medical randomized controlled trials (RCTs) and to explore risk factors for discontinuation and nonpublication of surgical RCTs. Background: Trial discontinuation has significant scientific ethical and economic implications. To date the prevalence of discontinuation of surgical RCTs is unknown. Methods: All RCT protocols approved between 2000 and 2003 by 6 ethics committees in Canada Germany and Switzerland were screened. Baseline characteristics were collected and if published full reports retrieved. Risk factors for early discontinuation for slow recruitment and nonpublication were explored using multivariable logistic regression analyses. Results: In total 863 RCT protocols involving adult patients were identified 127 in surgery (15) and 736 in medicine (85). Surgical trials were discontinued for any reason more often than medical trials [43 vs 27 risk difference 16 (95 confidence interval [CI]: 5 26); P = 0.001] and more often discontinued for slow recruitment [18 vs 11 risk difference 8 (95 CI: 0.1 16); P = 0.020]. The percentage of trials not published as full journal article was similar in surgical and medical trials (44 vs 40 risk difference 4 (95 CI: 5 to 14); P = 0.373). Discontinuation of surgical trials was a strong risk factor for nonpublication (odds ratio = 4.18 95 CI: 1.45 12.06; P = 0.008). Conclusions: Discontinuation and nonpublication rates were substantial in surgical RCTs and trial discontinuation was strongly associated with nonpublication. These findings need to be taken into account when interpreting surgical literature. Surgical trialists should consider feasibility studies before embarking on full scale trials.

Objectives To systematically review reports that queried abstract authors about reasons for not subsequently publishing abstract results as full-length articles. Study Design and Setting Systematic review of MEDLINE, EMBASE, The Cochrane Library, ISI Web of Science, and study bibliographies for empirical studies in which investigators examined subsequent full publication of results presented at a biomedical conference and reasons for nonpublication. Results The mean full publication rate was 55.9% [95% confidence interval (CI): 54.8%, 56.9%] for 24 of 27 eligible reports providing this information and 73.0% (95% CI: 71.2%, 74.7%) for seven reports of abstracts describing clinical trials. Twenty-four studies itemized 1,831 reasons for nonpublication, and six itemized 428 reasons considered the most important reason. “Lack of time” was the most frequently reported reason [weighted average = 30.2% (95% CI: 27.9%, 32.4%)] and the most important reason [weighted average = 38.4% (95% CI: 33.7%, 43.2%)]. Other commonly stated reasons were “lack of time and/or resources,” “publication not an aim,” “low priority,” “incomplete study,” and “trouble with co-authors.” Conclusions Across medical specialties, the main reasons for not subsequently publishing an abstract in full lie with factors related to the abstract author rather than with journals.

Diamond-Blackfan anemia (DBA) is a rare congenital red-cell aplasia characterized by anemia, bone-marrow erythroblastopenia, and congenital anomalies and is associated with heterozygous mutations in the ribosomal protein (RP) S19 gene (RPS19) in approximately 25% of probands. We report identification of de novo nonsense and splice-site mutations in another RP, RPS24 (encoded by RPS24 [10q22-q23]) in approximately 2% of RPS19 mutation-negative probands. This finding strongly suggests that DBA is a disorder of ribosome synthesis and that mutations in other RP or associated genes that lead to disrupted ribosomal biogenesis and/or function may also cause DBA.

To assess the effects of non-steroidal antiandrogen monotherapy compared with luteinizing hormone-releasing hormone agonists or surgical castration monotherapy for treating advanced hormone-sensitive stages of prostate cancer. We searched the Cochrane Prostatic Diseases and Urologic Cancers Group Specialized Register (PROSTATE), the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, Web of Science with Conference Proceedings, three trial registries and abstracts from three major conferences to 23 December 2013, together with reference lists, and contacted selected experts in the field and manufacturers. We included randomized controlled trials comparing non-steroidal antiandrogen monotherapy with medical or surgical castration monotherapy for men in advanced hormone-sensitive stages of prostate cancer. Two review authors independently examined full-text reports, identified relevant studies, assessed the eligibility of studies for inclusion, extracted data and assessed risk of bias as well as quality of evidence according to the GRADE working group guidelines. We used Review Manager 5.2 for data synthesis and the fixed-effect model as primary analysis (when heterogeneity was low with I(2) < 50%); we used a random-effects model when confronted with substantial or considerable heterogeneity (when I(2) ≥50%). A total of 11 studies involving 3060 randomly assigned participants were included in the present review. Use of non-steroidal antiandrogens resulted in lower overall survival times (hazard ratio [HR] 1.24, 95% confidence interval [CI] 1.05-1.48, six studies, 2712 participants) and greater clinical progression (1 year: risk ratio [RR] 1.25, 95% CI 1.08-1.45, five studies, 2067 participants; 70 weeks: RR 1.26, 95% CI 1.08-1.45, six studies, 2373 participants; 2 years: RR 1.14, 95% CI 1.04-1.25, three studies, 1336 participants), as well as treatment failure (1 year: RR 1.19, 95% CI 1.02-1.38, four studies, 1539 participants; 70 weeks: RR 1.27, 95% CI 1.05-1.52, five studies, 1845 participants; 2 years: RR 1.14, 95% CI 1.05-1.24, two studies, 808 participants), compared with medical or surgical castration. The quality of evidence for overall survival, clinical progression and treatment failure was rated as moderate according to GRADE. Use of non-steroidal antiandrogens increased the risk for treatment discontinuation as a result of adverse events (RR 1.82, 95% CI 1.13-2.94, eight studies, 1559 participants), including events such as breast pain (RR 22.97, 95% CI 14.79- 35.67, eight studies, 2670 participants) and gynaecomastia (RR 8.43, 95% CI 3.19-22.28, nine studies, 2774 participants) The risk of other adverse events, such as hot flushes (RR 0.23, 95% CI 0.19-0.27, nine studies, 2774 participants) was decreased when non-steroidal antiandrogens were used. The quality of evidence for breast pain, gynaecomastia and hot flushes was rated as moderate according to GRADE. The effects of non-steroidal antiandrogens on cancer-specific survival and biochemical progression remained unclear. Non-steroidal antiandrogen monotherapy compared with medical or surgical castration monotherapy for advanced prostate cancer is less effective in terms of overall survival, clinical progression, treatment failure and treatment discontinuation resulting from adverse events. Evidence quality was rated as moderate according to GRADE; therefore, further research is likely to have an important impact on results for patients with advanced but non-metastatic prostate cancer treated with non-steroidal antiandrogen monotherapy.

This article describes the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach to classifying the direction and strength of recommendations. The strength of a recommendation, separated into strong and weak, is defined as the extent to which one can be confident that the desirable effects of an intervention outweigh its undesirable effects. Alternative terms for a weak recommendation include conditional, discretionary, or qualified. The strength of a recommendation has specific implications for patients, the public, clinicians, and policy makers. Occasionally, guideline developers may choose to make "only-in-research" recommendations. Although panels may choose not to make recommendations, this choice leaves those looking for answers from guidelines without the guidance they are seeking. GRADE therefore encourages panels to, wherever possible, offer recommendations.

In the GRADE approach, the strength of a recommendation reflects the extent to which we can be confident that the composite desirable effects of a management strategy outweigh the composite undesirable effects. This article addresses GRADE's approach to determining the direction and strength of a recommendation. The GRADE describes the balance of desirable and undesirable outcomes of interest among alternative management strategies depending on four domains, namely estimates of effect for desirable and undesirable outcomes of interest, confidence in the estimates of effect, estimates of values and preferences, and resource use. Ultimately, guideline panels must use judgment in integrating these factors to make a strong or weak recommendation for or against an intervention.

Background Pruritus is a rare but troublesome symptom in palliative-care patients with a variety of underlying diseases. The pharmacotherapy of pruritus is often off-label, and an evidence-based evaluation is needed. Methods A Cochrane Review published in 2013 was updated with a systematic literature search up to January 2014. Randomized and controlled trials (RCTs) with adult palliative-care patients were included. Results In the 43 RCTs that were analyzed, three of which were more recent than the Cochrane Review, 8 clinically relevant active substances were investigated in a total of 19 RCTs. Effective drugs for pruritus in palliative-care patients included paroxetine for pruritus of diverse origins (1 RCT; strong effect) and indomethacin for HIV-induced prutitus (1 RCT; median effect = moderate reduction). Effective drugs for pruritus in uremia were gabapentin (2 RCTs; strong effect), nalfurafin (3 RCTs; moderate effect), naltrexone (3 RCTs; heterogeneous effects, ranging from weak to strong), and cromoglicic acid (2 RCTs; moderate to strong effect). Effective drugs for cholestatic pruritus were rifampicin (3 RCTs; moderate effect), flumecinol (2 RCTs; weak to moderate effect), and naltrexone (2 RCTs; moderate to strong effect). Undesired effects were most common with naltrexone (dizziness: 0% -50% , nausea: 0% -50% ) and nalfurafin (nasopharyngitis: 8% -12% , insomnia: 7% -15%). Conclusion In view of the diverse etiologies of pruritus in palliative-care patients, careful consideration should be given to the choice of drug used to treat it. The substances listed here have moderate to strong antipruritic effects and merit further study in RCTs of high methodological quality.

Summary The genetic basis of Diamond–Blackfan anaemia (DBA), a congenital erythroid hypoplasia that shows marked clinical heterogeneity, remains obscure. However, the fact that nearly one-quarter of patients harbour a variety of mutations in RPS19, a ribosomal protein gene, provides an opportunity to examine whether haplo-insufficiency of RPS19 protein can be demonstrated in certain cases. To that end, we identified 19 of 81 DBA index cases, both familial and sporadic, with RPS19 mutations. We found 14 distinct insertions, deletions, missense, nonsense and splice site mutations in the 19 probands, and studied mutations in 10 patients at the RNA level and in three patients at the protein level. Characterization of the mutations in 10 probands, including six with novel insertions, nonsense and splice site mutations, showed that the abnormal transcript was detectable in nine cases. The RPS19 mRNA and protein in CD34+ bone marrow cells identified haplo-insufficiency in three cases predicted to have one functional allele. Our data support the notion that, in addition to rare DBA patients with the deletion of one allele, the disease in certain other RPS19 mutant patients is because of RPS19 protein haplo-insufficiency.