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To evaluate reporting of minimal important difference (MID) estimates using anchor-based methods for patient-reported outcome measures (PROMs), and the association with reporting deficiencies on their credibility.Systematic survey of primary studies empirically estimating MIDs. We searched Medline, EMBASE, PsycINFO, and the Patient-Reported Outcome and Quality of Life Instruments Database until October 2018. We evaluated study reporting, focusing on participants' demographics, intervention(s), characteristics of PROMs and anchors, and MID estimation method(s). We assessed the impact of reporting issues on credibility of MID estimates.In 585 studies reporting on 5,324 MID estimates for 526 distinct PROMs, authors frequently failed to adequately report key characteristics of PROMs and MIDs, including minimum and maximum values of PROM scale, measure of variability accompanying the MID estimate and number of participants included in the MID calculation. Across MID estimates (n = 5,324), the most serious reporting issues impacting credibility included infrequent reporting of the correlation between the anchor and PROM (66%), inadequate details to judge precision of MID point estimate (13%), and insufficient information about the threshold used to ascertain MIDs (16%).Serious issues of incomplete reporting in the MID literature threaten the optimal use of MID estimates to inform the magnitude of effects of interventions on PROMs.

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von Willebrand disease (VWD) disproportionately affects women because of the potential for heavy menstrual bleeding (HMB), delivery complications, and postpartum hemorrhage (PPH). To systematically synthesize the evidence regarding first-line management of HMB, treatment of women requiring or desiring neuraxial analgesia, and management of PPH. We searched Medline and EMBASE through October 2019 for randomized trials, comparative observational studies, and case series comparing the effects of desmopressin, hormonal therapy, and tranexamic acid (TxA) on HMB; comparing different von Willebrand factor (VWF) levels in women with VWD who were undergoing labor and receiving neuraxial anesthesia; and measuring the effects of TxA on PPH. We conducted duplicate study selection, data abstraction, and appraisal of risk of bias. Whenever possible, we conducted meta-analyses. We assessed the quality of the evidence using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) approach. We included 1 randomized trial, 3 comparative observational studies, and 10 case series. Moderate-certainty evidence showed that desmopressin resulted in a smaller reduction of menstrual blood loss (difference in mean change from baseline, 41.6 [95% confidence interval, 16.6-63.6] points in a pictorial blood assessment chart score) as compared with TxA. There was very-low-certainty evidence about how first-line treatments compare against each other, the effects of different VWF levels in women receiving neuraxial anesthesia, and the effects of postpartum administration of TxA. Most of the evidence relevant to the gynecologic and obstetric management of women with VWD addressed by most guidelines is very low quality. Future studies that address research priorities will be key when updating such guidelines.

von Willebrand disease (VWD) is the most common inherited bleeding disorder. The management of patients with VWD who are undergoing surgeries is crucial to prevent bleeding complications. We systematically summarized the evidence on the management of patients with VWD who are undergoing major and minor surgeries to support the development of practice guidelines. We searched Medline and EMBASE from inception through October 2019 for randomized clinical trials (RCTs), comparative observational studies, and case series that compared maintaining factor VIII (FVIII) levels or von Willebrand factor (VWF) levels at >0.50 IU/mL for at least 3 days in patients undergoing major surgery, and those with options for perioperative management of patients undergoing minor surgery. Two authors screened and abstracted data and assessed the risk of bias. We conducted meta-analyses when possible. We evaluated the certainty of the evidence using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach. We included 7 case series for major surgeries and 2 RCTs and 12 case series for minor surgeries. Very-low-certainty evidence showed that maintaining FVIII levels or VWF levels of >0.50 IU/mL for at least 3 consecutive days showed excellent hemostatic efficacy (as labeled by the researchers) after 74% to 100% of major surgeries. Low- to very-low-certainty evidence showed that prescribing tranexamic acid and increasing VWF levels to 0.50 IU/mL resulted in fewer bleeding complications after minor procedures compared with increasing VWF levels to 0.50 IU/mL alone. Given the low-quality evidence for guiding management decisions, a shared-decision model leading to individualized therapy plans will be important in patients with VWD who are undergoing surgical and invasive procedures.

Objective To provide practical principles and examples to help GRADE users make optimal choices regarding their ratings of certainty of evidence using a minimally or partially contextualized approach. Study Design and Setting Based on the GRADE clarification of certainty of evidence in 2017, a project group within the GRADE Working Group conducted iterative discussions and presentations at GRADE Working Group meetings to refine this construct and produce practical guidance. Results Systematic review and health technology assessment authors need to clarify what it is in which they are rating their certainty of evidence (i.e., the target of their certainty rating). The decision depends on the degree of contextualization (partially or minimally contextualized), thresholds (null, small, moderate or large effect threshold), and where the point estimate lies in relation to the chosen threshold(s). When the 95% confidence interval crosses multiple possible thresholds (i.e., including both large benefit and large harm), it is not worthwhile for authors to determine the target of certainty rating. Conclusion GRADE provides practical principles to help systematic review and health technology assessment authors specify the target of their certainty of evidence rating.

Background: COVID-19–related acute illness is associated with an increased risk of venous thromboembolism (VTE). Objective: These evidence-based guidelines from the American Society of Hematology (ASH) are intended to support patients, clinicians, and other health care professionals in making decisions about the use of anticoagulation in patients with COVID-19. Methods: ASH formed a multidisciplinary guideline panel that included patient representatives and applied strategies to minimize potential bias from conflicts of interest. The McMaster University GRADE Centre supported the guideline development process and performed systematic evidence reviews (through November 2021). The panel prioritized clinical questions and outcomes according to their importance for clinicians and patients. The panel used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to assess evidence and make recommendations, which were subject to public comment. This is an update to guidelines published in February 2021 as part of the living phase of these guidelines. Results: The panel made one additional recommendation. The panel issued a conditional recommendation in favor of therapeutic-intensity over prophylactic-intensity anticoagulation in patients with COVID-19–related acute illness who do not have suspected or confirmed VTE. The panel emphasized the need for an individualized assessment of risk of thrombosis and bleeding. The panel also noted that heparin (unfractionated or low molecular weight) may be preferred because of a preponderance of evidence with this class of anticoagulants. Conclusion: This conditional recommendation was based on very low certainty in the evidence, underscoring the need for additional, high-quality, randomized controlled trials comparing different intensities of anticoagulation in patients with COVID-19–related acute illness.

Background: COVID-19–related critical illness is associated with an increased risk of venous thromboembolism (VTE). Objective: These evidence-based guidelines of the American Society of Hematology (ASH) are intended to support patients, clinicians, and other health care professionals in decisions about the use of anticoagulation for patients with COVID-19. Methods: ASH formed a multidisciplinary guideline panel, including 3 patient representatives, and applied strategies to minimize potential bias from conflicts of interest. The McMaster University Grading of Recommendations Assessment, Development and Evaluation (GRADE) Centre supported the guideline development process, including performing systematic evidence reviews (up to January 2022). The panel prioritized clinical questions and outcomes according to their importance for clinicians and patients. The panel used the GRADE approach to assess evidence and make recommendations, which were subject to public comment. This is an update to guidelines published in February 2021 and May 2021 as part of the living phase of these guidelines. Results: The panel made 1 additional recommendation: a conditional recommendation for the use of prophylactic-intensity over therapeutic-intensity anticoagulation for patients with COVID-19–related critical illness who do not have suspected or confirmed VTE. The panel emphasized the need for an individualized assessment of thrombotic and bleeding risk. Conclusions: This conditional recommendation was based on very low certainty in the evidence, underscoring the need for additional, high-quality, randomized controlled trials comparing different intensities of anticoagulation for patients with COVID-19–related critical illness.

ObjectiveThe Grades of Recommendations, Assessment, Development and Evaluation working group recently developed an innovative approach to interpreting results from network meta-analyses (NMA) through minimally and partially contextualised methods; however, the optimal method for presenting results for multiple outcomes using this approach remains uncertain. We; therefore, developed and iteratively modified a presentation method that effectively summarises NMA results of multiple outcomes for clinicians using this new interpretation approach.DesignQualitative descriptive study.SettingA steering group of seven individuals with experience in NMA and design validation studies developed two colour-coded presentation formats for evaluation. Through an iterative process, we assessed the validity of both formats to maximise their clarity and ease of interpretation.Participants26 participants including 20 clinicians who routinely provide patient care, 3 research staff/research methodologists and 3 residents.Main outcome measuresTwo team members used qualitative content analysis to independently analyse transcripts of all interviews. The steering group reviewed the analyses and responded with serial modifications of the presentation format.ResultsTo ensure that readers could easily discern the benefits and safety of each included treatment across all assessed outcomes, participants primarily focused on simple information presentations, with intuitive organisational decisions and colour coding. Feedback ultimately resulted in two presentation versions, each preferred by a substantial group of participants, and development of a legend to facilitate interpretation.ConclusionIterative design validation facilitated the development of two novel formats for presenting minimally or partially contextualised NMA results for multiple outcomes. These presentation approaches appeal to audiences that include clinicians with limited familiarity with NMAs.

Objectives The objective of the study was to develop an inventory summarizing all anchor-based minimal important difference (MID) estimates for patient-reported outcome measures (PROMs) available in the medical literature. Study Design and Setting We searched MEDLINE, EMBASE, CINAHL, PsycINFO, and the Patient-Reported Outcome and Quality of Life Instruments Database internal library (January 1989–October 2018). We included primary studies empirically calculating an anchor-based MID estimate for any PROM in adults and adolescents. Pairs of reviewers independently screened and selected studies, extracted data, and evaluated the credibility of the MIDs. Results We identified 585 eligible studies, the majority conducted in Europe (n = 211) and North America (n = 179), reporting 5,324 MID estimates for 526 distinct PROMs. Investigators conducted their studies in the context of patients receiving surgical (n = 105, 18%), pharmacological (n = 85, 15%), rehabilitation (n = 65, 11%), or a combination of interventions (n = 194, 33%). Of all MID estimates, 59% (n = 3,131) used a global rating of change anchor. Major credibility limitations included weak correlation (n = 1,246, 23%) or no information regarding the correlation (n = 3,498, 66%) between the PROM and anchor and imprecision in the MID estimate (n = 2,513, 47%). Conclusion A large number of MIDs for assisting in the interpretation of PROMs exist. The MID inventory will facilitate the use of MID estimates to inform the interpretation of the magnitude of treatment effects in clinical research and guideline development.

Background and Objective Guideline development groups or other health care decision makers frequently encounter situations that require a simultaneous comparison of multiple interventions. This sometimes becomes apparent either when they identify questions of interest, before they formulate recommendations, or it may surface only when recommendations have already been formulated based on pairwise comparisons. Methods Using examples from the World Health Organization, the European Commission, and a professional society, we developed a flexible approach to developing recommendations when a multiple-intervention comparison (MC) is needed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) evidence to decision (EtD) frameworks. We iteratively refined this approach through user testing and then included a module in GRADE's official software GRADEpro to test the approach in two real and one theoretical guideline recommendations. Results We found the approach feasible and that all EtD criteria should be considered in an MC approach. We judged that guideline development groups and other decision makers will benefit from the availability of a network meta-analyses (NMA) of intervention effects to support decisions; however, NMA supports only one of many criteria, that is, the balance of health benefits and harms, and is therefore helpful, but not essential to the approach we propose. When similar but not identical comparators are used to address MC, challenges may arise with intransitivity and the relative rankings of interventions. Conclusion We successfully applied the MC approach and software module in generating recommendations across different scenarios and identified challenges. The MC approach allows guideline groups and other decision makers to transparently and critically assess multiple options for a given health question. Application of the approach by others may lead to refinement and allow for better understanding of its impact in developing recommendations and making choices.

Background: von Willebrand disease (VWD) is a common inherited bleeding disorder. Significant variability exists in management options offered to patients. Objective: These evidence-based guidelines from the American Society of Hematology (ASH), the International Society on Thrombosis and Haemostasis (ISTH), the National Hemophilia Foundation (NHF), and the World Federation of Hemophilia (WFH) are intended to support patients, clinicians, and health care professionals in their decisions about management of VWD. Methods: ASH, ISTH, NHF, and WFH formed a multidisciplinary guideline panel. Three patient representatives were included. The panel was balanced to minimize potential bias from conflicts of interest. The University of Kansas Outcomes and Implementation Research Unit and the McMaster Grading of Recommendations Assessment, Development and Evaluation (GRADE) Centre supported the guideline development process, including performing and updating systematic evidence reviews (through November 2019). The panel prioritized clinical questions and outcomes according to their importance to clinicians and patients. The panel used the GRADE approach, including GRADE Evidence-to-Decision frameworks, to assess evidence and make recommendations, which were subject to public comment. Results: The panel agreed on 12 recommendations and outlined future research priorities. Conclusions: These guidelines make key recommendations regarding prophylaxis for frequent recurrent bleeding, desmopressin trials to determine therapy, use of antiplatelet agents and anticoagulant therapy, target VWF and factor VIII activity levels for major surgery, strategies to reduce bleeding during minor surgery or invasive procedures, management options for heavy menstrual bleeding, management of VWD in the context of neuraxial anesthesia during labor and delivery, and management in the postpartum setting.

Background Von Willebrand Disease (VWD) is a common inherited bleeding disorder. Patients with VWD suffering from severe bleeding may benefit from the use of secondary long-term prophylaxis. Aim Systematically summarize the evidence on the clinical outcomes of secondary long-term prophylaxis in patients with VWD and severe recurrent bleedings. Methods We searched Medline and EMBASE through October 2019 for relevant randomized clinical trials (RCTs) and comparative observational studies (OS) assessing the effects of secondary long-term prophylaxis in patients with VWD. We used Cochrane Risk of Bias (RoB) tool and the RoB for Non-Randomized Studies of interventions (ROBINS-I) tool to assess the quality of the included studies. We conducted random-effects meta-analyses and assessed the certainty of the evidence using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. Results We included 12 studies. Evidence from one placebo controlled RCT suggested that VWD prophylaxis as compared to no prophylaxis reduced the rate of bleeding episodes (Rate ratio [RR], .24; 95% confidence interval [CI], .17–.35; low certainty evidence), and of epistaxis (RR, .38; 95%CI, .21–.67; moderate certainty evidence), and may increase serious adverse events RR 2.73 (95%CI .12–59.57; low certainty). Evidence from four before-and-after studies in which researchers reported comparative data suggested that VWD prophylaxis reduced the rate of bleeding (RR .34; 95%CI, .25–.46; very low certainty evidence). Conclusion VWD prophylaxis treatment seems to reduce the risk of spontaneous bleeding, epistaxis, and hospitalizations. More RCTs should be conducted to increase the certainty in these benefits.

BACKGROUND: Guideline recommendations may be affected by flaws in the process, inappropriate panel member selection or conduct, conflicts of interest and other factors. To our knowledge, no validated tool exists to evaluate guideline development from the perspective of those directly involved in the process. Our objective was to develop and validate a universal tool, the PANELVIEW instrument, to assess guideline processes, methods and outcomes from the perspective of the participating guideline panellists and group members. METHODS: We performed a systematic literature search and surveys of guideline groups (identified through contacting international organizations and convenience sampling of working panels) to inform item generation. Subsequent groups of guideline methodologists and panellists reviewed items for face validity and missing items. We used surveys, interviews and expert review for item reduction and phrasing. For reliability assessment and feedback, we tested the PANELVIEW tool in 8 international guideline groups. RESULTS: We surveyed 62 members from 13 guideline panels, contacted 19 organizations and reviewed 20 source documents to generate items. Fifty-three additional key informants provided feedback about phrasing of the items and response options. We reduced the number of items from 95 to 34 across domains that included administration, training, conflict of interest, group dynamics, chairing, evidence synthesis, formulating recommendations and publication. The tool takes about 10 minutes to complete and showed acceptable measurement properties. INTERPRETATION: The PANELVIEW instrument fills a gap by enabling guideline organizations to involve clinicians, patients and other participants in evaluating their guideline processes. The tool can inform quality improvement of existing or new guideline programs, focusing on insight into and transparency of the guideline development process, methods and outcomes.

Objectives: Clear communication of systematic review findings will help readers and decision makers. We built on previous work to develop an approach that improves the clarity of statements to convey findings and that draws on Grading of Recommendations Assessment,\ud Development and Evaluation (GRADE).\ud \ud Study Design and Setting: We conducted workshops including 80 attendants and a survey of 110 producers and users of systematic reviews. We calculated acceptability of statements and\ud revised the wording of those that were unacceptable to ≥40% of participants.\ud \ud Results: Most participants agreed statements should be based on size of effect and certainty of evidence. Statements for low, moderate and high certainty evidence were acceptable to >60%. Key guidance, for example, includes statements for high, moderate and low certainty for a large effect on intervention x as: x results in a large reduction…; x likely results in a large reduction…; x may result in a large reduction…, respectively.\ud \ud Conclusions: Producers and users of systematic reviews found statements to communicate findings combining size and certainty of an effect acceptable. This article provides GRADE guidance and a wording template to formulate statements in systematic reviews and other\ud decision tools.\ud \ud Keywords: review literature as topic, health communication, Evidence-Based Medicine, Surveys and Questionnaires, Language, persuasive communication

ObjectivesExamining the availability of essential medicines is a necessary step to monitor country-level progress towards universal health coverage. We compared the 2017 essential medicine lists (EML) of 137 countries to the WHO Model List to assess differences by drug class and country setting.MethodsWe extracted all medicines prioritised at country level from most recently available national EMLs and compared each national EML with the 2017 WHO Model List of Essential Medicines (MLEM) as the reference standard. We assess EMLs by WHO region and for different types of medicine subgroups (eg, cancer, anti-infectives, cardiac, psychiatric and anaesthesia medicines) using within second-level anatomical therapeutic class (ATC) drug classes of the ATC Index.ResultsWe included 406 medicines from WHO’s 2017 MLEM to compare to 137 concurrent national EMLs. We found a median of 315 (range from 44 to 983) medicines listed on national EMLs. The global median F1 score was 0.59 (IQR 0.47–0.70, maximum possible score indicating alignment with MLEM is 1). The F1 score was the highest (ie, most similar to MLEM) in the South-East Asia region and the lowest in the European region (ie, most dissimilar to MLEM). The F1 score was highest for stomatological preparations (median: 1.00), gynaecological—anti-infectives and antiseptics (median: 1.00), and medicated dressings (median: 1.00), and lowest for 9 anatomical or pharmacological groups (median: 0.00, eg, treatments for bone diseases, digestive enzymes).ConclusionsMost countries are expected to improve their national health coverage by 2030 offering access to essential medicines, but our results revealed substantial gaps in selection of medicines at the national level compared with those recommended by WHO. It is crucial that governments consider investing in those effective medicines that are now neglected and continue monitoring progress towards essential medicine access as part of universal health coverage.

Von Willebrand Disease (VWD) is associated with significant morbidity as a result of excessive mucocutaneous bleeding symptoms. Patients with VWD can experience easy bruising, epistaxis, gastrointestinal and oral cavity bleeding, as well as heavy menstrual bleeding and bleeding after dental work, surgical procedures, and childbirth. Early diagnosis and treatment is important to prevent and treat these symptoms. We systematically reviewed the accuracy of diagnostic tests using different cut-off values of VWF:Ag and platelet-dependent VWF activity assays in the diagnosis of VWD. We searched Cochrane Central, MEDLINE, and EMBASE for eligible studies. Two investigators screened and abstracted data. Risk of bias was assessed using QUADAS-2 and certainty of evidence using the GRADE framework. We pooled estimates of sensitivity and specificity and reported patient important outcomes when relevant. This review included 21 studies that evaluated VWD diagnosis, including the approach to patients with VWF levels that have normalized with age (6 studies), VWF cut-off levels for the diagnosis of Type 1 VWD (9 studies), and platelet-dependent VWF activity/VWF:Ag ratio cut-off levels for the diagnosis of Type 2 VWD (6 studies). The results showed low certainty in the evidence for a net health benefit from reconsidering the diagnosis of VWD versus simply removing the disease in patients with VWF levels that have normalized with age. For the diagnosis of Type 1 VWD, in patients with VWF:Ag

Background and objective The prognostic value of age and other non-hematological factors in predicting outcomes in older patients with newly diagnosed acute myeloid leukemia (AML) undergoing antileukemic therapy is not well understood. We performed a systematic review to determine the association between these factors and mortality and health-related quality of life or fatigue among these patients. Methods We searched Medline and Embase through October 2021 for studies in which researchers quantified the relationship between age, comorbidities, frailty, performance status, or functional status; and mortality and health-related quality of life or fatigue in older patients with AML receiving antileukemic therapy. We assessed the risk of bias of the included studies using the Quality in Prognostic Studies tool, conducted random-effects meta-analyses, and assessed the quality of the evidence using the Grading of Recommendations, Assessment, Development and Evaluation approach. Results We included 90 studies. Meta-analysis showed that age (per 5-year increase, HR 1.16 95% CI 1.11–1.21, high-quality evidence), comorbidities (Hematopoietic Cell Transplantation-specific Comorbidity Index: 3+ VS less than 3, HR 1.60 95% CI 1.31–1.95, high-quality evidence), and performance status (Eastern Cooperative Oncology Group/ World Health Organization (ECOG/WHO): 2+ VS less than 2, HR 1.63 95% CI 1.43–1.86, high-quality evidence; ECOG/WHO: 3+ VS less than 3, HR 2.00 95% CI 1.52–2.63, moderate-quality evidence) were associated with long-term mortality. These studies provided inconsistent and non-informative results on short-term mortality (within 90 days) and quality of life. Conclusion High-quality or moderate-quality evidence support that age, comorbidities, performance status predicts the long-term prognosis of older patients with AML undergoing antileukemic treatment.

The aim of this systematic review was to determine whether secondary closure (SC) or primary closure (PC) is better at preventing postoperative complications after impacted mandibular third-molar extraction.The authors sought randomized controlled trials comparing the effects of PC and SC on pain, swelling, trismus, infection, and bleeding after impacted mandibular third-molar extraction. Screening, data extraction, and risk of bias assessments were conducted independently and in duplicate. The reviewers pooled results across studies using a random-effects meta-analysis and assessed the certainty of the evidence using the Grading of Recommendations Assessment, Development and Evaluation approach.This review identified 785 unique citations and included 40 trials. Compared with PC, SC was found to have trivial benefits for pain at day 7 and trismus within 1 week (moderate certainty). The incidence of infection and bleeding did not differ importantly between techniques (moderate certainty). However, SC is probably associated with less swelling on day 1 (standardized mean difference, -0.98; 95% CI, -1.22 to -0.73; moderate certainty) and day 3 (standardized mean difference, -0.87; 95% CI, -1.16 to -0.59; moderate certainty). There was very low certainty evidence for pain on days 1 and 3 and low certainty evidence for swelling on day 7.Clinicians choosing between closure techniques should be aware that SC probably imparts an important benefit only for swelling at days 1 and 3. There seems to be a trivial difference between the techniques in other outcomes.

Background In 2017, the European Commission’s Joint Research Centre (JRC) started developing a methodological framework for a guideline-based quality assurance (QA) scheme to improve cancer quality of care. During the first phase of the work, inconsistency emerged about the use of terminology for the definition, the conceptual underpinnings and the way QA relates to health questions that are answered in guidelines. The objective of this final of three articles is to propose a conceptual framework for an integrated approach to guideline and QA development and clarify terms and definitions for key elements. This work will inform the upcoming European Commission Initiative on Colorectal Cancer (ECICC). Methods A multidisciplinary group of 23 experts from key organizations in the fields of guideline development, performance measurement and quality assurance participated in a mixed method approach including face-to-face dialogue and several rounds of virtual meetings. Informed by results of a systematic literature review that indicated absence of an existing framework and practical examples, we first identified the relations of key elements in guideline-based QA and then developed appropriate concepts and terminology to provide guidance. Results Our framework connects the three key concepts of quality indicators, performance measures and performance indicators integrated with guideline development. Quality indicators are constructs used as a guide to monitor, evaluate, and improve the quality of the structure, process and outcomes of healthcare services; performance measures are tools that quantify or describe measurable elements of practice performance; and performance indicators are quantifiable and measurable units or scores of practice, which should be guided by guideline recommendations. Conclusions The inconsistency in the way key terms of QA are used and defined has confused the field. Our conceptual framework defines the role, meaning and interactions of the key elements for improving quality in healthcare. It directly builds on the questions asked in guidelines and answered through recommendations. These findings will be applied in the forthcoming ECICC and for the future updates of ECIBC. These are large-scale integrated projects aimed at improving healthcare quality across Europe through the development of guideline-based QA schemes; this will help in implementing and improving our approach.

Background: Prognostic models combine several prognostic factors to provide an estimate of the likelihood (or risk) of future events in individual patients, conditional on their prognostic factor values. A fundamental part of evaluating prognostic models is undertaking studies to determine whether their predictive performance, such as calibration and discrimination, is reproduced across settings. Systematic reviews and meta-analyses of studies evaluating prognostic models’ performance are a necessary step for selection of models for clinical practice and for testing the underlying assumption that their use will improve outcomes, including patient's reassurance and optimal future planning. Methods: In this paper, we highlight key concepts in evaluating the certainty of evidence regarding the calibration of prognostic models. Results and Conclusion: Four concepts are key to evaluating the certainty of evidence on prognostic models’ performance regarding calibration. The first concept is that the inference regarding calibration may take one of two forms: deciding whether one is rating certainty that a model's performance is satisfactory or, instead, unsatisfactory, in either case defining the threshold for satisfactory (or unsatisfactory) model performance. Second, inconsistency is the critical GRADE domain to deciding whether we are rating certainty in the model performance being satisfactory or unsatisfactory. Third, depending on whether one is rating certainty in satisfactory or unsatisfactory performance, different patterns of inconsistency of results across studies will inform ratings of certainty of evidence. Fourth, exploring the distribution of point estimates of observed to expected ratio across individual studies, and its determinants, will bear on the need for and direction of future research. © 2021

BackgroundCOVID-19–related acute illness is associated with an increased risk of venous thromboembolism (VTE).ObjectiveThese evidence-based guidelines of the American Society of Hematology (ASH) are intended to support patients, clinicians, and other health care professionals in decisions about the use of anticoagulation for thromboprophylaxis in patients with COVID-19 who do not have confirmed or suspected VTE.MethodsASH formed a multidisciplinary guideline panel, including 3 patient representatives, and applied strategies to minimize potential bias from conflicts of interest. The McMaster University GRADE Centre supported the guideline development process, including performing systematic evidence reviews (up to March 2021). The panel prioritized clinical questions and outcomes according to their importance for clinicians and patients. The panel used the grading of recommendations assessment, development, and evaluation (GRADE) approach to assess evidence and make recommendations, which were subject to public comment.ResultsThe panel agreed on 1 additional recommendation. The panel issued a conditional recommendation against the use of outpatient anticoagulant prophylaxis in patients with COVID-19 who are discharged from the hospital and who do not have suspected or confirmed VTE or another indication for anticoagulation.ConclusionsThis recommendation was based on very low certainty in the evidence, underscoring the need for high-quality randomized controlled trials assessing the role of postdischarge thromboprophylaxis. Other key research priorities include better evidence on assessing risk of thrombosis and bleeding outcomes in patients with COVID-19 after hospital discharge.

Digital, Background: The coronavirus disease 19 (covid-19) pandemic has underscored the need to expedite clinical research, which may lead investigators to shift away from measuring patient-important outcomes (PIO), limiting research applicability. We aim to investigate if randomized controlled trials (RCTs) of covid-19 pharmacological thera‑ pies include PIOs. Methods: We will perform a meta-epidemiological study of RCTs that included people at risk for, or with suspected, probable, or confrmed covid-19, examining any pharmacological treatment or blood product aimed at prophylaxis or treatment. We will obtain data from all RCTs identifed in a living network metanalysis (NMA). The main data sources are the living WHO covid-19 database up to 1 March 2021 and six additional Chinese databases up to 20 February 2021. Two reviewers independently will review each citation, full-text article, and abstract data. To categorize the out‑ comes according to their importance to patients, we will adapt a previously defned hierarchy: a) mortality, b) quality of life/ functional status/symptoms, c) morbidity, and d) surrogate outcomes. Outcomes within the category a) and b) will be considered critically important to patients, and outcomes within the category c) will be regarded as important. We will use descriptive statistics to assess the proportion of studies that report each category of outcomes. We will perform univariable and multivariable analysis to explore associations between trial characteristics and the likelihood of reporting PIOs. Discussion: The fndings from this meta-epidemiological study will help health care professionals and researchers understand if the current covid-19 trials are efectively assessing and reporting the outcomes that are important to patients. If a defciency in capturing PIOs is identifed, this information may help inform the development of future RCTs in covid-19. Systematic review registrations: Open Science Framework registration: osf.io/6xgjz., Ciencias Médicas y de la Salud

von Willebrand Disease (VWD) is associated with significant morbidity because of excessive bleeding. Early diagnosis and treatment are important to prevent and treat these symptoms. We systematically reviewed the accuracy of any von Willebrand factor (VWF) activity assay in the diagnosis and classification of patients for VWD. We searched Cochrane Central, MEDLINE, and EMBASE for eligible studies. The risk of bias was assessed using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS)-2 and the certainty of evidence using the GRADE framework. We pooled estimates of sensitivity and specificity. The review included 77 studies that evaluated the use of newer tests of VWF platelet binding activity (VWF:GPIbR, VWF:GPIbM) and VWF:RCo for the diagnosis of VWD (13 studies), VWF propeptide to VWF:Ag ratio, and desmopressin trial for the diagnosis of type 1C VWD (5 studies), VWF multimer analysis and VWF:CB/VWF:Ag ratio for the classification of type 2 VWD (11 studies), genetic testing and ristocetin-induced platelet aggregation to diagnose type 2B VWD (14 studies), genetic testing and FVIII:VWF binding to diagnose type 2N VWD (17 studies). Based on available diagnostic test accuracy, there appear to be comparable test accuracy results between newer tests of platelet binding activity of VWF function and VWF:RCo. The findings of these reviews support VWF multimer analysis or VWF:CB/VWF:Ag to diagnose type 2 VWD. The desmopressin trial test with 1- and 4-hour postinfusion blood work is the test of choice to confirm increased VWF clearance in patients with suspected VWD type 1C. Additionally, genetic testing is most useful in diagnosing type 2B VWD and has a role in the diagnostic algorithm of suspected type 2N VWD.

Objective To evaluate the efficacy and safety of antiviral antibody therapies and blood products for the treatment of novel coronavirus disease 2019 (covid-19). Design Living systematic review and network meta-analysis, with pairwise meta-analysis for outcomes with insufficient data. Data sources WHO covid-19 database, a comprehensive multilingual source of global covid-19 literature, and six Chinese databases (up to 21 July 2021). Study selection Trials randomising people with suspected, probable, or confirmed covid-19 to antiviral antibody therapies, blood products, or standard care or placebo. Paired reviewers determined eligibility of trials independently and in duplicate. Methods After duplicate data abstraction, we performed random effects bayesian meta-analysis, including network meta-analysis for outcomes with sufficient data. We assessed risk of bias using a modification of the Cochrane risk of bias 2.0 tool. The certainty of the evidence was assessed using the grading of recommendations assessment, development, and evaluation (GRADE) approach. We meta-analysed interventions with ≥100 patients randomised or ≥20 events per treatment arm. Results As of 21 July 2021, we identified 47 trials evaluating convalescent plasma (21 trials), intravenous immunoglobulin (IVIg) (5 trials), umbilical cord mesenchymal stem cells (5 trials), bamlanivimab (4 trials), casirivimab-imdevimab (4 trials), bamlanivimab-etesevimab (2 trials), control plasma (2 trials), peripheral blood non-haematopoietic enriched stem cells (2 trials), sotrovimab (1 trial), anti-SARS-CoV-2 IVIg (1 trial), therapeutic plasma exchange (1 trial), XAV-19 polyclonal antibody (1 trial), CT-P59 monoclonal antibody (1 trial) and INM005 polyclonal antibody (1 trial) for the treatment of covid-19. Patients with non-severe disease randomised to antiviral monoclonal antibodies had lower risk of hospitalisation than those who received placebo: casirivimab-imdevimab (odds ratio (OR) 0.29 (95% CI 0.17 to 0.47); risk difference (RD) −4.2%; moderate certainty), bamlanivimab (OR 0.24 (0.06 to 0.86); RD −4.1%; low certainty), bamlanivimab-etesevimab (OR 0.31 (0.11 to 0.81); RD −3.8%; low certainty), and sotrovimab (OR 0.17 (0.04 to 0.57); RD −4.8%; low certainty). They did not have an important impact on any other outcome. There was no notable difference between monoclonal antibodies. No other intervention had any meaningful effect on any outcome in patients with non-severe covid-19. No intervention, including antiviral antibodies, had an important impact on any outcome in patients with severe or critical covid-19, except casirivimab-imdevimab, which may reduce mortality in patients who are seronegative. Conclusion In patients with non-severe covid-19, casirivimab-imdevimab probably reduces hospitalisation; bamlanivimab-etesevimab, bamlanivimab, and sotrovimab may reduce hospitalisation. Convalescent plasma, IVIg, and other antibody and cellular interventions may not confer any meaningful benefit. Systematic review registration This review was not registered. The protocol established a priori is included as a data supplement. Funding This study was supported by the Canadian Institutes of Health Research (grant CIHR- IRSC:0579001321). Readers’ note This article is a living systematic review that will be updated to reflect emerging evidence. Interim updates and additional study data will be posted on our website ( www.covid19lnma.com ).

Objective To propose a taxonomy and framework that identifies and presents actionable statements in guidelines. Study design and setting We took an iterative approach reviewing case studies of guidelines produced by the World Health Organization and the American Society of Hematology to develop an initial conceptual framework. We then tested it using randomly selected recommendations from published guidelines addressing COVID-19 from different organizations, evaluated its results, and refined it before retesting. The urgency and availability of evidence for development of these recommendations varied. We consulted with experts in research methodology and guideline developers to improve the final framework. Results The resulting taxonomy and framework distinguishes five types of actional statements: formal recommendations; research recommendations; good practice statements; implementation considerations, tools and tips; and informal recommendations. These statements should respond to a priori established criteria and require a clear structure and recognizable presentation in a guideline. Most importantly, this framework identifies informal recommendations that differ from formal recommendations by how they consider evidence and in their development process. Conclusion The identification, standardization and explicit labelling of actionable statements according to the framework may support guideline developers to create actionable statements with clear intent, avoid informal recommendations and improve their understanding and implementation by users.

Background: COVID-19–related critical illness is associated with an increased risk of venous thromboembolism (VTE). Objective: These evidence-based guidelines of the American Society of Hematology (ASH) are intended to support patients, clinicians, and other health care professionals in making decisions about the use of anticoagulation for thromboprophylaxis in patients with COVID-19–related critical illness who do not have confirmed or suspected VTE. Methods: ASH formed a multidisciplinary guideline panel that included 3 patient representatives and applied strategies to minimize potential bias from conflicts of interest. The McMaster University Grading of Recommendations Assessment, Development and Evaluation (GRADE) Centre supported the guideline development process by performing systematic evidence reviews (up to 5 March 2021). The panel prioritized clinical questions and outcomes according to their importance for clinicians and patients. The panel used the GRADE approach to assess evidence and make recommendations, which were subject to public comment. This is an update on guidelines published in February 2021. Results: The panel agreed on 1 additional recommendation. The panel issued a conditional recommendation in favor of prophylactic-intensity over intermediate-intensity anticoagulation in patients with COVID-19–related critical illness who do not have confirmed or suspected VTE. Conclusions: This recommendation was based on low certainty in the evidence, which underscores the need for additional high-quality, randomized, controlled trials comparing different intensities of anticoagulation in critically ill patients. Other key research priorities include better evidence regarding predictors of thrombosis and bleeding risk in critically ill patients with COVID-19 and the impact of nonanticoagulant therapies (eg, antiviral agents, corticosteroids) on thrombotic risk.

Network meta-analyses (NMAs) simultaneously estimate the effects of multiple possible treatment options for a given clinical presentation. For allergists to benefit optimally from NMAs, they must understand the process and be able to interpret the results. Through a worked example published in Pediatric Allergy and Immunology, we summarize how to identify credible NMAs and interpret them with a focus on recent innovations in the GRADE approach (Grading of Recommendations Assessment, Development, and Evaluation). NMAs build on traditional systematic reviews and meta-analyses that consider only direct paired comparisons by including indirect evidence, thus allowing the simultaneous assessment of the relative effect of all pairs of competing alternatives. Our framework informs clinicians of how to identify credible NMAs and address the certainty of the evidence. Trustworthy NMAs fill a critical gap in providing key inferences using direct and indirect evidence to inform clinical decision making when faced with more than two competing courses of treatment options. This document will help allergists to identify trustworthy NMAs to enhance patient care.

Background Chronic rhinosinusitis with nasal polyposis (CRSwNP) is an inflammatory condition of the upper airways. Optimal management is unclear. Objective We compared the effects of mAbs and aspirin desensitization (ASA-D) for treatment of CRSwNP. Methods We searched the Medline, Embase, Cochrane Central Register of Controlled Trials, International Clinical Trials Registry Platform, US Food and Drug Administration, and the European Medicines Agency databases from inception to August 4, 2021, for randomized controlled trials comparing the effects of mAbs and ASA-D for CRSwNP. We conducted network meta-analysis of sinusitis symptoms, heath-related quality of life, rescue oral corticosteroids and surgery, endoscopic and radiologic scores, and adverse events. We used the Grades of Recommendation Assessment, Development and Evaluation (GRADE) approach to assess certainty of evidence. PROSPERO CRD42020177334. Results Twenty-nine randomized controlled trials evaluating 8 treatments (n = 3461) were included in the network meta-analysis. Compared to placebo, moderate to high certainty evidence showed that health-related quality of life (SNOT-22) improved with dupilumab (mean difference [MD] −19.91 [95% confidence interval (CI) −22.50, −17.32]), omalizumab (MD −16.09 [95% CI −19.88, −12.30]), mepolizumab (MD −12.89 [95% CI −16.58, −9.19], ASA-D (MD −10.61 [95% CI −14.51, −6.71]), and benralizumab (MD −7.68 [95% CI −12.09, −3.27]). The risk of rescue nasal polyp surgery likely decreased with dupilumab (risk difference [RD] −16.35% [95% CI −18.13, −13.48]), omalizumab (RD −7.40% [95% CI −11.04, −2.43]), mepolizumab (RD −12.33% [95% CI −15.56, −7.22]), and ASA-D (RD −16.00% [95% CI −19.79, 0.21]; all moderate certainty). Comparisons among agents show with moderate to high certainty that dupilumab ranks among the most beneficial for 7 of 7 outcomes, omalizumab for 2 of 7, mepolizumab for 1 of 7, and ASA-D for 1 of 7. Conclusions Multiple biologics and ASA-D credibly improve patient-important outcomes, with clinically important differences in effects among agents; dupilumab uniquely ranks among the most beneficial for all outcomes studied.

This is the twelfth version (eleventh update) of the living guideline, replacing earlier versions (available as data supplements). New recommendations will be published as updates to this guideline.What is the role of drugs in the treatment of patients with covid-19?The evidence base for therapeutics for covid-19 is evolving with numerous randomised controlled trials (RCTs) recently completed and under way. The emerging SARS-CoV-2 variants (such as omicron) and subvariants are also changing the role of therapeutics. This update provides updated recommendations for remdesivir, addresses the use of combination therapy with corticosteroids, interleukin-6 (IL-6) receptor blockers, and janus kinase (JAK) inhibitors in patients with severe or critical covid-19, and modifies previous recommendations for the neutralising monoclonal antibodies sotrovimab and casirivimab-imdevimab in patients with non-severe covid-19.• Remdesivir: a conditional recommendation for its use in patients with severe covid-19; and a conditional recommendation against its use in patients with critical covid-19. • Concomitant use of IL-6 receptor blockers (tocilizumab or sarilumab) and the JAK inhibitor baricitinib: these drugs may now be combined, in addition to corticosteroids, in patients with severe or critical covid-19. • Sotrovimab and casirivimab-imdevimab: strong recommendations against their use in patients with covid-19, replacing the previous conditional recommendations for their use.When moving from new evidence to updated recommendations, the Guideline Development Group (GDG) considered a combination of evidence assessing relative benefits and harms, values and preferences, and feasibility issues. For remdesivir, new trial data were added to a previous subgroup analysis and provided sufficiently trustworthy evidence to demonstrate benefits in patients with severe covid-19, but not critical covid-19. The GDG considered benefits of remdesivir to be modest and of moderate certainty for key outcomes such as mortality and mechanical ventilation, resulting in a conditional recommendation. For baricitinib, the GDG considered clinical trial evidence (RECOVERY) demonstrating reduced risk of death in patients already receiving corticosteroids and IL-6 receptor blockers. The GDG acknowledged that the clinical trials were not representative of the world population and that the risk-benefit balance may be less advantageous, particularly in patients who are immunosuppressed at higher risk of opportunistic infections (such as serious fungal, viral, or bacteria), those already deteriorating where less aggressive or stepwise addition of immunosuppressive medications may be preferred, and in areas where certain pathogens such as HIV or tuberculosis, are of concern. The panel anticipated that there would be situations where clinicians may opt for less aggressive immunosuppressive therapy or to combine medications in a stepwise fashion in patients who are deteriorating. The decision to combine the medications will depend on their availability, and the treating clinician's perception of the risk-benefit balance associated with combination immunosuppressive therapy, particularly in patient populations at risk of opportunistic infections who may have been under-represented in clinical trials. When making a strong recommendation against the use of monoclonal antibodies for patients with covid-19, the GDG considered in vitro neutralisation data demonstrating that sotrovimab and casirivimab-imdevimab evaluated in clinical trials have meaningfully reduced neutralisation activity of the currently circulating variants of SARS-CoV-2 and their subvariants. There was consensus among the panel that the absence of in vitro neutralisation activity strongly suggests absence of clinical effectiveness of these monoclonal antibodies. However, there was also consensus regarding the need for clinical trial evidence in order to confirm clinical efficacy of new monoclonal antibodies that reliably neutralise the circulating strains in vitro. Whether emerging new variants and subvariants might be susceptible to sotrovimab, casirivimab-imdevimab, or other anti-SARS-CoV-2 monoclonal antibodies cannot be predicted.• Recommended for patients with severe or critical covid-19—strong recommendations for systemic corticosteroids; IL-6 receptor blockers (tocilizumab or sarilumab) in combination with corticosteroids; and baricitinib as an alternative to IL-6 receptor blockers, in combination with corticosteroids. • Recommended for patients with non-severe covid-19 at highest risk of hospitalisation—a strong recommendation for nirmatrelvir/ritonavir; conditional recommendations for molnupiravir and remdesivir. • Not recommended for patients with non-severe covid-19—a conditional recommendation against systemic corticosteroids; a strong recommendation against convalescent plasma; a recommendation against fluvoxamine, except in the context of a clinical trial; and a strong recommendation against colchicine. • Not recommended for patients with non-severe covid-19 at low risk of hospitalisation—a conditional recommendation against nirmatrelvir/ritonavir. • Not recommended for patients with severe or critical covid-19—a recommendation against convalescent plasma except in the context of a clinical trial; and a conditional recommendation against the JAK inhibitors ruxolitinib and tofacitinib. • Not recommended, regardless of covid-19 disease severity—a strong recommendations against hydroxychloroquine and against lopinavir/ritonavir; and a recommendation against ivermectin except in the context of a clinical trial.This living guideline from the World Health Organization (WHO) incorporates new evidence to dynamically update recommendations for covid-19 therapeutics. The GDG typically evaluates a therapy when the WHO judges sufficient evidence is available to make a recommendation. While the GDG takes an individual patient perspective in making recommendations, it also considers resource implications, acceptability, feasibility, equity, and human rights. This guideline was developed according to standards and methods for trustworthy guidelines, making use of an innovative process to achieve efficiency in dynamic updating of recommendations. The methods are aligned with the WHO Handbook for Guideline Development and according to a pre-approved protocol (planning proposal) by the Guideline Review Committee (GRC). A box at the end of the article outlines key methodological aspects of the guideline process. MAGIC Evidence Ecosystem Foundation provides methodological support, including the coordination of living systematic reviews with network meta-analyses to inform the recommendations. The full version of the guideline is available online in MAGICapp and in PDF, with a summary version here in The BMJ. These formats should facilitate adaptation, which is strongly encouraged by WHO to contextualise recommendations in a healthcare system to maximise impact.Recommendations on anticoagulation are planned for the next update to this guideline.

Von Willebrand disease (VWD) can be associated with significant morbidity. Patients with VWD can experience bruising, mucocutaneous bleeding, and bleeding after dental and surgical procedures. Early diagnosis and treatment are important to minimize the risk of these complications. Several bleeding assessment tools (BATs) have been used to quantify bleeding symptoms as a screening tool for VWD. We systematically reviewed diagnostic test accuracy results of BATs to screen patients for VWD. We searched Cochrane Central, MEDLINE, and EMBASE for eligible studies, reference lists of relevant reviews, registered trials, and relevant conference proceedings. Two investigators screened and abstracted data. Risk of bias was assessed using the revised tool for the quality assessment of diagnostic accuracy studies and certainty of evidence using the Grading of Recommendations Assessment, Development and Evaluation framework. We pooled estimates of sensitivity and specificity. The review included 7 cohort studies that evaluated the use of BATs to screen adult and pediatric patients for VWD. The pooled estimates for sensitivity and specificity were 75% (95% confidence interval, 66-83) and 54% (29-77), respectively. Certainty of evidence varied from moderate to high. This systematic review provides accuracy estimates for validated BATs as a screening modality for VWD. A BAT is a useful initial screening test to determine who needs specific blood testing. The pretest probability of VWD (often determined by the clinical setting/patient population), along with sensitivity and specificity estimates, will influence patient management.

IntroductionMethodological studies (ie, studies that evaluate the design, conduct, analysis or reporting of other studies in health research) address various facets of health research including, for instance, data collection techniques, differences in approaches to analyses, reporting quality, adherence to guidelines or publication bias. As a result, methodological studies can help to identify knowledge gaps in the methodology of health research and strategies for improvement in research practices. Differences in methodological study names and a lack of reporting guidance contribute to lack of comparability across studies and difficulties in identifying relevant previous methodological studies. This paper outlines the methods we will use to develop an evidence-based tool—the MethodologIcal STudy reportIng Checklist—to harmonise naming conventions and improve the reporting of methodological studies.Methods and analysisWe will search for methodological studies in the Cumulative Index to Nursing and Allied Health Literature, Cochrane Library, Embase, MEDLINE, Web of Science, check reference lists and contact experts in the field. We will extract and summarise data on the study names, design and reporting features of the included methodological studies. Consensus on study terms and recommended reporting items will be achieved via video conference meetings with a panel of experts including researchers who have published methodological studies.Ethics and disseminationThe consensus study has been exempt from ethics review by the Hamilton Integrated Research Ethics Board. The results of the review and the reporting guideline will be disseminated in stakeholder meetings, conferences, peer-reviewed publications, in requests to journal editors (to endorse or make the guideline a requirement for authors), and on the Enhancing the QUAlity and Transparency Of health Research (EQUATOR) Network and reporting guideline websites.RegistrationWe have registered the development of the reporting guideline with the EQUATOR Network and publicly posted this project on the Open Science Framework (www.osf.io/9hgbq).

Clinical question What is the role of drugs in preventing covid-19? Why does this matter? There is widespread interest in whether drug interventions can be used for the prevention of covid-19, but there is uncertainty about which drugs, if any, are effective. Recommendations The second version of this living guideline reiterates the previous strong recommendation against the use of hydroxychloroquine and includes a new conditional recommendation against the use of tixagevimab-cilgavimab in individuals who do not have covid-19. How this guideline was created This living guideline is from the World Health Organization (WHO) and provides up to date covid-19 guidance to inform policy and practice worldwide. Magic Evidence Ecosystem Foundation (MAGIC) provides methodological support. A living systematic review with network analysis informs the recommendations. An international guideline development group (GDG) of content experts, clinicians, patients, an ethicist and methodologists produces recommendations following standards for trustworthy guideline development using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Understanding the recommendations The living network meta-analysis informing this guideline included 12 trials (8379 participants) comparing hydroxychloroquine to standard care/placebo, and one trial (5197 participants) comparing tixagevimab-cilgavimab to standard care/placebo. When moving from evidence to the continued strong recommendation against the use of hydroxychloroquine, the GDG emphasised additional evidence suggesting no or little effect on mortality and hospital admission, and an increased risk of adverse effects. For the new conditional recommendation against the use of tixagevimab-cilgavimab, the GDG emphasised in vitro evidence reducing the applicability of available trial data. While trial results demonstrated modest reduction in the occurrence of laboratory confirmed symptomatic covid-19, lack of in vitro neutralisation of new SARS-CoV-2 sub-lineages was considered to have rendered these results obsolete. Updates This is a living guideline. New recommendations will be published in this article and signposted by update notices to this guideline. Readers note This is the second version of the living guideline for drugs to prevent covid-19. It complements the WHO living guideline on drugs to treat covid-19 and living guidance regarding covid-19 related clinical management. When citing this article, please consider adding the update number and date of access for clarity.

Background Although quality indicators are frequently derived from guidelines, there is a substantial gap in collaboration between the corresponding parties. To optimise workflow, guideline recommendations and quality assurance should be aligned methodologically and practically. Learning from the European Commission Initiative on Breast Cancer (ECIBC), our objective was to bring the key knowledge and most important considerations from both worlds together to inform European Commission future initiatives. Methods We undertook several steps to address the problem. First, we conducted a feasibility study that included a survey, interviews and a review of manuals for an integrated guideline and quality assurance (QA) scheme that would support the European Commission. The feasibility study drew from an assessment of the ECIBC experience that followed commonly applied strategies leading to separation of the guideline and QA development processes. Secondly, we used results of a systematic review to inform our understanding of methodologies for integrating guideline and QA development. We then, in a third step, used the findings to prepare an evidence brief and identify key aspects of a methodological framework for integrating guidelines QA through meetings with key informants. Results Seven key themes emerged to be taken into account for integrating guidelines and QA schemes: (1) evidence-based integrated guideline and QA frameworks are possible, (2) transparency is key in clearly documenting the source and rationale for quality indicators, (3) intellectual and financial interests should be declared and managed appropriately, (4) selection processes and criteria for quality indicators need further refinement, (5) clear guidance on retirement of quality indicators should be included, (6) risks of an integrated guideline and QA Group can be mitigated, and (7) an extension of the GIN-McMaster Guideline Development Checklist should incorporate QA considerations. Discussion We concluded that the work of guideline and QA developers can be integrated under a common methodological framework and we provided key findings and recommendations. These two worlds, that are fundamental to improving health, can both benefit from integration.

Objective This article describes GRADE guidance for assessing imprecision when rating the certainty of the evidence from network meta-analysis. Study Design and Setting A project group within the GRADE working group conducted iterative discussions, computer simulations, and presentations at GRADE working group meetings to produce and obtain approval for this guidance. Results When addressing imprecision of a network estimate, reviewers should consider the 95% confidence or credible interval, and the optimal information size. If the 95% confidence or credible interval crosses a pre-specified threshold, reviewers should rate down the certainty of the evidence. If the 95% confidence interval does not cross any pre-specfied threshold, reviewers should consider the optimal information size. Because addressing the optimal information size may be challenging, reviewers can use the effect size to decide if any calculations are necessary. When the size of the effect is modest or the optimal information size is met, reviewers should not rate down for imprecision. Conclusion Reviewers should use this guidance when to appropriately address imprecision in the context of the assessment of certainty of evidence from network meta-analysis.

IntroductionIn an attempt to improve outcomes for patients with coronavirus disease 19 (COVID-19), several drugs, such as remdesivir, hydroxychloroquine (with or without azithromycin), and lopinavir/ritonavir, have been evaluated for treatment. While much attention focuses on potential benefits of these drugs, this must be weighed against their adverse effects.MethodsWe searched 32 databases in multiple languages from 1 December 2019 to 27 October 2020. We included randomized trials if they compared any of the drugs of interest to placebo or standard care, or against each other. A related world health organization (WHO) guideline panel selected the interventions to address and identified possible adverse effects that might be important to patients. Pairs of reviewers independently extracted data and assessed risk of bias. We analyzed data using a fixed-effects pairwise meta-analysis and assessed the certainty of evidence using the GRADE approach.ResultsWe included 16 randomized trials which enrolled 8226 patients. Compared to standard care or placebo, low certainty evidence suggests that remdesivir may not have an important effect on acute kidney injury (risk difference [RD] 8 fewer per 1000, 95% confidence interval (CI): 27 fewer to 21 more) or cognitive dysfunction/delirium (RD 3 more per 1000, 95% CI: 12 fewer to 19 more). Low certainty evidence suggests that hydroxychloroquine may increase the risk of serious cardiac toxicity (RD 10 more per 1000, 95% CI: 0 more to 30 more) and cognitive dysfunction/delirium (RD 33 more per 1000, 95% CI: 18 fewer to 84 more), whereas moderate certainty evidence suggests hydroxychloroquine probably increases the risk of diarrhoea (RD 106 more per 1000, 95% CI: 48 more to 175 more) and nausea and/or vomiting (RD 62 more per 1000, 95% CI: 23 more to 110 more) compared to standard care or placebo. Low certainty evidence suggests lopinavir/ritonavir may increase the risk of diarrhoea (RD 168 more per 1000, 95% CI: 58 more to 330 more) and nausea and/or vomiting (RD 160 more per 1000, 95% CI: 100 more to 210 more) compared to standard care or placebo.ConclusionHydroxychloroquine probably increases the risk of diarrhoea and nausea and/or vomiting and may increase the risk of cardiac toxicity and cognitive dysfunction/delirium. Remdesivir may have no effect on risk of acute kidney injury or cognitive dysfunction/delirium. Lopinavir/ritonavir may increase the risk of diarrhoea and nausea and/or vomiting. These findings provide important information to support the development of evidence-based management strategies for patients with COVID-19.

This article describes GRADE (grading of recommendations assessment, development and evaluation) guidance on how to make conclusions from a network meta-analysis of interventions that includes individual randomised controlled trials for one outcome at a time. The guidance is based on a partially contextualised approach in which review authors must establish ranges of magnitudes of effect that represent a trivial to no effect, small but important effect, moderate effect, and large effect. The principles guiding this framework are that interventions should be grouped in categories, based on the magnitude of the effect; and that the judgments that place interventions in such categories should consider the estimates of effect, the certainty of the evidence, and the rankings. We describe and illustrate the four steps of this framework using an example.

Background: Coronavirus disease 2019 (COVID-19)–related critical illness and acute illness are associated with a risk of venous thromboembolism (VTE). Objective: These evidence-based guidelines of the American Society of Hematology (ASH) are intended to support patients, clinicians, and other health care professionals in decisions about the use of anticoagulation for thromboprophylaxis for patients with COVID-19–related critical illness and acute illness who do not have confirmed or suspected VTE. Methods: ASH formed a multidisciplinary guideline panel and applied strict management strategies to minimize potential bias from conflicts of interest. The panel included 3 patient representatives. The McMaster University GRADE Centre supported the guideline-development process, including performing systematic evidence reviews (up to 19 August 2020). The panel prioritized clinical questions and outcomes according to their importance for clinicians and patients. The panel used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, including GRADE Evidence-to-Decision frameworks, to assess evidence and make recommendations, which were subject to public comment. Results: The panel agreed on 2 recommendations. The panel issued conditional recommendations in favor of prophylactic-intensity anticoagulation over intermediate-intensity or therapeutic-intensity anticoagulation for patients with COVID-19–related critical illness or acute illness who do not have confirmed or suspected VTE. Conclusions: These recommendations were based on very low certainty in the evidence, underscoring the need for high-quality, randomized controlled trials comparing different intensities of anticoagulation. They will be updated using a living recommendation approach as new evidence becomes available., Visual Abstract

Clinical questionWhat is the role of remdesivir in the treatment of severe covid-19? This guideline was triggered by the ACTT-1 trial published in the New England Journal of Medicine on 22 May 2020.Current practiceRemdesivir has received worldwide attention as a potentially effective treatment for severe covid-19. After rapid market approval in the US, remdesivir is already being used in clinical practice.RecommendationsThe guideline panel makes a weak recommendation for the use of remdesivir in severe covid-19 while recommending continuation of active enrolment of patients into ongoing randomised controlled trials examining remdesivir.How this guideline was createdAn international panel of patients, clinicians, and methodologists produced these recommendations in adherence with standards for trustworthy guidelines using the GRADE approach. The recommendations are based on a linked systematic review and network meta-analysis. The panel considered an individual patient perspective and allowed contextual factors (such as resources) to be taken into account for countries and healthcare systems.The evidenceThe linked systematic review (published 31 Jul 2020) identified two randomised trials with 1300 participants, showing low certainty evidence that remdesivir may be effective in reducing time to clinical improvement and may decrease mortality in patients with severe covid-19. Remdesivir probably has no important effect on need for invasive mechanical ventilation. Remdesivir may have little or no effect on hospital length of stay.Understanding the recommendationMost patients with severe covid-19 would likely choose treatment with remdesivir given the potential reduction in time to clinical improvement. However, given the low certainty evidence for critical outcomes and the fact that different perspectives, values, and preferences may alter decisions regarding remdesivir, the panel issued a weak recommendation with strong support for continued recruitment in randomised trials.