Publications by authors named "Gordon Guyatt"

1,115 Publications

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Definition of a critical bleed in patients with immune thrombocytopenia: Communication from the ISTH SSC Subcommittee on Platelet Immunology.

J Thromb Haemost 2021 Aug;19(8):2082-2088

Department of Medicine, McMaster Centre for Transfusion Research, McMaster University, Hamilton, ON, Canada.

Background: Immune thrombocytopenia (ITP) is an autoimmune disease characterized by low platelet counts and increased risk of bleeding. In preparation for an upcoming guideline, the ITP Emergency Management Guideline Panel, including clinical experts in hematology, emergency medicine, research methodology, and patient representatives, identified the need for a standardized definition of a critical ITP bleed. The goal of the definition was to distinguish critical bleeds from bleeds that may not require urgent treatment, typically in the context of severe thrombocytopenia.

Methods: The panel met in person and virtually to achieve consensus on the criteria for critical bleeding events among patients with ITP. Existing ITP bleeding scores and published definitions of major bleeds in patients receiving anticoagulation informed the definition of a critical ITP bleed. The Platelet Immunology Scientific Standardization Committee (SSC) of the International Society on Thrombosis and Haemostasis endorsed the definition.

Results: A critical ITP bleed was defined as: (a) a bleed in a critical anatomical site including intracranial, intraspinal, intraocular, retroperitoneal, pericardial, or intramuscular with compartment syndrome; or (2) an ongoing bleed that results in hemodynamic instability or respiratory compromise.

Conclusion: The definition of a critical ITP bleed was developed by the ITP Emergency Management Guideline Panel and endorsed by the Platelet Immunology SSC. It incorporates both anatomic and physiologic risk and pertains to patients with confirmed or suspected ITP who typically have severe thrombocytopenia (platelet count below 20 × 10 /L).
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http://dx.doi.org/10.1111/jth.15368DOI Listing
August 2021

Method's Corner: Allergist's guide to Network Meta-Analysis.

Pediatr Allergy Immunol 2021 Jul 29. Epub 2021 Jul 29.

Pediatric Epidemiology, Department of Pediatrics, Medical Faculty, Leipzig University, Leipzig, Germany.

Network meta-analyses (NMAs) simultaneously estimate 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.
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http://dx.doi.org/10.1111/pai.13609DOI Listing
July 2021

Opioid-sparing effects of medical cannabis or cannabinoids for chronic pain: a systematic review and meta-analysis of randomised and observational studies.

BMJ Open 2021 Jul 28;11(7):e047717. Epub 2021 Jul 28.

Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada

Objective: To assess the efficacy and harms of adding medical cannabis to prescription opioids among people living with chronic pain.

Design: Systematic review.

Data Sources: CENTRAL, EMBASE and MEDLINE.

Main Outcomes And Measures: Opioid dose reduction, pain relief, sleep disturbance, physical and emotional functioning and adverse events.

Study Selection Criteria And Methods: We included studies that enrolled patients with chronic pain receiving prescription opioids and explored the impact of adding medical cannabis. We used Grading of Recommendations Assessment, Development and Evaluation to assess the certainty of evidence for each outcome.

Results: Eligible studies included five randomised trials (all enrolling chronic cancer-pain patients) and 12 observational studies. All randomised trials instructed participants to maintain their opioid dose, which resulted in a very low certainty evidence that adding cannabis has little or no impact on opioid use (weighted mean difference (WMD) -3.4 milligram morphine equivalent (MME); 95% CI (CI) -12.7 to 5.8). Randomised trials provided high certainty evidence that cannabis addition had little or no effect on pain relief (WMD -0.18 cm; 95% CI -0.38 to 0.02; on a 10 cm Visual Analogue Scale (VAS) for pain) or sleep disturbance (WMD -0.22 cm; 95% CI -0.4 to -0.06; on a 10 cm VAS for sleep disturbance; minimally important difference is 1 cm) among chronic cancer pain patients. Addition of cannabis likely increases nausea (relative risk (RR) 1.43; 95% CI 1.04 to 1.96; risk difference (RD) 4%, 95% CI 0% to 7%) and vomiting (RR 1.5; 95% CI 1.01 to 2.24; RD 3%; 95% CI 0% to 6%) (both moderate certainty) and may have no effect on constipation (RR 0.85; 95% CI 0.54 to 1.35; RD -1%; 95% CI -4% to 2%) (low certainty). Eight observational studies provided very low certainty evidence that adding cannabis reduced opioid use (WMD -22.5 MME; 95% CI -43.06 to -1.97).

Conclusion: Opioid-sparing effects of medical cannabis for chronic pain remain uncertain due to very low certainty evidence.CRD42018091098.
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http://dx.doi.org/10.1136/bmjopen-2020-047717DOI Listing
July 2021

GRADE guidelines 33: Addressing imprecision in a network meta-analysis.

J Clin Epidemiol 2021 Jul 19. Epub 2021 Jul 19.

Department of Medicine, University Health Network, 200 Elizabeth Street, Toronto, ON, M5G 2C4, Canada.

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.

Conclusions: Reviewers should use this guidance when to appropriately address imprecision in the context of the assessment of certainty of evidence from network meta-analysis.
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http://dx.doi.org/10.1016/j.jclinepi.2021.07.011DOI Listing
July 2021

Cough symptom severity in patients with refractory or unexplained chronic cough: a systematic survey and conceptual framework.

Eur Respir Rev 2021 Sep 13;30(161). Epub 2021 Jul 13.

Dept of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, ON, Canada

Background: Cough severity represents an important subjective endpoint in assessing the effectiveness of therapies for patients with chronic cough. Although cough-specific quality of life questionnaires exist, a widely available cough severity instrument with established measurement properties remains unavailable.

Aims: To identify and summarise the results of studies reporting on the experience of patients with chronic cough and, in the process, develop a conceptual framework to inform development of a patient-reported outcome measurement (PROM) addressing cough severity.

Results: We identified 61 eligible studies reporting on patient experience with chronic cough. Studies provided 82 potential items, of which 43 proved unique and relevant to cough severity. The urge-to-cough sensation and the cough symptom itself represented broad domains of cough severity. Two subdomains under urge-to-cough included frequency (1 item) and intensity (1 item). Five subdomains under cough symptoms included control (2 items), frequency (6 items), bout duration (1 item), intensity (8 items), and associated features/sequelae (24 items).

Conclusions: Our systematic survey and conceptual framework identified items and domains of cough severity in patients with refractory or unexplained chronic cough. The results support item generation and content validity for a PROM assessing cough severity.
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http://dx.doi.org/10.1183/16000617.0104-2021DOI Listing
September 2021

Interventional treatments for chronic, axial or radicular, non-cancer, spinal pain: a protocol for a systematic review and network meta-analysis of randomised trials.

BMJ Open 2021 Jul 9;11(7):e046025. Epub 2021 Jul 9.

Michael G. DeGroote Institute for Pain Research and Care, McMaster University, Hamilton, Ontario, Canada

Introduction: Chronic, non-cancer, axial or radicular spinal pain is a common condition associated with considerable socioeconomic burden. Clinicians frequently offer patients various interventional procedures for the treatment of chronic spine pain; however, the comparative effectiveness and safety of available procedures remains uncertain.

Methods: We will conduct a systematic review of randomised controlled trials that explores the effectiveness and harms of interventional procedures for the management of axial or radicular, chronic, non-cancer, spine pain. We will identify eligible studies through a systematic search of Medline, EMBASE, CINAHL, Cochrane Central Register of Controlled Trials and Web of Science from inception without language restrictions. Eligible trials will: (1) enrol primarily adult patients (≥18 years old) with axial or radicular, chronic, non-cancer, spine pain, (2) randomise patients to different, currently available, interventional procedures or to an interventional procedure and a placebo/sham procedure or usual care, and (3) measure outcomes at least 1 month after randomisation.Pairs of reviewers will independently screen articles identified through searches and extract information and assess risk of bias of eligible trials. We will use a modified Cochrane instrument to evaluate risk of bias. We will use frequentist random-effects network meta-analyses to assess the relative effects of interventional procedures, and five a priori hypotheses to explore between studies subgroup effects. We will use the Grading of Recommendations Assessment, Development and Evaluation approach to assess the certainty in evidence for each outcome, including direct, indirect and network estimates.

Ethics And Dissemination: No research ethics approval is required for this systematic review, as no confidential patient data will be used. We will disseminate our findings through publication in a peer-reviewed journal and conference presentations, and our review will support development of a Rapid Recommendations providing contextualised clinical guidance based on this body of evidence.

Prospero Registration Number: CRD42020170667.
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http://dx.doi.org/10.1136/bmjopen-2020-046025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8273478PMC
July 2021

2021 American College of Rheumatology/Vasculitis Foundation Guideline for the Management of Antineutrophil Cytoplasmic Antibody-Associated Vasculitis.

Arthritis Rheumatol 2021 Aug 8;73(8):1366-1383. Epub 2021 Jul 8.

Cleveland Clinic, Cleveland, Ohio.

Objective: To provide evidence-based recommendations and expert guidance for the management of antineutrophil cytoplasmic antibody-associated vasculitis (AAV), including granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA).

Methods: Clinical questions regarding the treatment and management of AAV were developed in the population, intervention, comparator, and outcome (PICO) format (47 for GPA/MPA, 34 for EGPA). Systematic literature reviews were conducted for each PICO question. The Grading of Recommendations Assessment, Development and Evaluation methodology was used to assess the quality of evidence and formulate recommendations. Each recommendation required ≥70% consensus among the Voting Panel.

Results: We present 26 recommendations and 5 ungraded position statements for GPA/MPA, and 15 recommendations and 5 ungraded position statements for EGPA. This guideline provides recommendations for remission induction and maintenance therapy as well as adjunctive treatment strategies in GPA, MPA, and EGPA. These recommendations include the use of rituximab for remission induction and maintenance in severe GPA and MPA and the use of mepolizumab in nonsevere EGPA. All recommendations are conditional due in part to the lack of multiple randomized controlled trials and/or low-quality evidence supporting the recommendations.

Conclusion: This guideline presents the first recommendations endorsed by the American College of Rheumatology and the Vasculitis Foundation for the management of AAV and provides guidance to health care professionals on how to treat these diseases.
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http://dx.doi.org/10.1002/art.41773DOI Listing
August 2021

2021 American College of Rheumatology/Vasculitis Foundation Guideline for the Management of Polyarteritis Nodosa.

Arthritis Care Res (Hoboken) 2021 Aug 8;73(8):1061-1070. Epub 2021 Jul 8.

Cleveland Clinic Foundation, Cleveland, Ohio.

Objective: To provide evidence-based recommendations and expert guidance for the management of systemic polyarteritis nodosa (PAN).

Methods: Twenty-one clinical questions regarding diagnostic testing, treatment, and management were developed in the population, intervention, comparator, and outcome (PICO) format for systemic, non-hepatitis B-related PAN. Systematic literature reviews were conducted for each PICO question. The Grading of Recommendations Assessment, Development and Evaluation methodology was used to assess the quality of evidence and formulate recommendations. Each recommendation required ≥70% consensus among the Voting Panel.

Results: We present 16 recommendations and 1 ungraded position statement for PAN. Most recommendations were graded as conditional due to the paucity of evidence. These recommendations support early treatment of severe PAN with cyclophosphamide and glucocorticoids, limiting toxicity through minimizing long-term exposure to both treatments, and the use of imaging and tissue biopsy for disease diagnosis. These recommendations endorse minimizing risk to the patient by using established therapy at disease onset and identify new areas where adjunctive therapy may be warranted.

Conclusion: These recommendations provide guidance regarding diagnostic strategies, use of pharmacologic agents, and imaging for patients with PAN.
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http://dx.doi.org/10.1002/acr.24633DOI Listing
August 2021

2021 American College of Rheumatology/Vasculitis Foundation Guideline for the Management of Giant Cell Arteritis and Takayasu Arteritis.

Arthritis Rheumatol 2021 Aug 8;73(8):1349-1365. Epub 2021 Jul 8.

Cleveland Clinic Foundation, Cleveland, Ohio.

Objective: To provide evidence-based recommendations and expert guidance for the management of giant cell arteritis (GCA) and Takayasu arteritis (TAK) as exemplars of large vessel vasculitis.

Methods: Clinical questions regarding diagnostic testing, treatment, and management were developed in the population, intervention, comparator, and outcome (PICO) format for GCA and TAK (27 for GCA, 27 for TAK). Systematic literature reviews were conducted for each PICO question. The Grading of Recommendations Assessment, Development and Evaluation methodology was used to rate the quality of the evidence. Recommendations were developed by the Voting Panel, comprising adult and pediatric rheumatologists and patients. Each recommendation required ≥70% consensus among the Voting Panel.

Results: We present 22 recommendations and 2 ungraded position statements for GCA, and 20 recommendations and 1 ungraded position statement for TAK. These recommendations and statements address clinical questions relating to the use of diagnostic testing, including imaging, treatments, and surgical interventions in GCA and TAK. Recommendations for GCA include support for the use of glucocorticoid-sparing immunosuppressive agents and the use of imaging to identify large vessel involvement. Recommendations for TAK include the use of nonglucocorticoid immunosuppressive agents with glucocorticoids as initial therapy. There were only 2 strong recommendations; the remaining recommendations were conditional due to the low quality of evidence available for most PICO questions.

Conclusion: These recommendations provide guidance regarding the evaluation and management of patients with GCA and TAK, including diagnostic strategies, use of pharmacologic agents, and surgical interventions.
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http://dx.doi.org/10.1002/art.41774DOI Listing
August 2021

2021 American College of Rheumatology/Vasculitis Foundation Guideline for the Management of Polyarteritis Nodosa.

Arthritis Rheumatol 2021 Aug 8;73(8):1384-1393. Epub 2021 Jul 8.

Cleveland Clinic Foundation, Cleveland, Ohio.

Objective: To provide evidence-based recommendations and expert guidance for the management of systemic polyarteritis nodosa (PAN).

Methods: Twenty-one clinical questions regarding diagnostic testing, treatment, and management were developed in the population, intervention, comparator, and outcome (PICO) format for systemic, non-hepatitis B-related PAN. Systematic literature reviews were conducted for each PICO question. The Grading of Recommendations Assessment, Development and Evaluation methodology was used to assess the quality of evidence and formulate recommendations. Each recommendation required ≥70% consensus among the Voting Panel.

Results: We present 16 recommendations and 1 ungraded position statement for PAN. Most recommendations were graded as conditional due to the paucity of evidence. These recommendations support early treatment of severe PAN with cyclophosphamide and glucocorticoids, limiting toxicity through minimizing long-term exposure to both treatments, and the use of imaging and tissue biopsy for disease diagnosis. These recommendations endorse minimizing risk to the patient by using established therapy at disease onset and identify new areas where adjunctive therapy may be warranted.

Conclusion: These recommendations provide guidance regarding diagnostic strategies, use of pharmacologic agents, and imaging for patients with PAN.
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http://dx.doi.org/10.1002/art.41776DOI Listing
August 2021

2021 American College of Rheumatology/Vasculitis Foundation Guideline for the Management of Antineutrophil Cytoplasmic Antibody-Associated Vasculitis.

Arthritis Care Res (Hoboken) 2021 Aug 8;73(8):1088-1105. Epub 2021 Jul 8.

Cleveland Clinic, Cleveland, Ohio.

Objective: To provide evidence-based recommendations and expert guidance for the management of antineutrophil cytoplasmic antibody-associated vasculitis (AAV), including granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA).

Methods: Clinical questions regarding the treatment and management of AAV were developed in the population, intervention, comparator, and outcome (PICO) format (47 for GPA/MPA, 34 for EGPA). Systematic literature reviews were conducted for each PICO question. The Grading of Recommendations Assessment, Development and Evaluation methodology was used to assess the quality of evidence and formulate recommendations. Each recommendation required ≥70% consensus among the Voting Panel.

Results: We present 26 recommendations and 5 ungraded position statements for GPA/MPA, and 15 recommendations and 5 ungraded position statements for EGPA. This guideline provides recommendations for remission induction and maintenance therapy as well as adjunctive treatment strategies in GPA, MPA, and EGPA. These recommendations include the use of rituximab for remission induction and maintenance in severe GPA and MPA and the use of mepolizumab in nonsevere EGPA. All recommendations are conditional due in part to the lack of multiple randomized controlled trials and/or low-quality evidence supporting the recommendations.

Conclusion: This guideline presents the first recommendations endorsed by the American College of Rheumatology and the Vasculitis Foundation for the management of AAV and provides guidance to health care professionals on how to treat these diseases.
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http://dx.doi.org/10.1002/acr.24634DOI Listing
August 2021

2021 American College of Rheumatology/Vasculitis Foundation Guideline for the Management of Giant Cell Arteritis and Takayasu Arteritis.

Arthritis Care Res (Hoboken) 2021 Aug 8;73(8):1071-1087. Epub 2021 Jul 8.

Cleveland Clinic Foundation, Cleveland, Ohio.

Objective: To provide evidence-based recommendations and expert guidance for the management of giant cell arteritis (GCA) and Takayasu arteritis (TAK) as exemplars of large vessel vasculitis.

Methods: Clinical questions regarding diagnostic testing, treatment, and management were developed in the population, intervention, comparator, and outcome (PICO) format for GCA and TAK (27 for GCA, 27 for TAK). Systematic literature reviews were conducted for each PICO question. The Grading of Recommendations Assessment, Development and Evaluation methodology was used to rate the quality of the evidence. Recommendations were developed by the Voting Panel, comprising adult and pediatric rheumatologists and patients. Each recommendation required ≥70% consensus among the Voting Panel.

Results: We present 22 recommendations and 2 ungraded position statements for GCA, and 20 recommendations and 1 ungraded position statement for TAK. These recommendations and statements address clinical questions relating to the use of diagnostic testing, including imaging, treatments, and surgical interventions in GCA and TAK. Recommendations for GCA include support for the use of glucocorticoid-sparing immunosuppressive agents and the use of imaging to identify large vessel involvement. Recommendations for TAK include the use of nonglucocorticoid immunosuppressive agents with glucocorticoids as initial therapy. There were only 2 strong recommendations; the remaining recommendations were conditional due to the low quality of evidence available for most PICO questions.

Conclusion: These recommendations provide guidance regarding the evaluation and management of patients with GCA and TAK, including diagnostic strategies, use of pharmacologic agents, and surgical interventions.
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http://dx.doi.org/10.1002/acr.24632DOI Listing
August 2021

Prognostic value of natriuretic peptides in heart failure: systematic review and meta-analysis.

Heart Fail Rev 2021 Jul 5. Epub 2021 Jul 5.

Ted Rogers Center for Heart Research, University Health Network, Toronto, ON, Canada.

Risk models, informing optimal long-term medical management, seldom use natriuretic peptides (NP) in ascertaining the absolute risk of outcomes for HF patients. Individual studies evaluating the prognostic value of NPs in HF patients have reported varying effects, arriving at best estimates requires a systematic review. We systematically summarized the best evidence regarding the prognostic value of brain natriuretic peptide (BNP) and NT-proBNP in predicting mortality and hospitalizations in ambulatory heart failure (HF) patients. We searched bibliographic databases from 2005 to 2018 and included studies evaluating the association of BNP or NT-proBNP with mortality or hospitalization using multivariable Cox proportional hazard models. We pooled hazard ratios using random-effect models, explored heterogeneity using pre-specified subgroup analyses, and evaluated the certainty of evidence using the Grading of Recommendations and Development Evaluation framework. We identified 67 eligible studies reporting on 76,178 ambulatory HF patients with a median BNP of 407 pg/mL (261-574 pg/mL). Moderate to high-quality evidence showed that a 100-pg/mL increase in BNP was associated with a 14% increased hazard of mortality (HR 1.14, 95% CI 1.06-1.22); a 1-log-unit increase was associated with a 51% increased hazard of mortality (HR 1.51, 95% CI 1.41-1.61) and 48% increased hazard of mortality or hospitalization (HR 1.48, 95% CI 1.29-1.69). With moderate to high certainty, we observed a 14% independent relative increase in mortality, translating to a clinically meaningful increase in absolute risk even for low-risk patients. The observed associations may help in developing more accurate risk models that incorporate NPs and accurately prognosticate HF patients.
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http://dx.doi.org/10.1007/s10741-021-10136-3DOI Listing
July 2021

Users' Guide to Medical Decision Analysis.

Mayo Clin Proc 2021 Jul 2. Epub 2021 Jul 2.

Institute for Evidence-Based Healthcare, Faculty of Health Sciences & Medicine, Bond University, Gold Coast, Queensland, Australia.

Clinicians regularly have to trade benefits and harms to choose between testing and treatment strategies. This process is often done by making global and implicit judgments. A decision analysis is an analytic method that makes this process more explicit, reproducible, and evidence-based. While clinicians are unlikely to conduct their own decision analysis, they will read publications of such analyses or use guidelines based on them. This review outlines the anatomy of a decision tree and provides clinicians with the tools to critically appraise a decision analysis and apply its results to medical decision making. Clinicians reading about a decision analysis can make two judgments. The first judgment is about the credibility of the methods, such as whether the decision analysis addressed a relevant clinical question, included all important outcomes, used the current best evidence to derive variables in the model, and adopted the appropriate time horizon. The second judgment is about rating confidence in the preferred course of action by determining the certainty in the model variables, whether the results are robust in sensitivity analyses and if the results are applicable to a specific patient. Results from a valid and robust decision analysis can inform both guideline panels and the patient-clinician dyad engaged in shared decision-making.
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http://dx.doi.org/10.1016/j.mayocp.2021.02.003DOI Listing
July 2021

Decision aids linked to evidence summaries and clinical practice guidelines: results from user-testing in clinical encounters.

BMC Med Inform Decis Mak 2021 06 29;21(1):202. Epub 2021 Jun 29.

MAGIC Evidence Ecosystem Foundation, Oslo, Norway.

Background: Tools for shared decision-making (e.g. decision aids) are intended to support health care professionals and patients engaged in clinical encounters involving shared decision-making. However, decision aids are hard to produce, and onerous to update. Consequently, they often do not reflect best current evidence, and show limited uptake in practice. In response, we initiated the Sharing Evidence to Inform Treatment decisions (SHARE-IT) project. Our goal was to develop and refine a new generation of decision aids that are generically produced along digitally structured guidelines and evidence summaries.

Methods: Applying principles of human-centred design and following the International Patient Decision Aid Standards (IPDAS) and GRADE methods for trustworthy evidence summaries we developed a decision aid prototype in collaboration with the Developing and Evaluating Communication strategies to support Informed Decisions and practice based on Evidence project (DECIDE). We iteratively user-tested the prototype in clinical consultations between clinicians and patients. Semi-structured interviews of participating clinicians and patients were conducted. Qualitative content analysis of both user-testing sessions and interviews was performed and results categorized according to a revised Morville's framework of user-experience. We made it possible to produce, publish and use these decision aids in an electronic guideline authoring and publication platform (MAGICapp).

Results: Direct observations and analysis of user-testing of 28 clinical consultations between physicians and patients informed four major iterations that addressed readability, understandability, usability and ways to cope with information overload. Participants reported that the tool supported natural flow of the conversation and induced a positive shift in consultation habits towards shared decision-making. We integrated the functionality of SHARE-IT decision aids in MAGICapp, which has since generated numerous decision aids.

Conclusion: Our study provides a proof of concept that encounter decision aids can be generically produced from GRADE evidence summaries and clinical guidelines. Online authoring and publication platforms can help scale up production including continuous updating of electronic encounter decision aids, fully integrated with evidence summaries and clinical practice guidelines.
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http://dx.doi.org/10.1186/s12911-021-01541-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8240084PMC
June 2021

Evaluating adults' health-related values and preferences about unprocessed red meat and processed meat consumption: protocol for a cross-sectional mixed-methods study.

F1000Res 2020 11;9:346. Epub 2020 May 11.

Iberoamerican Cochrane Centre, Biomedical Research Institute San Pau (IIB Sant Pau), Barcelona, Spain.

People need to choose from a wide range of foods, and in addition to availability and accessibility, people's values and preferences largely determine their daily food choices. Given the potential adverse health consequences of red and processed meat and the limited knowledge on individuals' health-related values and preferences on the topic, such data would be useful in the development of recommendations regarding meat consumption. We will perform a cross-sectional mixed methods study. The study population will consist of adult omnivores currently consuming a minimum of three weekly servings of either unprocessed red meat or processed meat. We will explore participants' willingness to stop or reduce their unprocessed red meat, or their processed meat consumption through a direct-choice exercise. This exercise will consist of presenting a scenario tailored to each individual's average weekly consumption. That is, based on a systematic review and meta-analysis of the best estimate of the risk reduction in overall cancer incidence and cancer mortality, we will ask participants if they would stop their consumption, and/or reduce their average consumption. We will also present the corresponding certainty of the evidence for the potential risk reductions. Finally, we will measure their meat consumption three months after the interview and determine if they have made any changes to their average consumption. The research protocol was approved by the ethics committees in Canada (Research Ethics Board, Dalhousie University), Spain (Comitè Ètic d'Investigació Clínica de l'IDIAP Jordi Gol), Poland (The Bioethics Committee of the Jagiellonian University), and Brazil (National Research Ethics Commission). The study is based on voluntary participation and informed written consent. Results from this project will be disseminated through publications and presentations.
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http://dx.doi.org/10.12688/f1000research.23593.2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8176263PMC
July 2021

Symptomatic fever management in children: A systematic review of national and international guidelines.

PLoS One 2021 17;16(6):e0245815. Epub 2021 Jun 17.

Gerhard Kienle Chair, Health Department, University of Witten/Herdecke, Herdecke, Germany.

Introduction: Divergent attitudes towards fever have led to a high level of inconsistency in approaches to its management. In an attempt to overcome this, clinical practice guidelines (CPGs) for the symptomatic management of fever in children have been produced by several healthcare organizations. To date, a comprehensive assessment of the evidence level of the recommendations made in these CPGs has not been carried out.

Methods: Searches were conducted on Pubmed, google scholar, pediatric society websites and guideline databases to locate CPGs from each country (with date coverage from January 1995 to September 2020). Rather than assessing overall guideline quality, the level of evidence for each recommendation was evaluated according to criteria of the Oxford Centre for Evidence-Based Medicine (OCEBM). A GRADE assessment was undertaken to assess the body of evidence related to a single question: the threshold for initiating antipyresis. Methods and results are reported according to the PRISMA statement.

Results: 74 guidelines were retrieved. Recommendations for antipyretic threshold, type and dose; ambient temperature; dress/covering; activity; fluids; nutrition; proctoclysis; external applications; complementary/herbal recommendations; media; and age-related treatment differences all varied widely. OCEBM evidence levels for most recommendations were low (Level 3-4) or indeterminable. The GRADE assessment revealed a very low level of evidence for a threshold for antipyresis.

Conclusion: There is no recommendation on which all guidelines agree, and many are inconsistent with the evidence-this is true even for recent guidelines. The threshold question is of fundamental importance and has not yet been answered. Guidelines for the most frequent intervention (antipyresis) remain problematic.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0245815PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8211223PMC
June 2021

The association between preoperative modified frailty index and postoperative complications in Chinese elderly patients with hip fractures.

BMC Geriatr 2021 06 16;21(1):370. Epub 2021 Jun 16.

Department of Health Research Methods, Evidence and Impact, McMaster University, Hamilton, Canada.

Objectives: To investigate the role of a preoperative modified frailty index (mFI) based on data from medical records in predicting postoperative complications among older Chinese patients with hip fractures.

Methods: This retrospective cohort study included consecutive older patients with hip fracture admitted to the Department of Orthopaedics, West China Hospital, Sichuan University, from December 2010 to June 2017 who underwent surgical repair. We selected 33 variables, including characteristics of hip fracture, to construct a mFI. Each variable was coded with a value of 0 when a deficit was absent or 1 when it was present. We calculated the mFI as the proportion of positive items and defined frailty as mFI value greater than or equal to 0.21 according to threshold proposed by Hoover et al. We examined the relationship between mFI and severity of postoperative complications and the occurrence of in-hospital pneumonia including statistical adjustment for several demographics (e.g. age, gender, and marital status) and habits (smoking and alcohol intake), time from fracture to surgery in the multivariable model.

Results: We included 965 patients (34% male; mean age: 76.77 years; range: 60 to 100 years) with a prevalence of frailty of 13.06%. The presence of frailty was associated with a higher severity of complications (OR: 2.07; 95% CI: 1.40 to 3.05). Frail patients were more likely to develop in-hospital pneumonia than non-frail patients (OR: 2.08; 95% CI: 1.28 to 3.39).

Conclusion: The preoperative modified frailty index based on data from medical records proved significantly associated with postoperative complications among older patients with hip fractures undergoing hip surgery.
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http://dx.doi.org/10.1186/s12877-021-02330-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8207648PMC
June 2021

When applying GRADE, how do we decide the target of certainty of evidence rating?

Evid Based Ment Health 2021 Jun 14. Epub 2021 Jun 14.

Health Research Methods, Evidence & Impact, McMaster University, Hamilton, Ontario, Canada.

The Grades of Recommendation, Assessment, Development and Evaluation' (GRADE) offers a widely adopted, transparent and structured process for developing and presenting summaries of evidence, including the certainty of evidence, for systematic reviews and recommendations in healthcare. GRADE defined certainty of evidence as 'the extent of our confidence that the estimates of the effect are correct (in the context of systematic review), or are adequate to support a particular decision or recommendation (in the context of guideline)'. Realising the incoherence in the conceptualisation, the GRADE working group re-clarified the certainty of evidence as 'the certainty that a true effect lies on one side of a specified threshold, or within a chosen range'. Following the new concept, in the context of both systematic reviews and health technology assessments, it is desirable for GRADE users to specify the thresholds and clarify of which effect they are certain. To help GRADE users apply GRADE in accordance with the new conceptualisation, GRADE defines three levels of contextualisation: minimally, partially and fully contextualised approaches, and provides possible thresholds for each level of contextualisation. In this article, we will use a hypothetic systematic review to illustrate the application of the minimally and partially contextualised approaches, and discuss the application of a fully contextualised approach in deciding how we are rating our certainty (i.e.target of the rating of certainty of evidence).
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http://dx.doi.org/10.1136/ebmental-2020-300170DOI Listing
June 2021

Three week compared to seven week run-in period length and the assessment of pre-randomization adherence: A study within a trial.

Contemp Clin Trials 2021 Jun 5;107:106466. Epub 2021 Jun 5.

Population Health Research Institute, Hamilton, Canada; Department of Health Research Methods, Evidence and Impact, McMaster University, Canada; Department of Medicine, McMaster University, Canada.

Background/aims: To examine how measuring adherence at 3 weeks by self-report and pill counts compares to measurements at 7 weeks in a pre-randomization run-in period.

Methods: Study within a trial of an international parallel group randomized controlled trial (RCT) that compares spironolactone to placebo. Adults receiving dialysis enter an 8-week active run-in period with spironolactone. Adherence was assessed by both self-report and pill counts in a subgroup of participants at both 3 weeks and 7 weeks.

Results: 332 participants entered the run-in period of which 166 had complete data. By self-report, 146/166 (94.0%) and 153/166 (92.2%) had at least 80% adherence at 3 and 7 weeks respectively (kappa = 0.27 (95% C.I. 0.16 to 0.38). By pill counts, the mean (SD) adherence was 96.5% (16.1%) and 92.4% (18.2%) at 3 and 7 weeks respectively (r = 0.32) with a mean (SD) difference of 3.1% (17.8%) and a 95% limit of agreement from -31.7% to +37.9%. The proportion of adherent participants by self-report and pill counts at 3 weeks agreed in 87.4% of participants (McNemar's p-value 0.58, kappa 0.11, p = 0.02) and at 7 weeks agreed in 92.2% (McNemar's p-value 0.82, kappa 0.47, p < 0.001).

Conclusions: Three and seven-week run-in periods and both self-reported and pill count assessments performed similarly.

Trial Registration: ClinicalTrials.gov Identifier: NCT03020303.
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http://dx.doi.org/10.1016/j.cct.2021.106466DOI Listing
June 2021

RIGHT for acupuncture: An extension of the RIGHT statement for clinical practice guidelines on acupuncture.

J Clin Epidemiol 2021 Jun 4. Epub 2021 Jun 4.

Clinical Research and Data Center, South China Research Center for Acupuncture and Moxibustion, Medical College of Acu-Moxi and Rehabilitation, Guangzhou University of Chinese Medicine, Guangzhou, China. Electronic address:

Objective: In 2017, the International Standard for Reporting Items for practice Guideline in HealThcare (RIGHT) published reporting guidelines to enhance transparency and clarity in the process of developing clinical practice guidelines (CPGs). Given the original tool was developed in 2017 and demanded in developing and reporting high quality of acupuncture CPGs, an extension with a focus on a specific reporting checklist was warranted.

Study Design And Setting: The study was designed based on the methodology recommended by the Enhancing the Quality and Transparency Of Health Research (EQUATOR) Network with modification accordingly. A reporting checklist and its elaboration and explanations for users were developed.

Results: A checklist of seven sections (Basic information, Background, Evidence, Recommendations, Funding, Declaration and management of interest, Other information), twenty-three first level items and forty-three second level items was developed. We clarified the rationales of the items and provided explanations and examples of each item for additional guidance.

Conclusion: The RIGHT for Acupuncture checklist identifies a set of items to be reported when reviewing clinical practice guidelines on acupuncture. This extension can be expected to improve the reporting quality of CPGs on acupuncture.
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http://dx.doi.org/10.1016/j.jclinepi.2021.05.021DOI Listing
June 2021

Update on the JCE GRADE series and other GRADE article types.

J Clin Epidemiol 2021 Jun 2. Epub 2021 Jun 2.

Department of Health Research Methods, Evidence, and Impact, Michael G. DeGroote Cochrane Canada & McMaster GRADE Centres, McMaster University, Hamilton, ON, Canada; Institute for Evidence in Medicine, Medical Center and Faculty of Medicine, University of Freiburg, Germany.

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http://dx.doi.org/10.1016/j.jclinepi.2021.05.023DOI Listing
June 2021

Comparing Renal Replacement Therapy Modalities in Critically Ill Patients With Acute Kidney Injury: A Systematic Review and Network Meta-Analysis.

Crit Care Explor 2021 May 12;3(5):e0399. Epub 2021 May 12.

Department of Health Research Methods, Evidence and Impact, McMaster University, Hamilton, ON, Canada.

Objectives: To compare different modalities of renal replacement therapy in critically ill adults with acute kidney injury.

Data Sources: We searched Medline, PubMed, Embase, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov from inception to 25 May, 2020. We included randomized controlled trials comparing the efficacy and safety of different renal replacement therapy modalities in critically ill patients with acute kidney injury.

Study Selection: Ten reviewers (working in pairs) independently screened studies for eligibility, extracted data, and assessed risk of bias.

Data Extraction: We performed random-effects frequentist network meta-analyses and used the Grading of Recommendations, Assessment, Development, and Evaluation approach to assess certainty of evidence. The primary analysis was a four-node analysis: continuous renal replacement therapy, intermittent hemodialysis, slow efficiency extended dialysis, and peritoneal dialysis. The secondary analysis subdivided these four nodes into nine nodes including continuous veno-venous hemofiltration, continuous veno-venous hemodialysis, continuous veno-venous hemodiafiltration, continuous arterio-venous hemodiafiltration, intermittent hemodialysis, intermittent hemodialysis with hemofiltration, slow efficiency extended dialysis, slow efficiency extended dialysis with hemofiltration, and peritoneal dialysis. We set the minimal important difference threshold for mortality as 2.5% (relative difference, 0.04).

Data Synthesis: Thirty randomized controlled trials ( = 3,774 patients) proved eligible. There may be no difference in mortality between continuous renal replacement therapy and intermittent hemodialysis (relative risk, 1.04; 95% CI, 0.93-1.18; low certainty), whereas continuous renal replacement therapy demonstrated a possible increase in mortality compared with slow efficiency extended dialysis (relative risk, 1.06; 95% CI, 0.85-1.33; low certainty) and peritoneal dialysis (relative risk, 1.16; 95% CI, 0.92-1.49; low certainty). Continuous renal replacement therapy may increase renal recovery compared with intermittent hemodialysis (relative risk, 1.15; 95% CI, 0.91-1.45; low certainty), whereas both continuous renal replacement therapy and intermittent hemodialysis may be worse for renal recovery compared with slow efficiency extended dialysis and peritoneal dialysis (low certainty). Peritoneal dialysis was probably associated with the shortest duration of renal support and length of ICU stay compared with other interventions (low certainty for most comparisons). Slow efficiency extended dialysis may be associated with shortest length of hospital stay (low or moderate certainty for all comparisons) and days of mechanical ventilation (low certainty for all comparisons) compared with other interventions. There was no difference between continuous renal replacement therapy and intermittent hemodialysis in terms of hypotension (relative risk, 0.92; 95% CI, 0.72-1.16; moderate certainty) or other complications of therapy, but an increased risk of hypotension and bleeding was seen with both modalities compared with peritoneal dialysis (low or moderate certainty). Complications of slow efficiency extended dialysis were not sufficiently reported to inform comparisons.

Conclusions: The results of this network meta-analysis suggest there is no difference in mortality between continuous renal replacement therapy and intermittent hemodialysis although continuous renal replacement therapy may increases renal recovery compared with intermittent hemodialysis. Slow efficiency extended dialysis with hemofiltration may be the most effective intervention at reducing mortality. Peritoneal dialysis is associated with good efficacy, and the least number of complications however may not be practical in all settings. Importantly, all conclusions are based on very low to moderate certainty evidence, limited by imprecision. At the very least, ICU clinicians should feel comfortable that the differences between continuous renal replacement therapy, intermittent hemodialysis, slow efficiency extended dialysis, and, where clinically appropriate, peritoneal dialysis are likely small, and any of these modalities is a reasonable option to employ in critically ill patients.
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http://dx.doi.org/10.1097/CCE.0000000000000399DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8162503PMC
May 2021

Evidence-based medicine curricula and barriers for physicians in training: a scoping review.

Int J Med Educ 2021 May 28;12:101-124. Epub 2021 May 28.

Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada.

Objectives: To describe the published literature on EBM curricula for physicians in training and barriers during curriculum implementation.

Methods: We performed a systematic search and review of the medical literature on PubMed, Embase, ERIC, Scopus and Web of Science from the earliest available date until September 4, 2019.

Results: We screened 9,042 references and included 29 full-text studies and 14 meeting abstracts. Eighteen studies had moderate validity, and 6 had high validity. The EBM curricular structure proved highly variable in between studies. The majority of the EBM curricula was longitudinal with different lengths. Only five studies reported using Kern's six-step approach for curriculum development. Twenty-one articles reported on EBM skills and knowledge, and only 5/29 full-text articles used a validated assessment tool. Time was the main barrier to EBM curriculum implementation. All the included studies and abstracts, independent of the EBM curriculum structure or evaluation method used, found an improvement in the residents' attitudes and/or EBM skills and knowledge.

Conclusions: The current body of literature available to guide educators in EBM curriculum development is enough to constitute a strong scaffold for developing any EBM curriculum. Given the amount of time and resources needed to develop and implement an EBM curriculum, it is very important to follow the curriculum development steps and use validated assessment tools.
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http://dx.doi.org/10.5116/ijme.6097.ccc0DOI Listing
May 2021

SGLT-2 inhibitors or GLP-1 receptor agonists for adults with type 2 diabetes: a clinical practice guideline.

BMJ 2021 05 11;373:n1091. Epub 2021 May 11.

Department of Health Research Methods, Evidence and Impact, McMaster University, Hamilton, ON, Canada

Clinical Question: What are the benefits and harms of sodium-glucose cotransporter 2 (SGLT-2) inhibitors and glucagon-like peptide 1 (GLP-1) receptor agonists when added to usual care (lifestyle interventions and/or other diabetes drugs) in adults with type 2 diabetes at different risk for cardiovascular and kidney outcomes?

Current Practice: Clinical decisions about treatment of type 2 diabetes have been led by glycaemic control for decades. SGLT-2 inhibitors and GLP-1 receptor agonists are traditionally used in people with elevated glucose level after metformin treatment. This has changed through trials demonstrating atherosclerotic cardiovascular disease (CVD) and chronic kidney disease (CKD) benefits independent of medications' glucose-lowering potential.

Recommendations: The guideline panel issued risk-stratified recommendations concerning the use of SGLT-2 inhibitors or GLP-1 receptor agonists in adults with type 2 diabetes• Three or fewer cardiovascular risk factors without established CVD or CKD: Weak recommendation against starting SGLT-2 inhibitors or GLP-1 receptor agonists.• More than three cardiovascular risk factors without established CVD or CKD: Weak recommendation for starting SGLT-2 inhibitors and weak against starting GLP-1 receptor agonists.• Established CVD or CKD: Weak recommendation for starting SGLT-2 inhibitors and GLP-1 receptor agonists.• Established CVD and CKD: Strong recommendation for starting SGLT-2 inhibitors and weak recommendation for starting GLP-1 receptor agonists.• For those committed to further reducing their risk for CVD and CKD outcomes: Weak recommendation for starting SGLT-2 inhibitors rather than GLP-1 receptor agonists.

How This Guideline Was Created: An international panel including patients, clinicians, and methodologists created these recommendations following standards for trustworthy guidelines and using the GRADE approach. The panel applied an individual patient perspective.

The Evidence: A linked systematic review and network meta-analysis (764 randomised trials included 421 346 participants) of benefits and harms found that SGLT-2 inhibitors and GLP-1 receptor agonists generally reduce overall death, and incidence of myocardial infarctions, and end-stage kidney disease or kidney failure (moderate to high certainty evidence). These medications exert different effects on stroke, hospitalisations for heart failure, and key adverse events in different subgroups. Absolute effects of benefit varied widely based on patients' individual risk (for example, from five fewer deaths in the lowest risk to 48 fewer deaths in the highest risk, for 1000 patients treated over five years). A prognosis review identified 14 eligible risk prediction models, one of which (RECODe) informed most baseline risk estimates in evidence summaries to underpin the risk-stratified recommendations. Concerning patients' values and preferences, the recommendations were supported by evidence from a systematic review of published literature, a patient focus group study, a practical issues summary, and a guideline panel survey.

Understanding The Recommendation: We stratified the recommendations by the levels of risk for CVD and CKD and systematically considered the balance of benefits, harms, other considerations, and practical issues for each risk group. The strong recommendation for SGLT-2 inhibitors in patients with CVD and CKD reflects what the panel considered to be a clear benefit. For all other adults with type 2 diabetes, the weak recommendations reflect what the panel considered to be a finer balance between benefits, harms, and burdens of treatment options. Clinicians using the guideline can identify their patient's individual risk for cardiovascular and kidney outcomes using credible risk calculators such as RECODe. Interactive evidence summaries and decision aids may support well informed treatment choices, including shared decision making.
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http://dx.doi.org/10.1136/bmj.n1091DOI Listing
May 2021

Incidence and impact of primary graft dysfunction in adult heart transplant recipients: A systematic review and meta-analysis.

J Heart Lung Transplant 2021 Jul 20;40(7):642-651. Epub 2021 Mar 20.

Peter Munk Cardiac Center, Toronto General Hospital-University Health Network, Ontario, Canada; Department of Health Research Methods, Evidence, and Impact, McMaster University, Ontario, Canada. Electronic address:

Purpose: Primary graft dysfunction (PGD) is a leading cause of early mortality after heart transplant (HTx). To identify PGD incidence and impact on mortality, and to elucidate risk factors for PGD, we systematically reviewed studies using the ISHLT 2014 Consensus Report definition and reporting the incidence of PGD in adult HTx recipients.

Methods: We conducted a systematic search in January 2020 including studies reporting the incidence of PGD in adult HTx recipients. We used a random effects model to pool the incidence of PGD among HTx recipients and, for each PGD severity, the mortality rate among those who developed PGD. For prognostic factors evaluated in ≥2 studies, we used random effects meta-analyses to pool the adjusted odds ratios for development of PGD. The GRADE framework informed our certainty in the evidence.

Results: Of 148 publications identified, 36 observational studies proved eligible. With moderate certainty, we observed pooled incidences of 3.5%, 6.6%, 7.7%, and 1.6% and 1-year mortality rates of 15%, 21%, 41%, and 35% for mild, moderate, severe and isolated right ventricular-PGD, respectively. Donor factors (female sex, and undersized), recipient factors (creatinine, and pre-HTx use of amiodarone, and temporary or durable mechanical support), and prolonged ischemic time proved associated with PGD post-HTx.

Conclusion: Our review suggests that the incidence of PGD may be low but its risk of mortality high, increasing with PGD severity. Prognostic factors, including undersized donor, recipient use of amiodarone pre-HTx and recipient creatinine may guide future studies in exploring donor and/or recipient selection and risk mitigation strategies.
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http://dx.doi.org/10.1016/j.healun.2021.03.015DOI Listing
July 2021

Prophylaxis against covid-19: living systematic review and network meta-analysis.

BMJ 2021 04 26;373:n949. Epub 2021 Apr 26.

Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, ON, Canada.

Objective: To determine and compare the effects of drug prophylaxis on SARS-CoV-2 infection and covid-19.

Design: Living systematic review and network meta-analysis.

Data Sources: World Health Organization covid-19 database, a comprehensive multilingual source of global covid-19 literature to 25 March 2021, and six additional Chinese databases to 20 February 2021.

Study Selection: Randomised trials of people at risk of covid-19 who were assigned to receive prophylaxis or no prophylaxis (standard care or placebo). Pairs of reviewers independently screened potentially eligible articles.

Methods: Random effects bayesian network meta-analysis was performed after duplicate data abstraction. Included studies were assessed for risk of bias using a modification of the Cochrane risk of bias 2.0 tool, and certainty of evidence was assessed using the grading of recommendations assessment, development, and evaluation (GRADE) approach.

Results: The first iteration of this living network meta-analysis includes nine randomised trials-six of hydroxychloroquine (n=6059 participants), one of ivermectin combined with iota-carrageenan (n=234), and two of ivermectin alone (n=540), all compared with standard care or placebo. Two trials (one of ramipril and one of bromhexine hydrochloride) did not meet the sample size requirements for network meta-analysis. Hydroxychloroquine has trivial to no effect on admission to hospital (risk difference 1 fewer per 1000 participants, 95% credible interval 3 fewer to 4 more; high certainty evidence) or mortality (1 fewer per 1000, 2 fewer to 3 more; high certainty). Hydroxychloroquine probably does not reduce the risk of laboratory confirmed SARS-CoV-2 infection (2 more per 1000, 18 fewer to 28 more; moderate certainty), probably increases adverse effects leading to drug discontinuation (19 more per 1000, 1 fewer to 70 more; moderate certainty), and may have trivial to no effect on suspected, probable, or laboratory confirmed SARS-CoV-2 infection (15 fewer per 1000, 64 fewer to 41 more; low certainty). Owing to serious risk of bias and very serious imprecision, and thus very low certainty of evidence, the effects of ivermectin combined with iota-carrageenan on laboratory confirmed covid-19 (52 fewer per 1000, 58 fewer to 37 fewer), ivermectin alone on laboratory confirmed infection (50 fewer per 1000, 59 fewer to 16 fewer) and suspected, probable, or laboratory confirmed infection (159 fewer per 1000, 165 fewer to 144 fewer) remain very uncertain.

Conclusions: Hydroxychloroquine prophylaxis has trivial to no effect on hospital admission and mortality, probably increases adverse effects, and probably does not reduce the risk of SARS-CoV-2 infection. Because of serious risk of bias and very serious imprecision, it is highly uncertain whether ivermectin combined with iota-carrageenan and ivermectin alone reduce the risk of SARS-CoV-2 infection.

Systematic Review Registration: This review was not registered. The protocol established a priori is included as a supplement.

Readers' Note: This article is a living systematic review that will be updated to reflect emerging evidence. Updates may occur for up to two years from the date of original publication.
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http://dx.doi.org/10.1136/bmj.n949DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8073806PMC
April 2021

Antemortem Heparin in Organ Donation after Circulatory Death Determination (DCDD): A Systematic Review of the Literature.

Transplantation 2021 Apr 21. Epub 2021 Apr 21.

Division of Critical Care, Department of Medicine, Western University, London, Canada Department of Internal Medicine, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates. Ted Rogers Centre for Heart Research, Peter Munk Cardiac Center, Toronto, Canada Division of Critical Care, Department of Medicine, McMaster University Department of Health Research Methods, Evidence, and Impact (HEI), McMaster University, Hamilton, Canada Division of Cardiology, Department of Medicine, McMaster University Population Health Research Institute, Hamilton, Canada Department of Anesthesiology, Université de Sherbrooke, Quebec, Canada Department of Epidemiology and Biostatistics, Western University, London, Canada Department of Surgery and Microbiology and Immunology, Schulich School of Medicine & Dentistry, Western University, London, Canada Multi-Organ Transplant Program, Department of Surgery, Toronto General Hospital, Toronto, Canada Department of Medicine, McMaster University, Hamilton, Canada.

Donation after circulatory death determination (DCDD) frequently involves antemortem heparin administration to mitigate peri-arrest microvascular thrombosis. We systematically reviewed the literature to: (1) describe heparin administration practices, and (2) explore the effects on transplant outcomes. We searched MEDLINE and EMBASE for studies reporting DCDD heparin practices including use, dosage, and timing (Objective 1). To explore associations between antemortem heparin and transplant outcomes (Objective 2), we (i) summarized within-study comparisons and (ii) used meta-regression analyses to examine associations between proportions of donors that received heparin and transplant outcomes. We assessed risk of bias using the Newcastle Ottawa Scale and applied the GRADE methodology to determine certainty in the evidence. For Objective 1, among 55 eligible studies, 48 reported heparin administration to at least some donors (range: 15.8% to 100%) at variable doses (up to 1000 units/kg) and times relative to withdrawal of life sustaining therapy. For Objective 2, seven studies that directly compared liver transplants with and without antemortem heparin reported lower rates of primary nonfunction, hepatic artery thrombosis, graft failure at 5 years, or recipient mortality (low certainty of evidence). In contrast, meta-regression analysis of 32 liver transplant studies detected no associations between the proportion of donors that received heparin and rates of early allograft dysfunction, primary nonfunction, hepatic artery thrombosis, biliary ischemia, graft failure, re-transplantation, or patient survival (very low certainty of evidence). In conclusion, antemortem heparin practices vary substantially with an uncertain effect on transplant outcomes. Given the controversies surrounding antemortem heparin, clinical trials may be warranted.
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http://dx.doi.org/10.1097/TP.0000000000003793DOI Listing
April 2021

GRADE guidelines 32: GRADE offers guidance on choosing targets of GRADE certainty of evidence ratings.

J Clin Epidemiol 2021 Apr 20;137:163-175. Epub 2021 Apr 20.

Department of Health Research Methods, Evidence and Impact, McMaster University, 1280 Main Street West, Hamilton, Ontario, Canada, L8S 4L8; Department of Medicine, McMaster University, 1280 Main Street West, Hamilton, Ontario, Canada, L8S 4K1.

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.
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http://dx.doi.org/10.1016/j.jclinepi.2021.03.026DOI Listing
April 2021
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