Publications by authors named "Paul E Alexander"

33 Publications

Early multidrug treatment of SARS-CoV-2 infection (COVID-19) and reduced mortality among nursing home (or outpatient/ambulatory) residents.

Med Hypotheses 2021 Jun 5;153:110622. Epub 2021 Jun 5.

Concerned Ontario Doctors, Toronto, ON, Canada. Electronic address:

The outbreak of COVID-19 from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread all over the world with tremendous morbidity and mortality in the elderly. In-hospital treatment addresses the multifaceted nature of the illness including initial viral replication, cytokine storm, and endothelial injury with thrombosis. We identified nine reports of early treatment outcomes in COVID-19 nursing home patients. Multi-drug therapy including hydroxychloroquine with one or more anti-infectives, corticosteroids, and antithrombotic anti-blood clotting agents can be extended to seniors in the nursing home setting without hospitalization. Data from nine studies found hydroxychloroquine-based multidrug regimens were associated with a statistically significant > 60% reduction in mortality. Going forward, we conclude that early empiric treatment for the elderly with COVID-19 in the nursing home setting (or similar congregated settings with elderly residents/patients e.g. LTF or ALF) has a reasonable probability of success and acceptable safety. This group remains our highest at-risk group and warrants acute treatment focus prior to symptoms worsening. Given the rapidity and severity of SARS-CoV-2 outbreaks in nursing homes, in-center treatment of acute COVID-19 patients is a reasonable strategy to reduce the risks of hospitalization and death. If elderly high-risk patients in such congregated nursing home type settings are allowed to worsen with no early treatment, they may be too sick and fragile to benefit from in-hospital therapeutics and are at risk for pulmonary failure, life-ending micro-thrombi of the lungs, kidneys etc. The issue is timing of therapeutics, and we argue that early treatment before hospitalization, is the right time and can potentially save lives, especially among our higher-risk elderly populations hit hardest by severe illness and death from COVID-19. We must reiterate, we are talking about 'early' treatment before the disease is far along in the disease sequelae where the patient then needs hospitalization and aggressive interventions. We are referring to the initial days e.g. day one, post infection when symptoms emerge or there is strong clinical suspicion. This early therapeutic option deserves serious and urgent consideration by the medical establishment and respective decision-makers. Doctors must be allowed their clinical discretion in how they optimally treat their patients. Doctors must be brave and trust their skilled judgements and do all to save the lives of their patients. We therefore hypothesize that early outpatient ambulatory treatment, once initiated as soon as symptoms begin in high-risk positive persons, would significantly reduce hospitalizations and prevent deaths. Specifically, the provision of early multi-drug sequenced therapy with repurposed drugs will reduce hospitalization and death in elderly patients being cared for in long-term-care facilities. The most important implications of our hypothesis are: 1) hospitalizations and deaths would be reduced 2) transmission would be reduced due to the mitigation of symptoms and 3) recovery following infection and treatment provides for natural exposure immunity that is broad based, durable, and robust (helping towards natural immunity within the population). The end result is reduced strain on hospitals and systems that would allow for other non-COVID illnesses to receive care.
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http://dx.doi.org/10.1016/j.mehy.2021.110622DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8178530PMC
June 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

Multifaceted highly targeted sequential multidrug treatment of early ambulatory high-risk SARS-CoV-2 infection (COVID-19).

Rev Cardiovasc Med 2020 12;21(4):517-530

Emergency Medicine, Phoenix, 85016, AZ, USA.

The SARS-CoV-2 virus spreading across the world has led to surges of COVID-19 illness, hospitalizations, and death. The complex and multifaceted pathophysiology of life-threatening COVID-19 illness including viral mediated organ damage, cytokine storm, and thrombosis warrants early interventions to address all components of the devastating illness. In countries where therapeutic nihilism is prevalent, patients endure escalating symptoms and without early treatment can succumb to delayed in-hospital care and death. Prompt early initiation of sequenced multidrug therapy (SMDT) is a widely and currently available solution to stem the tide of hospitalizations and death. A multipronged therapeutic approach includes 1) adjuvant nutraceuticals, 2) combination intracellular anti-infective therapy, 3) inhaled/oral corticosteroids, 4) antiplatelet agents/anticoagulants, 5) supportive care including supplemental oxygen, monitoring, and telemedicine. Randomized trials of individual, novel oral therapies have not delivered tools for physicians to combat the pandemic in practice. No single therapeutic option thus far has been entirely effective and therefore a combination is required at this time. An urgent immediate pivot from single drug to SMDT regimens should be employed as a critical strategy to deal with the large numbers of acute COVID-19 patients with the aim of reducing the intensity and duration of symptoms and avoiding hospitalization and death.
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http://dx.doi.org/10.31083/j.rcm.2020.04.264DOI Listing
December 2020

Summary for Clinicians: Clinical Practice Guideline on Pharmacologic Management of Chronic Obstructive Pulmonary Disease.

Ann Am Thorac Soc 2021 01;18(1):11-16

Division of Pulmonary and Critical Care Medicine, Department of Medicine, Mount Auburn Hospital/Beth Israel Lahey Health, Cambridge, Massachusetts; and.

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http://dx.doi.org/10.1513/AnnalsATS.202007-880CMEDOI Listing
January 2021

Triple Therapy versus Dual or Monotherapy with Long-Acting Bronchodilators for Chronic Obstructive Pulmonary Disease. A Systematic Review and Meta-analysis.

Ann Am Thorac Soc 2020 10;17(10):1308-1318

McMaster University, Hamilton, Ontario, Canada.

There is uncertainty on the use of using triple therapy (inhaled corticosteroids/long-acting β-agonist/long-acting muscarinic antagonist) inhaler therapy for patients with chronic obstructive pulmonary disease (COPD), who complain of dyspnea and/or exercise intolerance. We conducted a systematic review and meta-analyses to estimate the safety and efficacy of using triple therapy compared with long-acting β-agonist/long-acting muscarinic antagonist dual therapy or monotherapy with a single long-acting bronchodilator in patients with stable COPD who complained of dyspnea and/or exercise intolerance. A search of MEDLINE, Embase, and the Cochrane Library databases was conducted for randomized controlled trials pertaining to the clinical question. A systematic approach was used to screen, abstract, and critically appraise the studies. The grading of recommendations assessment, development, and evaluation method was applied to rate the certainty/quality of the evidence. Eleven studies were eligible for inclusion ( = 14,145 patients). Pairwise random-effects meta-analysis revealed an increase in risk of pneumonia (relative risk, 1.47; 95% confidence interval [95% CI], 1.20-1.80;  < 0.001) and decreased risk of acute exacerbations of COPD (AECOPDs) (relative risk, 0.75; 95% CI, 0.68-0.82;  < 0.001) with triple therapy compared with treatment with dual and monotherapy long-acting bronchodilator therapy. No significant difference in dyspnea scores (standardized mean difference, 0.09; 95% CI, -0.02 to 0.19;  = 0.09) or risk of hospitalization (rate ratio, 0.78; 95% CI, 0.58-1.06;  = 0.11) was noted. When subgroup analysis based on inhaler class was performed, no significant difference was noted between the groups in any of the critical outcomes studied. For patients with a history of one or more AECOPDs in the past year, triple therapy resulted in 230 fewer AECOPDs and 16 more cases of pneumonia per 1,000 patients. In patients with COPD who complain of dyspnea and/or exercise intolerance, triple therapy is not superior to maintenance long-acting bronchodilator therapy, except in patients with a history of one or more exacerbations in the past year, in whom the benefits of reduction in AECOPD outweigh the increased risk of pneumonia.
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http://dx.doi.org/10.1513/AnnalsATS.202001-023OCDOI Listing
October 2020

Dual LABA/LAMA Therapy versus LABA or LAMA Monotherapy for Chronic Obstructive Pulmonary Disease. A Systematic Review and Meta-analysis in Support of the American Thoracic Society Clinical Practice Guideline.

Ann Am Thorac Soc 2020 09;17(9):1133-1143

McMaster University, Hamilton, Onatrio, Canada.

There is uncertainty on the optimal first-line therapy for symptomatic chronic obstructive pulmonary disease (COPD). Long-acting β-receptor agonists (LABAs) and long-acting muscarinic antagonists (LAMAs) have long been mainstays of treatment, though it is still not clear if dual therapy with LABA/LAMA is superior to monotherapy for symptomatic COPD. To clarify the evidence landscape, we conducted a systematic review to answer the following question: in patients with COPD who complain of dyspnea and/or exercise intolerance, is LABA/LAMA combination therapy more effective and equally safe compared with LABA or LAMA monotherapy? A search of Medline, EMBASE, and the Cochrane Library databases was conducted by a medical librarian for randomized controlled trials enrolling patients with COPD who complain of dyspnea and/or exercise intolerance that compare LABA/LAMA combination therapy to LABA or LAMA monotherapy. A systematic approach was used to screen, abstract, and critically appraise the emerging study evidence. The Grading of Recommendations Assessment, Development, and Evaluation method was applied to rate the certainty and quality of the evidence. A total of 24 studies were eligible for inclusion ( = 45,441). Pairwise random-effects meta-analysis revealed reductions in hospital admissions (11% reduction;  < 0.01) and acute exacerbations of COPD (20% reduction;  < 0.002), all in favor of LABA/LAMA dual therapy. Although there is reduced dyspnea (0.10 standardized mean difference;  < 0.001) and improved health-related quality of life (-0.13 standardized mean difference;  < 0.001), both values did not meet a clinical meaningful difference threshold. LABA/LAMA combination therapy showed no difference in treatment-emergent adverse effects (risk ratio, 0.99;  = 0.34) when compared with either LAMA or LABA monotherapy. Based on the reviewed evidence, in patients with symptomatic COPD who complain of dyspnea and/or exercise intolerance, dual LABA/LAMA therapy is superior to either LABA or LAMA monotherapy based on the reduced risk of exacerbations and hospitalizations.
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http://dx.doi.org/10.1513/AnnalsATS.201912-915OCDOI Listing
September 2020

Pharmacologic Management of Chronic Obstructive Pulmonary Disease. An Official American Thoracic Society Clinical Practice Guideline.

Am J Respir Crit Care Med 2020 05;201(9):e56-e69

: This document provides clinical recommendations for the pharmacologic treatment of chronic obstructive pulmonary disease (COPD). It represents a collaborative effort on the part of a panel of expert COPD clinicians and researchers along with a team of methodologists under the guidance of the American Thoracic Society.: Comprehensive evidence syntheses were performed on all relevant studies that addressed the clinical questions and critical patient-centered outcomes agreed upon by the panel of experts. The evidence was appraised, rated, and graded, and recommendations were formulated using the Grading of Recommendations, Assessment, Development, and Evaluation approach.: After weighing the quality of evidence and balancing the desirable and undesirable effects, the guideline panel made the following recommendations: ) a strong recommendation for the use of long-acting β-agonist (LABA)/long-acting muscarinic antagonist (LAMA) combination therapy over LABA or LAMA monotherapy in patients with COPD and dyspnea or exercise intolerance; ) a conditional recommendation for the use of triple therapy with inhaled corticosteroids (ICS)/LABA/LAMA over dual therapy with LABA/LAMA in patients with COPD and dyspnea or exercise intolerance who have experienced one or more exacerbations in the past year; ) a conditional recommendation for ICS withdrawal for patients with COPD receiving triple therapy (ICS/LABA/LAMA) if the patient has had no exacerbations in the past year; ) no recommendation for or against ICS as an additive therapy to long-acting bronchodilators in patients with COPD and blood eosinophilia, except for those patients with a history of one or more exacerbations in the past year requiring antibiotics or oral steroids or hospitalization, for whom ICS is conditionally recommended as an additive therapy; ) a conditional recommendation against the use of maintenance oral corticosteroids in patients with COPD and a history of severe and frequent exacerbations; and ) a conditional recommendation for opioid-based therapy in patients with COPD who experience advanced refractory dyspnea despite otherwise optimal therapy.: The task force made recommendations regarding the pharmacologic treatment of COPD based on currently available evidence. Additional research in populations that are underrepresented in clinical trials is needed, including studies in patients with COPD 80 years of age and older, those with multiple chronic health conditions, and those with a codiagnosis of COPD and asthma.
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http://dx.doi.org/10.1164/rccm.202003-0625STDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7193862PMC
May 2020

Interferon beta-1a for patients with moderate to severe acute respiratory distress syndrome: a systematic review and meta-analysis of randomized trials.

Pol Arch Intern Med 2020 04 3;130(4):287-296. Epub 2020 Apr 3.

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

Introduction: Acute respiratory distress syndrome (ARDS) is a life-threatening disease characterized by respiratory failure with rapidly progressing inflammation. Currently, no effective pharmacological treatment for ARDS is available.

Objectives: We conducted this systematic review and meta‑ analysis to examine the use of interferon beta-1a in patients with ARDS.

Methods: Data sources included the following databases: MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials. We retained trials from 1996 to February 25, 2020 that comparatively examined the use of interferon beta-1a in patients with ARDS. Two reviewers identified eligible studies, independently extracted study data, and assessed the risk of bias. The authors evaluated the certainty of evidence using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach.

Results: We included 2 trials (n = 392 patients). No significant differences in 28-day hospital mortality (risk ratio [RR], 0.59; 95% CI, 0.13-2.67; P = 0.49; very low certainty) and the number of ventilator-free days (mean difference, 4.85 days; 95% CI, -3.25 to 12.93; P = 0.24, very low certainty) were observed in patients treated with interferon beta-1a compared with those not receiving this drug. Interferon beta-1a also had no significant impact on the risk of adverse events (RR, 0.98%; 95% CI, 0.94-1.03; P = 0.47; low certainty).

Conclusions: The use of interferon beta-1a does not appear to improve mortality or reduce the number of ventilator-free days and adverse events in patients with ARDS. This review is based on 2 small studies reporting a limited number of events, which raises questions regarding the true effects of interferon beta-1a. The analysis of 1 study revealed increased mortality with the concomitant use of corticosteroids and interferon beta-1a, suggesting a need for careful consideration of this drug-drug interaction.
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http://dx.doi.org/10.20452/pamw.15279DOI Listing
April 2020

Surviving Sepsis Campaign: Guidelines on the Management of Critically Ill Adults with Coronavirus Disease 2019 (COVID-19).

Crit Care Med 2020 06;48(6):e440-e469

Department of Medicine and Surgery, Milano-Bicocca University, Milano, Italy.

Background: The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of a rapidly spreading illness, Coronavirus Disease 2019 (COVID-19), affecting thousands of people around the world. Urgent guidance for clinicians caring for the sickest of these patients is needed.

Methods: We formed a panel of 36 experts from 12 countries. All panel members completed the World Health Organization conflict of interest disclosure form. The panel proposed 53 questions that are relevant to the management of COVID-19 in the ICU. We searched the literature for direct and indirect evidence on the management of COVID-19 in critically ill patients in the ICU. We identified relevant and recent systematic reviews on most questions relating to supportive care. We assessed the certainty in the evidence using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach, then generated recommendations based on the balance between benefit and harm, resource and cost implications, equity, and feasibility. Recommendations were either strong or weak, or in the form of best practice recommendations.

Results: The Surviving Sepsis Campaign COVID-19 panel issued 54 statements, of which four are best practice statements, nine are strong recommendations, and 35 are weak recommendations. No recommendation was provided for six questions. The topics were: 1) infection control, 2) laboratory diagnosis and specimens, 3) hemodynamic support, 4) ventilatory support, and 5) COVID-19 therapy.

Conclusion: The Surviving Sepsis Campaign COVID-19 panel issued several recommendations to help support healthcare workers caring for critically ill ICU patients with COVID-19. When available, we will provide new evidence in further releases of these guidelines.
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http://dx.doi.org/10.1097/CCM.0000000000004363DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7176264PMC
June 2020

Surviving Sepsis Campaign: guidelines on the management of critically ill adults with Coronavirus Disease 2019 (COVID-19).

Intensive Care Med 2020 05 28;46(5):854-887. Epub 2020 Mar 28.

Department of Medicine and Surgery, Milano-Bicocca University, Milan, Italy.

Background: The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of a rapidly spreading illness, Coronavirus Disease 2019 (COVID-19), affecting thousands of people around the world. Urgent guidance for clinicians caring for the sickest of these patients is needed.

Methods: We formed a panel of 36 experts from 12 countries. All panel members completed the World Health Organization conflict of interest disclosure form. The panel proposed 53 questions that are relevant to the management of COVID-19 in the ICU. We searched the literature for direct and indirect evidence on the management of COVID-19 in critically ill patients in the ICU. We identified relevant and recent systematic reviews on most questions relating to supportive care. We assessed the certainty in the evidence using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach, then generated recommendations based on the balance between benefit and harm, resource and cost implications, equity, and feasibility. Recommendations were either strong or weak, or in the form of best practice recommendations.

Results: The Surviving Sepsis Campaign COVID-19 panel issued 54 statements, of which 4 are best practice statements, 9 are strong recommendations, and 35 are weak recommendations. No recommendation was provided for 6 questions. The topics were: (1) infection control, (2) laboratory diagnosis and specimens, (3) hemodynamic support, (4) ventilatory support, and (5) COVID-19 therapy.

Conclusion: The Surviving Sepsis Campaign COVID-19 panel issued several recommendations to help support healthcare workers caring for critically ill ICU patients with COVID-19. When available, we will provide new recommendations in further releases of these guidelines.
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http://dx.doi.org/10.1007/s00134-020-06022-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7101866PMC
May 2020

Corticosteroids for patients with acute respiratory distress syndrome: a systematic review and meta-analysis of randomized trials.

Pol Arch Intern Med 2020 04 18;130(4):276-286. Epub 2020 Mar 18.

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

Introduction: Acute respiratory distress syndrome (ARDS) is a rapidly progressing, inflammatory lung disease with a high mortality rate and no specific pharmacological treatment available.

Objectives: We conducted a systematic review and meta‑analysis on corticosteroid use in ARDS.

Methods: We searched 4 medical literature databases and retained randomized controlled trials on the use of corticosteroids in hospitalized adults with ARDS, which could be found there until February 2020. Two reviewers identified eligible studies, independently extracted data, and evaluated the risk of bias. The authors assessed the certainty of evidence using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach.

Results: We included 7 randomized controlled trials involving 851 patients. They showed that corticosteroids reduced all‑cause mortality (risk ratio [RR], 0.75; 95% CI, 0.59-0.95; P = 0.02; moderate certainty) and the duration of mechanical ventilation (mean difference [MD], -4.93 days; 95% CI; -7.81 to -2.06; P <0.001; low certainty), and increased the number of ventilator‑free days (MD, 4.28 days; 95% CI, 2.67-5.88; P <0.001; moderate certainty), as compared with placebo. Corticosteroids also increased the risk of hyperglycemia (RR, 1.12%; 95% CI, 1.01-1.24; P = 0.03; moderate certainty), and the effect on neuromuscular weakness was unclear (RR, 1.3; 95% CI, 0.8-2.11; P = 0.28; low certainty).

Conclusions: These results suggest that systemic corticosteroids may potentially improve mortality, shorten ventilation times, and increase the number of ventilator‑free days in patients with ARDS. However, the studies included different corticosteroid classes and initiated drug administration at different times, as well as used various dosing regimens. Thus, caution in the actual clinical application of these results is recommended.
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http://dx.doi.org/10.20452/pamw.15239DOI Listing
April 2020

Clinical Practice Guidelines by the Infectious Diseases Society of America: 2018 Update on Diagnosis, Treatment, Chemoprophylaxis, and Institutional Outbreak Management of Seasonal Influenzaa.

Clin Infect Dis 2019 03;68(6):e1-e47

Division of Pediatric Infectious Diseases, University of Utah, Salt Lake City.

These clinical practice guidelines are an update of the guidelines published by the Infectious Diseases Society of America (IDSA) in 2009, prior to the 2009 H1N1 influenza pandemic. This document addresses new information regarding diagnostic testing, treatment and chemoprophylaxis with antiviral medications, and issues related to institutional outbreak management for seasonal influenza. It is intended for use by primary care clinicians, obstetricians, emergency medicine providers, hospitalists, laboratorians, and infectious disease specialists, as well as other clinicians managing patients with suspected or laboratory-confirmed influenza. The guidelines consider the care of children and adults, including special populations such as pregnant and postpartum women and immunocompromised patients.
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http://dx.doi.org/10.1093/cid/ciy866DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6653685PMC
March 2019

Evidence to Decision framework provides a structured "roadmap" for making GRADE guidelines recommendations.

J Clin Epidemiol 2018 12 22;104:103-112. Epub 2018 Sep 22.

Department of Supportive Care Medicine, Department of Hematology, City of Hope, 1500 East Duarte Road, Duarte, CA 91010, USA.

Objectives: It is unclear how guidelines panelists discuss and consider factors (criteria) that are formally and not formally included in the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. To describe the use of decision criteria, we explored how panelists adhered to GRADE criteria and sought to identify any emerging non-GRADE criteria when the panelists used the Evidence to Decision (EtD) framework as part of GRADE application.

Study Design And Setting: We used conventional and summative qualitative analyses to identify themes emerging from face-to-face, panel meeting discussions. Forty-eight members from 12 countries participated in the development of five guidelines for the management of venous thromboembolism by the American Society of Hematology.

Results: Ten themes corresponded to the GRADE approach and represented all panel discussions. Over half (53%) of the total panel discussions concerned the use of research evidence. When evidence was considered sufficient and clear, the decision-making process proved rapid.

Conclusion: The GRADE EtD framework provides structure to guidelines panel meetings, and ensures that the panelists consider all established formal GRADE criteria as they decide on the recommendation text, strength, and direction (for or against an intervention). This is the first study assessing the use of GRADE's EtD framework during real-time guidelines development using panel discussions. Given the widespread use of GRADE, this study provides important information for practice recommendations generated when guidelines panels explicitly follow, in a transparent and systematic manner, the structured GRADE EtD framework. By recognizing the extent to which panels discuss and consider GRADE and other (non-GRADE) criteria for producing guideline recommendations, we are one step closer to understanding the decision-making process in panels that use a structured framework such as the GRADE EtD framework.
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http://dx.doi.org/10.1016/j.jclinepi.2018.09.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7275375PMC
December 2018

Applying GRADE to a network meta-analysis of antidepressants led to more conservative conclusions.

J Clin Epidemiol 2018 10 22;102:87-98. Epub 2018 May 22.

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

Objective: To explore the impact of applying the Grading of Recommendations and Assessment, Development, and Evaluation (GRADE) approach to assess the certainty of the evidence in a published network meta-analysis (NMA) of antidepressant therapies.

Study Design And Settings: We applied the GRADE approach to rate the certainty of the evidence for two outcomes, efficacy and acceptability, in each of the 66 paired comparisons within a previously published NMA assessing the relative efficacy and acceptability of 12 new-generation antidepressants.

Results: For the outcome of efficacy, of the 25 comparisons in which the 95% CrI of OR excluded 1, 18 had certainty of evidence rated high or moderate. For the outcome of acceptability, of the 13 comparisons whose 95% CrI excluded 1, 10 had certainty of evidence rated high or moderate. Of the 11 comparisons involving sertraline, the antidepressants that the authors of the NMA suggested to be best, only 3 demonstrated it to be more effective and only 3 showed better tolerance, based on a 95% CrI excluding 1 and a high or moderate rating of certainty.

Conclusions: In this example, application of GRADE highlighted varying evidence certainty, led to more conservative conclusions, and potentially avoided unwarranted strong inferences based on low certainty evidence.
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http://dx.doi.org/10.1016/j.jclinepi.2018.05.009DOI Listing
October 2018

UpToDate adherence to GRADE criteria for strong recommendations: an analytical survey.

BMJ Open 2017 Nov 16;7(11):e018593. Epub 2017 Nov 16.

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

Introduction: UpToDate is widely used by clinicians worldwide and includes more than 9400 recommendations that apply the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework. GRADE guidance warns against strong recommendations when certainty of the evidence is low or very low (discordant recommendations) but has identified five paradigmatic situations in which discordant recommendations may be justified.

Objectives: Our objective was to document the strength of recommendations in UpToDate and assess the frequency and appropriateness of discordant recommendations.

Design: Analytical survey of all recommendations in UpToDate.

Methods: We identified all GRADE recommendations in UpToDate and examined their strength (strong or weak) and certainty of the evidence (high, moderate or low certainty). We identified all discordant recommendations as of January 2015, and pairs of reviewers independently classified them either into one of the five appropriate paradigms or into one of three categories inconsistent with GRADE guidance, based on the evidence presented in UpToDate.

Results: UpToDate included 9451 GRADE recommendations, of which 6501 (68.8%) were formulated as weak recommendations and 2950 (31.2%) as strong. Among the strong, 844 (28.6%) were based on high certainty in effect estimates, 1740 (59.0%) on moderate certainty and 366 (12.4%) on low certainty. Of the 349 discordant recommendations 204 (58.5%) were judged appropriately (consistent with one of the five paradigms); we classified 47 (13.5%) as good practice statements; 38 (10.9%) misclassified the evidence as low certainty when it was at least moderate and 60 (17.2%) warranted a weak rather than a strong recommendation.

Conclusion: The proportion of discordant recommendations in UpToDate is small (3.7% of all recommendations) and the proportion that is truly problematic (strong recommendations that would best have been weak) is very small (0.6%). Clinicians should nevertheless be cautious and look for clear explanations-in UpToDate and elsewhere-when guidelines offer strong recommendations based on low certainty evidence.
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http://dx.doi.org/10.1136/bmjopen-2017-018593DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5701989PMC
November 2017

Advances in the GRADE approach to rate the certainty in estimates from a network meta-analysis.

J Clin Epidemiol 2018 01 17;93:36-44. Epub 2017 Oct 17.

Department of Health Research Methods, Evidence and Impact, McMaster University, 1280 Main St W, Hamilton, Ontario L8S 4K1, Canada. Electronic address:

This article describes conceptual advances of the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) working group guidance to evaluate the certainty of evidence (confidence in evidence, quality of evidence) from network meta-analysis (NMA). Application of the original GRADE guidance, published in 2014, in a number of NMAs has resulted in advances that strengthen its conceptual basis and make the process more efficient. This guidance will be useful for systematic review authors who aim to assess the certainty of all pairwise comparisons from an NMA and who are familiar with the basic concepts of NMA and the traditional GRADE approach for pairwise meta-analysis. Two principles of the original GRADE NMA guidance are that we need to rate the certainty of the evidence for each pairwise comparison within a network separately and that in doing so we need to consider both the direct and indirect evidence. We present, discuss, and illustrate four conceptual advances: (1) consideration of imprecision is not necessary when rating the direct and indirect estimates to inform the rating of NMA estimates, (2) there is no need to rate the indirect evidence when the certainty of the direct evidence is high and the contribution of the direct evidence to the network estimate is at least as great as that of the indirect evidence, (3) we should not trust a statistical test of global incoherence of the network to assess incoherence at the pairwise comparison level, and (4) in the presence of incoherence between direct and indirect evidence, the certainty of the evidence of each estimate can help decide which estimate to believe.
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http://dx.doi.org/10.1016/j.jclinepi.2017.10.005DOI Listing
January 2018

Antiretroviral therapy for pregnant women living with HIV or hepatitis B: a systematic review and meta-analysis.

BMJ Open 2017 Sep 11;7(9):e019022. Epub 2017 Sep 11.

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

Objective: To assess the impact of various antiretroviral/antiviral regimens in pregnant women living with HIV or hepatitis B virus (HBV).

Design: We performed random effects meta-analysis for HIV-related outcomes and network meta-analysis for HBV outcomes, and used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework to assess quality separately for each outcome.

Data Sources: Embase and Medline to February 2017.

Eligibility Criteria: For maternal outcomes, we considered randomised controlled trials (RCTs) comparing tenofovir-based regimens with those with alternative nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs). For child outcomes, we included RCTs and comparative observational studies of tenofovir-based regimens versus alternative NRTIs regimens or, for HBV, placebo.

Results: Ten studies (seven RCTs) met the inclusion criteria for maternal and child outcomes, and an additional 33 studies (12 RCTs) met the inclusion criteria for HBV-specific outcomes. The most common comparison was tenofovir and emtricitabine versus zidovudine and lamivudine. There was no apparent difference between tenofovir-based regimens and alternatives in maternal outcomes, including serious laboratory adverse events (low certainty) and serious clinical adverse events (moderate certainty). There was no difference between NRTIs in vertical transmission of HIV: 1 more per 1000, 8 fewer to 10 more, low certainty; or vertical transmission of HBV: 7 fewer per 1000, 10 fewer to 38 more, moderate certainty. We found moderate certainty evidence that tenofovir/emtricitabine increases the risk of stillbirths and early neonatal mortality (51 more per 1000, 11 more to 150 more) and the risk of early premature delivery at <34 weeks (42 more per 1000, 2 more to 127 more).

Conclusions: Tenofovir/emtricitabine is likely to increase stillbirth/early neonatal death and early premature delivery compared with zidovudine/lamivudine, but certainty is low when they are not coprescribed with lopinavir/ritonavir. Other outcomes are likely similar between antiretrovirals.

Trial Registration Number: PROSPERO CRD42017054392.
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http://dx.doi.org/10.1136/bmjopen-2017-019022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6027063PMC
September 2017

GRADE equity guidelines 2: considering health equity in GRADE guideline development: equity extension of the guideline development checklist.

J Clin Epidemiol 2017 Oct 9;90:68-75. Epub 2017 May 9.

The Centre for Global Health, Institute of Population Health, University of Ottawa, 75 Laurier Ave E, Ottawa, Ontario, K1N 6N5, Canada.

Objective: To provide guidance for guideline developers on how to consider health equity at key stages of the guideline development process.

Study Design And Setting: Literature review followed by group discussions and consensus building.

Results: The key stages at which guideline developers could consider equity include setting priorities, guideline group membership, identifying the target audience(s), generating the guideline questions, considering the importance of outcomes and interventions, deciding what evidence to include and searching for evidence, summarizing the evidence and considering additional information, wording of recommendations, and evaluation and use. We provide examples of how guidelines have actually considered equity at each of these stages.

Conclusion: Guideline projects should consider the aforementioned suggestions for recommendations that are equity sensitive.
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http://dx.doi.org/10.1016/j.jclinepi.2017.01.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6538524PMC
October 2017

Canadian Primary Care Physicians' Attitudes Toward Understanding Clinical Practice Guidelines for Diabetes Screening.

Can J Diabetes 2016 Dec 30;40(6):580-585. Epub 2016 Aug 30.

Department of Clinical Epidemiology and Biostatistics, McMaster University Health Sciences Centre, Hamilton, Ontario, Canada.

Objectives: The Canadian Task Force on Preventive Health Care (CTFPHC) produces guidelines for Canadian physicians regarding screening and prevention. To better appreciate the barriers to and facilitators of guideline adherence, we sought to explore physicians' views of guidelines in general and their understanding of this CTFPHC diabetes screening guideline in particular because they pertain to screening and positive treatment.

Methods: We included Canadian physicians (N=10) who agreed to be interviewed regarding their use of guidelines as part of practice, focusing on the CTFPHC 2012 diabetes screening guideline. Individual semistructured interviews explored primary care physicians' experiences and perspectives on the use, relevance and feasibility of guidelines as part of practice, approaches to screening for diabetes, and suggestions for improving guidelines.

Results: Overall, physicians recognized the need for guidelines and the benefits of using Grading of Recommendations Assessment, Development and Evaluation (GRADE) methods in the guideline development process. Physicians also noted several barriers to guideline adherence, including the lack of opportunity for physicians to provide input during guideline formulation, insufficient guidance on interpreting GRADE's weak or conditional recommendations, and feasibility issues concerning using risk calculators. The predominant challenge raised by physicians was the unclear guidance for pharmacologic interventions; all respondents were unclear about the guidelines' implicit assumption that screen-positive patients would be treated with statins and aspirin (ASA).

Conclusions: These interviews suggest the need for greater clarity in guideline recommendations, including clarification of the quality of evidence ratings and the strength of recommendation grading. Our low participation rate raises the issue of representativeness; replication in samples with greater willingness to participate would be desirable.
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http://dx.doi.org/10.1016/j.jcjd.2016.05.018DOI Listing
December 2016

Transfusion of fresher vs older red blood cells in hospitalized patients: a systematic review and meta-analysis.

Blood 2016 Jan 1;127(4):400-10. Epub 2015 Dec 1.

Health Research Methods (HRM), Health Sciences Building (HSB), Department of Clinical Epidemiology and Biostatistics, McMaster University, West Hamilton, ON, Canada;

The impact of transfusing fresher vs older red blood cells (RBCs) on patient-important outcomes remains controversial. Two recently published large trials have provided new evidence. We summarized results of randomized trials evaluating the impact of the age of transfused RBCs. We searched MEDLINE, EMBASE, CINAHL, the Cochrane Database for Systematic Reviews, and Cochrane CENTRAL for randomized controlled trials enrolling patients who were transfused fresher vs older RBCs and reported outcomes of death, adverse events, and infection. Independently and in duplicate, reviewers determined eligibility, risk of bias, and abstracted data. We conducted random effects meta-analyses and rated certainty (quality or confidence) of evidence using the GRADE approach. Of 12 trials that enrolled 5229 participants, 6 compared fresher RBCs with older RBCs and 6 compared fresher RBCs with current standard practice. There was little or no impact of fresher vs older RBCs on mortality (relative risk [RR], 1.04; 95% confidence interval [CI], 0.94-1.14; P = .45; I(2) = 0%, moderate certainty evidence) or on adverse events (RR, 1.02; 95% CI, 0.91-1.14; P = .74; I(2) = 0%, low certainty evidence). Fresher RBCs appeared to increase the risk of nosocomial infection (RR, 1.09; 95% CI, 1.00-1.18; P = .04; I(2) = 0%, risk difference 4.3%, low certainty evidence). Current evidence provides moderate certainty that use of fresher RBCs does not influence mortality, and low certainty that it does not influence adverse events but could possibly increase infection rates. The existing evidence provides no support for changing practices toward fresher RBC transfusion.
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http://dx.doi.org/10.1182/blood-2015-09-670950DOI Listing
January 2016

Sensitivity subgroup analysis based on single-center vs. multi-center trial status when interpreting meta-analyses pooled estimates: the logical way forward.

J Clin Epidemiol 2016 06 17;74:80-92. Epub 2015 Nov 17.

Department of Clinical Epidemiology & Biostatistics, McMaster University, Michael DeGroote Centre for Learning & Discovery, Room 3208, 1200 Main Street West, Hamilton, Ontario L8N 3Z5, Canada; John D. Cameron Endowed Chair in Genetic Epidemiology, McMaster University, Michael DeGroote Centre for Learning & Discovery, Room 3208, 1200 Main Street West, Hamilton, Ontario L8N 3Z5, Canada; Population Genomics Program, McMaster University, Michael DeGroote Centre for Learning & Discovery, Room 3208, 1200 Main Street West, Hamilton, Ontario L8N 3Z5, Canada.

Objectives: Prior studies regarding whether single-center trial estimates are larger than multi-center are equivocal. We examined the extent to which single-center trials yield systematically larger effects than multi-center trials.

Study Design And Setting: We searched the 119 core clinical journals and the Cochrane Database of Systematic Reviews for meta-analyses (MAs) of randomized controlled trials (RCTs) published during 2012. In this meta-epidemiologic study, for binary variables, we computed the pooled ratio of ORs (RORs), and for continuous outcomes mean difference in standardized mean differences (SMDs), we conducted weighted random-effects meta-regression and random-effects MA modeling. Our primary analyses were restricted to MAs that included at least five RCTs and in which at least 25% of the studies used each of single trial center (SC) and more trial center (MC) designs.

Results: We identified 81 MAs for the odds ratio (OR) and 43 for the SMD outcome measures. Based on our analytic plan, our primary analysis (core) is based on 25 MAs/241 RCTs (binary outcome) and 18 MAs/173 RCTs (continuous outcome). Based on the core analysis, we found no difference in magnitude of effect between SC and MC for binary outcomes [RORs: 1.02; 95% confidence interval (CI): 0.83, 1.24; I(2) 20.2%]. Effect sizes were systematically larger for SC than MC for the continuous outcome measure (mean difference in SMDs: -0.13; 95% CI: -0.21, -0.05; I(2) 0%).

Conclusions: Our results do not support prior findings of larger effects in SC than MC trials addressing binary outcomes but show a very similar small increase in effect in SC than MC trials addressing continuous outcomes. Authors of systematic reviews would be wise to include all trials irrespective of SC vs. MC design and address SC vs. MC status as a possible explanation of heterogeneity (and consider sensitivity analyses).
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http://dx.doi.org/10.1016/j.jclinepi.2015.08.027DOI Listing
June 2016

A number of factors explain why WHO guideline developers make strong recommendations inconsistent with GRADE guidance.

J Clin Epidemiol 2016 Feb 21;70:111-22. Epub 2015 Sep 21.

Department of Clinical Epidemiology & Biostatistics, McMaster University Health Sciences Centre, Room 2C12, 1200 Main Street West, Hamilton, Ontario L8S 4K1, Canada.

Objective: Many strong recommendations issued by the World Health Organization (WHO) are based on low- or very low-quality (low certainty) evidence (discordant recommendations). Many such discordant recommendations are inconsistent with the Grading of Recommendations Assessment, Development and Evaluation (GRADE) guidance. We sought to understand why WHO makes discordant recommendations inconsistent with GRADE guidance.

Study Design And Setting: We interviewed panel members involved in guidelines approved by WHO (2007-2012) that included discordant recommendations. Interviews, recorded and transcribed, focused on use of GRADE including the reasoning underlying, and factors contributing to, discordant recommendations.

Results: Four themes emerged: strengths of GRADE, challenges and barriers to GRADE, strategies to improve GRADE application, and explanations for discordant recommendations. Reasons for discordant recommendations included skepticism about the value of making conditional recommendations; political considerations; high certainty in benefits (sometimes warranted, sometimes not) despite assessing evidence as low certainty; and concerns that conditional recommendations will be ignored.

Conclusion: WHO panelists make discordant recommendations inconsistent with GRADE guidance for reasons that include limitations in their understanding of GRADE. Ensuring optimal application of GRADE at WHO and elsewhere likely requires selecting panelists who have a commitment to GRADE principles, additional training of panelists, and formal processes to maximize adherence to GRADE principles.
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http://dx.doi.org/10.1016/j.jclinepi.2015.09.006DOI Listing
February 2016

High statistical heterogeneity is more frequent in meta-analysis of continuous than binary outcomes.

J Clin Epidemiol 2016 Feb 18;70:129-35. Epub 2015 Sep 18.

Clinical Epidemiology and Biostatistics, McMaster University, 1280 Main Street West, Hamilton, Ontario L8S 4K1, Canada.

Objectives: We compared the distribution of heterogeneity in meta-analyses of binary and continuous outcomes.

Study Design And Setting: We searched citations in MEDLINE and Cochrane databases for meta-analyses of randomized trials published in 2012 that reported a measure of heterogeneity of either binary or continuous outcomes. Two reviewers independently performed eligibility screening and data abstraction. We evaluated the distribution of I(2) in meta-analyses of binary and continuous outcomes and explored hypotheses explaining the difference in distributions.

Results: After full-text screening, we selected 671 meta-analyses evaluating 557 binary and 352 continuous outcomes. Heterogeneity as assessed by I(2) proved higher in continuous than in binary outcomes: the proportion of continuous and binary outcomes reporting an I(2) of 0% was 34% vs. 52%, respectively, and reporting an I(2) of 60-100% was 39% vs. 14%. In continuous but not binary outcomes, I(2) increased with larger number of studies included in a meta-analysis. Increased precision and sample size do not explain the larger I(2) found in meta-analyses of continuous outcomes with a larger number of studies.

Conclusions: Meta-analyses evaluating continuous outcomes showed substantially higher I(2) than meta-analyses of binary outcomes. Results suggest differing standards for interpreting I(2) in continuous vs. binary outcomes may be appropriate.
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http://dx.doi.org/10.1016/j.jclinepi.2015.09.005DOI Listing
February 2016

Senior GRADE methodologists encounter challenges as part of WHO guideline development panels: an inductive content analysis.

J Clin Epidemiol 2016 Feb 15;70:123-8. Epub 2015 Sep 15.

Department of Clinical Epidemiology & Biostatistics, McMaster University Health Sciences Centre, 1280 Main Street West, Hamilton, Ontario L8S 4K1, Canada.

Background: The World Health Organization (WHO) classifies a substantial proportion of their recommendations as strong despite low or very low confidence (certainty) in estimates of effect. Such discordant recommendations are often inconsistent with Grading of Recommendations Assessment, Development and Evaluation (GRADE) guidance.

Objective: To gain the perspective of senior WHO methodology chairs regarding panels' use of GRADE, particularly regarding discordant recommendations.

Data Sources: Senior active GRADE methodologists who had served on at least two WHO panels and were an author on at least one peer-reviewed published article on GRADE methodology.

Methods: Five eligible methodologists participated in detailed semistructured interviews. Respondents answered questions regarding how they were viewed by other panelists and WHO leadership, and how they handled situations when panelists made discordant recommendations they felt were inappropriate. They also provided information on how the process can be improved. Interviews were recorded and transcribed, and inductive content analysis was used to derive codes, categories, and emergent themes.

Results: Three themes emerged from the interviews of five methodologists: (1) The perceived role of methodologists in the process, (2) Contributors to discordant recommendations, and (3) Strategies for improvement. Salient findings included (1) a perceived tension between methodologists and WHO panels as a result of panel members' resistance to adhering to GRADE guidance; (2) both financial and nonfinancial conflicts of interest among panel members as an explanation for discordant recommendations; and (3) the need for greater clarity of, and support for, the role of methodologists as co-chairs of panels.

Conclusions: These findings suggest that the role of the GRADE methodologist as a co-chair needs to be clarified by the WHO leadership. They further suggest the need for additional training for panelists, quality monitoring, and feedback to ensure optimal use of GRADE in guideline development at WHO.
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http://dx.doi.org/10.1016/j.jclinepi.2015.09.003DOI Listing
February 2016

Corticosteroid Therapy for Patients Hospitalized With Community-Acquired Pneumonia: A Systematic Review and Meta-analysis.

Ann Intern Med 2015 Oct;163(7):519-28

Background: Community-acquired pneumonia (CAP) is common and often severe.

Purpose: To examine the effect of adjunctive corticosteroid therapy on mortality, morbidity, and duration of hospitalization in patients with CAP.

Data Sources: MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials through 24 May 2015.

Study Selection: Randomized trials of systemic corticosteroids in hospitalized adults with CAP.

Data Extraction: Two reviewers independently extracted study data and assessed risk of bias. Quality of evidence was assessed with the Grading of Recommendations Assessment, Development, and Evaluation system by consensus among the authors.

Data Synthesis: The median age was typically in the 60s, and approximately 60% of patients were male. Adjunctive corticosteroids were associated with possible reductions in all-cause mortality (12 trials; 1974 patients; risk ratio [RR], 0.67 [95% CI, 0.45 to 1.01]; risk difference [RD], 2.8%; moderate certainty), need for mechanical ventilation (5 trials; 1060 patients; RR, 0.45 [CI, 0.26 to 0.79]; RD, 5.0%; moderate certainty), and the acute respiratory distress syndrome (4 trials; 945 patients; RR, 0.24 [CI, 0.10 to 0.56]; RD, 6.2%; moderate certainty). They also decreased time to clinical stability (5 trials; 1180 patients; mean difference, -1.22 days [CI, -2.08 to -0.35 days]; high certainty) and duration of hospitalization (6 trials; 1499 patients; mean difference, -1.00 day [CI, -1.79 to -0.21 days]; high certainty). Adjunctive corticosteroids increased frequency of hyperglycemia requiring treatment (6 trials; 1534 patients; RR, 1.49 [CI, 1.01 to 2.19]; RD, 3.5%; high certainty) but did not increase frequency of gastrointestinal hemorrhage.

Limitations: There were few events and trials for many outcomes. Trials often excluded patients at high risk for adverse events.

Conclusion: For hospitalized adults with CAP, systemic corticosteroid therapy may reduce mortality by approximately 3%, need for mechanical ventilation by approximately 5%, and hospital stay by approximately 1 day.

Primary Funding Source: None.
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http://dx.doi.org/10.7326/M15-0715DOI Listing
October 2015

World Health Organization strong recommendations based on low-quality evidence (study quality) are frequent and often inconsistent with GRADE guidance.

J Clin Epidemiol 2016 Apr 19;72:98-106. Epub 2014 Dec 19.

Department of Clinical Epidemiology & Biostatistics, McMaster University Health Sciences Centre, 1200 Main Street West, Room 2C12, Hamilton, Ontario L8S 4K1, Canada.

Objectives: In 2007 the World Health Organization (WHO) adopted the GRADE system for development of public health guidelines. Previously we found that many strong recommendations issued by WHO are based on evidence for which there is only low or very low confidence in the estimates of effect (discordant recommendations). GRADE guidance indicates that such discordant recommendations are rarely appropriate but suggests five paradigmatic situations in which discordant recommendations may be warranted. We sought to provide insight into the many discordant recommendations in WHO guidelines.

Study Design And Setting: We examined all guidelines that used the GRADE method and were approved by the WHO Guideline Review Committee between 2007 and 2012. Teams of reviewers independently abstracted data from eligible guidelines and classified recommendations either into one of the five paradigms for appropriately-formulated discordant recommendations or into three additional categories in which discordant recommendations were inconsistent with GRADE guidance: 1) the evidence warranted moderate or high confidence (a misclassification of evidence) rather than low or very low confidence; 2) good practice statements; or 3) uncertainty in the estimates of effect would best lead to a conditional (weak) recommendation.

Results: The 33 eligible guidelines included 160 discordant recommendations, of which 98 (61.3%) addressed drug interventions and 132 (82.5%) provided some rationale (though not entirely explicit at times) for the strong recommendation. Of 160 discordant recommendations, 25 (15.6%) were judged consistent with one of the five paradigms for appropriate recommendations; 33 (21%) were based on evidence warranting moderate or high confidence in the estimates of effect; 29 (18%) were good practice statements; and 73 (46%) warranted a conditional, rather than a strong recommendation.

Conclusion: WHO discordant recommendations are often inconsistent with GRADE guidance, possibly threatening the integrity of the process. Further training in GRADE methods for WHO guideline development group members may be necessary, along with further research on what motivates the formulation of such recommendations.
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http://dx.doi.org/10.1016/j.jclinepi.2014.10.011DOI Listing
April 2016

World Health Organization recommendations are often strong based on low confidence in effect estimates.

J Clin Epidemiol 2014 Jun 3;67(6):629-34. Epub 2014 Jan 3.

McMaster University Health Sciences Centre, 1200 Main Street West, Room 2C12, Hamilton, Ontario L8S 4K1, Canada. Electronic address:

Objectives: Expert guideline panelists are sometimes reluctant to offer weak/conditional/contingent recommendations. Grading of Recommendations Assessment, Development and Evaluation (GRADE) guidance warns against strong recommendations when confidence in effect estimates is low or very low, suggesting that such recommendations may seldom be justified. We aim to characterize the classification of strength of recommendations and confidence in estimates in World Health Organization (WHO) guidelines that used the GRADE approach and graded both strength and confidence (GRADEd).

Study Design And Setting: We reviewed all WHO guidelines (January 2007 to December 2012), identified those that were GRADEd, and, in these, examined the classifications of strong and weak and associated confidence in estimates (high, moderate, low, and very low).

Results: We identified 116 WHO guidelines in which 43 (37%) were GRADEd and had 456 recommendations, of which 289 (63.4%) were strong and 167 (36.6%) were conditional/weak. Of the 289 strong recommendations, 95 (33.0%) were based on evidence warranting low confidence in estimates and 65 (22.5%) on evidence warranting very low confidence in estimates (55.5% strong recommendations overall based on low or very low confidence in estimates).

Conclusion: Strong recommendations based on low or very low confidence estimates are very frequently made in WHO guidelines. Further study to determine the reasons for such high uncertainty recommendations is warranted.
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http://dx.doi.org/10.1016/j.jclinepi.2013.09.020DOI Listing
June 2014
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