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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. •The application of the Grading of Recommendations Assessments, Development, and Evaluation approach to a number of network meta-analyses in the 3 years since the original guidance publication has led to advances that have strengthened the conceptual basis.•We present, discuss, and illustrate four conceptual advances. These are based on two principles: we need to rate the certainty of the evidence of each pairwise comparison within a network separately and that we need to consider both the direct and indirect evidence contributing to each network estimate.•Although maximizing the efficiency of the process is desirable, as illustrated in the conceptual advances, use of these strategies requires careful judgment.

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. 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. 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. 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.

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). 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). 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). 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.

Patients who had undergone successful TAVR were randomly assigned to receive either a rivaroxaban-based antithrombotic regimen or an antiplatelet-based antithrombotic regimen. At 17 months, the primary outcome of death or thromboembolic complications occurred more frequently with rivaroxaban.

In this single-group, phase 2 study, the use of trastuzumab deruxtecan resulted in a response in 60% of women with HER2-positive advanced breast cancer who had received a median of six previous lines of therapy. The drug was associated with myelosuppression and gastrointestinal toxicity; interstitial lung disease was reported in 13.6% of the patients.

On the basis of estimates from a nationally representative sample of U.S. emergency departments from 2004 through 2013, approximately 23,000 emergency department visits annually are attributed to adverse events related to dietary supplements. Herbals (botanical products), complementary nutritionals (e.g., amino acids), and micronutrients (vitamins and minerals) are all considered to be dietary supplements by the Dietary Supplement Health and Education Act of 1994. 1 Although supplements cannot be marketed for the treatment or prevention of disease, they are often taken to address symptoms or illnesses, as well as to maintain or improve overall health. 2 The estimated number of supplement products increased from 4000 in 1994 3 to more than 55,000 in 2012 (the most recent year for which data are publicly available), 4 and approximately half of all adults in the United States report having used . . .

In women with HER2-positive metastatic breast cancer who had previously received HER2-targeted therapy, tucatinib, a new selective inhibitor of the HER2 tyrosine kinase, was added to trastuzumab and capecitabine and compared with trastuzumab and capecitabine plus placebo. Progression-free survival at 1 year was 33% with tucatinib and 12% with placebo.

Objective To review the evidence for the short term association between air pollution and stroke.Design Systematic review and meta-analysis of observational studiesData sources Medline, Embase, Global Health, Cumulative Index to Nursing and Allied Health Literature (CINAHL), and Web of Science searched to January 2014 with no language restrictions.Eligibility criteria Studies investigating the short term associations (up to lag of seven days) between daily increases in gaseous pollutants (carbon monoxide, sulphur dioxide, nitrogen dioxide, ozone) and particulate matter (<2.5 µm or <10 µm diameter (PM2.5 and PM10)), and admission to hospital for stroke or mortality.Main outcome measures Admission to hospital and mortality from stroke.Results From 2748 articles, 238 were reviewed in depth with 103 satisfying our inclusion criteria and 94 contributing to our meta-estimates. This provided a total of 6.2 million events across 28 countries. Admission to hospital for stroke or mortality from stroke was associated with an increase in concentrations of carbon monoxide (relative risk 1.015 per 1 ppm, 95% confidence interval 1.004 to 1.026), sulphur dioxide (1.019 per 10 ppb, 1.011 to 1.027), and nitrogen dioxide (1.014 per 10 ppb, 1.009 to 1.019). Increases in PM2.5 and PM10 concentration were also associated with admission and mortality (1.011 per 10 μg/m3 (1.011 to 1.012) and 1.003 per 10 µg/m3 (1.002 to 1.004), respectively). The weakest association was seen with ozone (1.001 per 10 ppb, 1.000 to 1.002). Strongest associations were observed on the day of exposure with more persistent effects observed for PM2·5.Conclusion Gaseous and particulate air pollutants have a marked and close temporal association with admissions to hospital for stroke or mortality from stroke. Public and environmental health policies to reduce air pollution could reduce the burden of stroke.Systematic review registration PROSPERO-CRD42014009225.

There is growing evidence of vaccine delays or refusals due to a lack of trust in the importance, safety, or effectiveness of vaccines, alongside persisting access issues. Although immunisation coverage is reported administratively across the world, no similarly robust monitoring system exists for vaccine confidence. In this study, vaccine confidence was mapped across 149 countries between 2015 and 2019. In this large-scale retrospective data-driven analysis, we examined global trends in vaccine confidence using data from 290 surveys done between September, 2015, and December, 2019, across 149 countries, and including 284 381 individuals. We used a Bayesian multinomial logit Gaussian process model to produce estimates of public perceptions towards the safety, importance, and effectiveness of vaccines. Associations between vaccine uptake and a large range of putative drivers of uptake, including vaccine confidence, socioeconomic status, and sources of trust, were determined using univariate Bayesian logistic regressions. Gibbs sampling was used for Bayesian model inference, with 95% Bayesian highest posterior density intervals used to capture uncertainty. Between November, 2015, and December, 2019, we estimate that confidence in the importance, safety, and effectiveness of vaccines fell in Afghanistan, Indonesia, Pakistan, the Philippines, and South Korea. We found significant increases in respondents strongly disagreeing that vaccines are safe between 2015 and 2019 in six countries: Afghanistan, Azerbaijan, Indonesia, Nigeria, Pakistan, and Serbia. We find signs that confidence has improved between 2018 and 2019 in some EU member states, including Finland, France, Ireland, and Italy, with recent losses detected in Poland. Confidence in the importance of vaccines (rather than in their safety or effectiveness) had the strongest univariate association with vaccine uptake compared with other determinants considered. When a link was found between individuals' religious beliefs and uptake, findings indicated that minority religious groups tended to have lower probabilities of uptake. To our knowledge, this is the largest study of global vaccine confidence to date, allowing for cross-country comparisons and changes over time. Our findings highlight the importance of regular monitoring to detect emerging trends to prompt interventions to build and sustain vaccine confidence. European Commission, Wellcome, and Engineering and Physical Sciences Research Council.

Objectives To examine the prospective associations between consumption of sugar sweetened beverages, artificially sweetened beverages, and fruit juice with type 2 diabetes before and after adjustment for adiposity, and to estimate the population attributable fraction for type 2 diabetes from consumption of sugar sweetened beverages in the United States and United Kingdom. Design Systematic review and meta-analysis. Data sources and eligibility PubMed, Embase, Ovid, and Web of Knowledge for prospective studies of adults without diabetes, published until February 2014. The population attributable fraction was estimated in national surveys in the USA, 2009-10 (n=4729 representing 189.1 million adults without diabetes) and the UK, 2008-12 (n=1932 representing 44.7 million). Synthesis methods Random effects meta-analysis and survey analysis for population attributable fraction associated with consumption of sugar sweetened beverages. Results Prespecified information was extracted from 17 cohorts (38 253 cases/10 126 754 person years). Higher consumption of sugar sweetened beverages was associated with a greater incidence of type 2 diabetes, by 18% per one serving/day (95% confidence interval 9% to 28%, I2 for heterogeneity=89%) and 13% (6% to 21%, I2=79%) before and after adjustment for adiposity; for artificially sweetened beverages, 25% (18% to 33%, I2=70%) and 8% (2% to 15%, I2=64%); and for fruit juice, 5% (−1% to 11%, I2=58%) and 7% (1% to 14%, I2=51%). Potential sources of heterogeneity or bias were not evident for sugar sweetened beverages. For artificially sweetened beverages, publication bias and residual confounding were indicated. For fruit juice the finding was non-significant in studies ascertaining type 2 diabetes objectively (P for heterogeneity=0.008). Under specified assumptions for population attributable fraction, of 20.9 million events of type 2 diabetes predicted to occur over 10 years in the USA (absolute event rate 11.0%), 1.8 million would be attributable to consumption of sugar sweetened beverages (population attributable fraction 8.7%, 95% confidence interval 3.9% to 12.9%); and of 2.6 million events in the UK (absolute event rate 5.8%), 79 000 would be attributable to consumption of sugar sweetened beverages (population attributable fraction 3.6%, 1.7% to 5.6%). Conclusions Habitual consumption of sugar sweetened beverages was associated with a greater incidence of type 2 diabetes, independently of adiposity. Although artificially sweetened beverages and fruit juice also showd positive associations with incidence of type 2 diabetes, the findings were likely to involve bias. None the less, both artificially sweetened beverages and fruit juice were unlikely to be healthy alternatives to sugar sweetened beverages for the prevention of type 2 diabetes. Under assumption of causality, consumption of sugar sweetened beverages over years may be related to a substantial number of cases of new onset diabetes.