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A 10-member ensemble simulation with the NASA GISS-E2-1-G climate model shows a clear bifurcation in the Atlantic Meridional Overturning Circulation (AMOC) strength under the SSP2-4.5 extended scenario. At 26°N, the bifurcation leads to 8 strong AMOC and 2 much weaker AMOC states, while at 48°N, it leads to 8 stable AMOC-on and 2 nearly AMOC-off states, the latter lasting approximately 800 years. A variety of fully coupled models have demonstrated tipping points in AMOC through hosing experiments, i.e. prescribing sufficient fresh water inputs in the subpolar North Atlantic. In the GISS simulations, there are no external fresh water perturbations. The bifurcation arises freely in the coupled system and is the result of stochastic variability (noise-induced bifurcation) associated with sea ice transport and melting in the Irminger Sea after a slowing of the GHG forcing. While the AMOC strength follows the near shut-down of the Labrador Sea deep convection initially, the Irminger Sea salinity and deep mixing determine the timing of the AMOC recovery or near collapse at 48°N, which varies widely across the ensemble members. Other feedbacks such as ice-albedo, ice-evaporation, E-P, and the overturning salt-advection feedback play a secondary role that may enhance or reduce the primary mechanism which is ice melt. We believe this is the first time that a coupled climate model has shown such a bifurcation across an initial condition ensemble and might imply that there is a chance for significant and prolonged AMOC slow down due to internal variability of the system.

A bi-stable mode of the Atlantic Meridional Overturning Circulation (AMOC) is found in a 10-member ensemble simulation of the SSP2-4.5 scenario using the NASA GISS-E2-1-G climate model. Local feedbacks in the subpolar North Atlantic region in conjunction with internal variability in sea-ice transport and melt play a critical role in causing the divergent behavior of the AMOC in the ensemble members. While other fully coupled models have demonstrated the important role of surface freshening in leading to AMOC shutdown, either through hosing experiments or increased precipitation and greenhouse gas warming at high latitudes, in the GISS simulations, there are no external freshwater perturbations. This is the first time that a CMIP-class model has shown such a bifurcation across an initial condition ensemble.

DISCLOSURES: Funding for this summary was contributed by Arnold Ventures, The Donaghue Foundation, Harvard Pilgrim Health Care, and Kaiser Foundation Health Plan to the Institute for Clinical and Economic Review (ICER), an independent organization that evaluates the evidence on the value of health care interventions. ICER's annual policy summit is supported by dues from AbbVie, America's Health Insurance Plans, Anthem, Alnylam, AstraZeneca, Biogen, Blue Shield of CA, Boehringer-Ingelheim, Cambia Health Services, CVS, Editas, Evolve Pharmacy, Express Scripts, Genentech/Roche, GlaxoSmithKline, Harvard Pilgrim, Health Care Service Corporation, HealthFirst, Health Partners, Humana, Johnson & Johnson (Janssen), Kaiser Permanente, LEO Pharma, Mallinckrodt, Merck, Novartis, National Pharmaceutical Council, Pfizer, Premera, Prime Therapeutics, Regeneron, Sanofi, Sun Life Financial, uniQure, and United Healthcare. Whittington, Rind, and Pearson are employed by ICER. Through their affiliated institutions, Synnott and Lin received funding from ICER for the work described in this summary. In addition, Synnott reports support from Biogen for the Tufts Medical Center Cost-Effectiveness Analysis Registry, which is maintained by the Center for the Evaluation of Value and Risk in Health.

DISCLOSURES: Funding for this summary was contributed by Arnold Ventures, California Health Care Foundation, The Donaghue Foundation, Harvard Pilgrim Health Care, and Kaiser Foundation Health Plan to the Institute for Clinical and Economic Review (ICER), an independent organization that evaluates the evidence on the value of health care interventions. ICER's annual policy summit is supported by dues from AbbVie, Aetna, America's Health Insurance Plans, Anthem, Alnylam, AstraZeneca, Biogen, Blue Shield of CA, Boehringer-Ingelheim, Cambia Health Services, CVS, Editas, Evolve Pharmacy, Express Scripts, Genentech/Roche, GlaxoSmithKline, Harvard Pilgrim, Health Care Service Corporation, HealthFirst, Health Partners, Humana, Johnson & Johnson (Janssen), Kaiser Permanente, LEO Pharma, Mallinckrodt, Merck, Novartis, National Pharmaceutical Council, Pfizer, Premera, Prime Therapeutics, Regeneron, Sanofi, Spark Therapeutics, uniQure, and United Healthcare. Beinfeld, McKenna, Rind, and Pearson are employed by ICER. Touchette received funding from ICER for work on this report and has also received fees from Monument Analytics and AstraZeneca, unrelated to this work. The University of Illinois at Chicago (UIC) and Touchette hold a patent for the model described in this report. The model is included in ICER's Interactive Modeler, for which a fee is paid to UIC and Touchette. Atlas also received funding from ICER for work on this report.

DISCLOSURES: Funding for this summary was contributed by Arnold Ventures, California Health Care Foundation, The Donaghue Foundation, Harvard Pilgrim Health Care, and Kaiser Foundation Health Plan to the Institute for Clinical and Economic Review (ICER), an independent organization that evaluates the evidence on the value of health care interventions. ICER's annual policy summit is supported by dues from AbbVie, Aetna, America's Health Insurance Plans, Anthem, Alnylam, AstraZeneca, Biogen, Blue Shield of CA, Boehringer-Ingelheim, Cambia Health Services, CVS, Editas, Evolve Pharmacy, Express Scripts, Genentech/Roche, GlaxoSmithKline, Harvard Pilgrim, Health Care Service Corporation, HealthFirst, Health Partners, Humana, Johnson & Johnson (Janssen), Kaiser Permanente, LEO Pharma, Mallinckrodt, Merck, Novartis, National Pharmaceutical Council, Pfizer, Premera, Prime Therapeutics, Regeneron, Sanofi, Spark Therapeutics, uniQure, and United Healthcare. Agboola, Rind, Herron-Smith, and Pearson are employed by ICER. Walton and Quach, through the University of Illinois at Chicago, received funding from ICER for development of the economic model described in this report.

BACKGROUND: Oral semaglutide is the first oral formulation of a glucagon-like peptide 1 (GLP-1) receptor agonist to be approved in the United States for glycemic control in people with type 2 diabetes mellitus (T2DM). While oral semaglutide is not indicated for reduction of cardiovascular event risk, its label does include evidence of no increase in cardiovascular risk in people who received oral semaglutide. OBJECTIVE: To estimate the incremental value of oral semaglutide added to existing antihyperglycemic treatment for people with T2DM with additional risk for cardiovascular disease. METHODS: We estimated the lifetime cost-effectiveness of oral semaglutide added to current antihyperglycemic treatment for T2DM using a microsimulation model based primarily on the UK Prospective Diabetes Study (UKPDS) Outcomes Model 2 (OM2) equations. Oral semaglutide added to current antihyperglycemic treatment was separately compared with (a) ongoing background antihyperglycemic treatment, (b) sitagliptin, (c) empagliflozin, and (d) liraglutide. Comparators sitagliptin, empagliflozin, and liraglutide were added to ongoing antihyperglycemic treatment. We applied hazard ratios derived from a network meta-analysis for cardiovascular and renal outcomes to the UKPDS OM2 estimated baseline rates. Health state utilities and costs were derived from the published literature. We estimated total costs, life-years (LYs), quality-adjusted life-years (QALYs), clinical events, and cost per major adverse cardiovascular event (MACE) avoided, over a lifetime time horizon using discount rates of 3% for costs and outcomes. RESULTS: The lifetime total cost for people treated with oral semaglutide was $311,300, with costs for the other comparators ranging from $262,800 (background treatment alone) to $287,800 (liraglutide). Oral semaglutide resulted in the fewest MACE, including the fewest cardiovascular deaths. Among the 5 modeled treatment strategies, oral semaglutide had the highest LYs gained (8.43 vs. 7.76 [background treatment alone] to 8.29 [empagliflozin and liraglutide]) and the highest QALYs gained (4.11 vs. 3.70 [background treatment alone] to 4.03 [empagliflozin]). Oral semaglutide would likely be considered cost-effective compared with liraglutide (incremental cost-effectiveness ratio [ICER] = $40,100), and moderately cost-effective versus background treatment alone ([ICER] = $117,500/QALY) and sitagliptin (ICER = $145,200/QALY). The ICER for oral semaglutide compared with empagliflozin was approximately $458,400 per QALY. CONCLUSIONS: As modeled, oral semaglutide as an add-on therapy to background antihyperglycemic treatment produced incremental benefits in MACE avoided, along with greater QALYs compared with background antihyperglycemic treatment alone. Oral semaglutide use resulted in better outcomes than background treatment alone or sitagliptin, and similar outcomes to liraglutide or empagliflozin with overlapping 95% confidence ranges for QALYs. Oral semaglutide was estimated to be cost-effective compared with liraglutide and to have incremental cost-effectiveness ratios between $100,000 and $150,000 per QALY versus sitagliptin and background therapy alone, but it did not meet these thresholds compared with empagliflozin. DISCLOSURES: Funding for this study was provided by the Institute for Clinical and Economic Review, an independent organization that evaluates the evidence on the value of health care interventions. ICER reports grants from Laura and John Arnold Foundation, California Health Care Foundation, Harvard Pilgrim Health Care, and Kaiser Foundation Health Plan. ICER's annual policy summit is supported by dues from AbbVie, Aetna, America's Health Insurance Plans, Anthem, Alnylam, AstraZeneca, Biogen, Blue Shield of CA, Cambia Health Services, CVS, Editas, Evolve Pharmacy, Express Scripts, Genentech/Roche, GlaxoSmithKline, Harvard Pilgrim, Health Care Service Corporation, Health Partners, Humana, Johnson & Johnson (Janssen), Kaiser Permanente, LEO Pharma, Mallinckrodt, Merck, Novartis, National Pharmaceutical Council, Premera, Prime Therapeutics, Regeneron, Sanofi, Spark Therapeutics, uniQure, and United Healthcare. Rind, Fazioli, Chapman, and Pearson are employed by ICER. Guzauskas and Hansen have nothing to disclose. Study results were presented at the New England Comparative Effectiveness Public Advisory Council (New England CEPAC), November 14, 2019, at Brown University, Providence, RI.

DISCLOSURES: Funding for this summary was contributed by Arnold Ventures, California Health Care Foundation, Harvard Pilgrim Health Care, and Kaiser Foundation Health Plan to the Institute for Clin...

DISCLOSURES: Funding for this summary was contributed by Arnold Ventures, California Health Care Foundation, Harvard Pilgrim Health Care, and Kaiser Foundation Health Plan to the Institute for Clin...

DISCLOSURES: Funding for this summary was contributed by Arnold Ventures, Commonwealth Fund, California Health Care Foundation, National Institute for Health Care Management (NIHCM), New England St...

DISCLOSURES: Funding for this summary was contributed by the Laura and John Arnold Foundation and California Health Care Foundation to the Institute for Clinical and Economic Review (ICER), an inde...

Background and ObjectivesAducanumab was granted accelerated approval with a conflicting evidence base, near-unanimous Food and Drug Administration Advisory Committee vote to reject approval, and a widely criticized launch price of $56,000 per year. The objective of this analysis was to estimate its cost-effectiveness.MethodsWe developed a Markov model to compare aducanumab in addition to supportive care to supportive care alone over a lifetime horizon. Results were presented from both the health system and modified societal perspective. The model tracked the severity of disease and the care setting. Incremental cost-effectiveness ratios were calculated and a threshold analysis was conducted to estimate at what price aducanumab would meet commonly used cost-effectiveness thresholds.ResultsUsing estimates of effectiveness based on pooling of data from both pivotal trials, patients treated with aducanumab spent 4 more months in earlier stages of Alzheimer disease. Over the lifetime time horizon, treating a patient with aducanumab results in 0.154 more quality-adjusted life-years (QALYs) gained per patient and 0.201 equal value of life-years gained (evLYG) per patient from the health care system perspective, with additional costs of approximately $204,000 per patient. The incremental outcomes were similar for the modified societal perspective. At the launch price of $56,000 per year, the cost-effectiveness ranged from $1.02 million per evLYG to $1.33 million per QALY gained from the health care system perspective and from $938,000 per evLYG to $1.27 million per QALY gained in the modified societal perspective. The annual price to meet commonly used cost-effectiveness thresholds ranged from $2,950 to $8,360, which represents a discount of 85%–95% off from the annual launch price set by the manufacturer. Using estimates of effectiveness based only on the trial that suggested a benefit, the mean incremental cost was greater than $400,000 per QALY gained.ConclusionPatients treated with aducanumab received minimal improvements in health outcomes at considerable cost. This resulted in incremental cost-effectiveness ratios that far exceeded commonly used value thresholds, even under optimistic treatment effectiveness assumptions. These findings are subject to the substantial uncertainty regarding whether aducanumab provides any true net health benefit, but evidence available currently suggests that an annual price of aducanumab of $56,000 is not in reasonable alignment with its clinical benefits.

DISCLOSURES: Funding for this summary was contributed by the Laura and John Arnold Foundation, Blue Shield of California, and California Health Care Foundation to the Institute for Clinical and Eco...

Objective The gene therapy voretigene neparvovec (VN) is the first Food and Drug Administration–approved treatment for vision loss owing to the ultra-rare RPE65-mediated inherited retinal disorders. We modeled the cost-utility of VN compared with standard of care (SoC). Study Design A 2-state Markov model, alive and dead, with a lifetime horizon. Methods Visual acuity (VA) and visual field (VF) were tracked to model quality-adjusted life-years (QALYs). VN led to an improvement in VA and VF that we assumed was maintained for 10 years followed by a 10-year waning period. The cost of VN was $850 000, and other direct medical costs for depression and trauma were included for a US healthcare system perspective. A modified societal perspective also included direct nonmedical costs and indirect costs. Results VN provided an additional 1.3 QALYs over the remaining lifetime of an individual. The average total lifetime direct medical cost for individuals treated with VN was $1 039 000 compared with $213 400 for SoC, leading to an incremental cost-effectiveness ratio (ICER) of $643 800/QALY from the US healthcare system perspective. Direct nonmedical costs totalled $1 070 900 for VN and $1 203 300 for SoC, and indirect costs totalled $405 400 for VN and $482 900 for SoC, leading to an ICER of $480 100/QALY from the modified societal perspective. Conclusions At the current price, VN was unlikely to reach traditional cost-effectiveness standards compared with SoC. VN has important implications for both development and pricing of future gene therapies; therefore clinical and economic analyses must be carefully considered.

Standard vector calculus formulas of Cartesian three space are projected onto the surface of a sphere. This produces symmetric equations with three nonindependent horizontal velocity components. Each orthogonal axis has a velocity component that rotates around its axis (eastward velocity rotates around the north–south axis) and a specific angular momentum component that is the product of the velocity component multiplied by the cosine of axis' latitude. Angular momentum components align with the fixed axes and simplify several formulas, whereas the rotating velocity components are not orthogonal and vary with location. Three symmetric coordinates allow vector resolution and calculus operations continuously over the whole spherical surface, which is not possible with only two coordinates. The symmetric equations are applied to one-layer shallow water models on cubed-sphere and icosahedral grids, the latter being computationally simple and applicable to an ocean domain. Model results are presented for three different initial conditions and five different resolutions.

Simulations of the CMIP6 historical period 1850–2014, characterized by the emergence of anthropogenic climate drivers like greenhouse gases, are presented for different configurations of the NASA Goddard Institute for Space Studies (GISS) Earth System ModelE2.1. The GISS‐E2.1 ensembles are more sensitive to greenhouse gas forcing than their CMIP5 predecessors (GISS‐E2) but warm less during recent decades due to a forcing reduction that is attributed to greater longwave opacity in the GISS‐E2.1 pre‐industrial simulations. This results in an atmosphere less sensitive to increases in opacity from rising greenhouse gas concentrations, demonstrating the importance of the base climatology to forcing and forced climate trends. Most model versions match observed temperature trends since 1979 from the ocean to the stratosphere. The choice of ocean model is important to the transient climate response, as found previously in CMIP5 GISS‐E2: the model that more efficiently exports heat to the deep ocean shows a smaller rise in tropospheric temperature. Model sea level rise over the historical period is traced to excessive drawdown of aquifers to meet irrigation demand with a smaller contribution from thermal expansion. This shows how fully coupled models can provide indirect observational constraints upon forcing, in this case, constraining irrigation rates with observed sea level changes. The overall agreement of GISS‐E2.1 with observed trends is familiar from evaluation of its predecessors, as is the conclusion that these trends are almost entirely anthropogenic in origin. We thank two anonymous reviewers for their comments that substantially improved this article. Development of GISS‐E2.1 was supported by the NASA Modeling, Analysis, and Prediction (MAP) Program. CMIP6 simulations with GISS‐E2.1 were made possible by the NASA High‐End Computing (HEC) Program through the NASA Center for Climate Simulation (NCCS) at Goddard Space Flight Center. We thank Ellen Salmon and the NCCS staff for hosting and providing convenient access to the model output. Peer Reviewed "Article signat per 47 autors/es: Ron L. Miller, Gavin A. Schmidt, Larissa S. Nazarenko, Susanne E. Bauer, Maxwell Kelley, Reto Ruedy, Gary L. Russell , Andrew S. Ackerman, Igor Aleinov, Michael Bauer, Rainer Bleck, Vittorio Canuto, Grégory Cesana, Ye Cheng, Thomas L. Clune, Ben I. Cook, Carlos A. Cruz, Anthony D. Del Genio, Gregory S. Elsaesser, Greg Faluvegi, Nancy Y. Kiang, Daehyun Kim, Andrew A. Lacis , Anthony Leboissetie,r Allegra N. LeGrande, Ken K. Lo, John Marshall, Elaine E. Matthews, Sonali McDermid, Keren Mezuman, Lee T. Murray, Valdar Oinas, Clara Orbe, Carlos Pérez García‐Pando, Jan P. Perlwitz, Michael J. Puma, David Rind, Anastasia Romanou, Drew T. Shindell, Shan Sun, Nick Tausnev, Kostas Tsigaridis, George Tselioudis, Ensheng Weng, Jingbo Wu, Mao‐Sung Yao"

Funding for this summary was contributed by the Laura and John Arnold Foundation and California Health Care Foundation to the Institute for Clinical and Economic Review (ICER), an independent organization that evaluates the evidence on the value of health care interventions. ICER's annual policy summit is supported by dues from Aetna, AHIP, Anthem, Blue Shield of California, CVS Caremark, Express Scripts, Harvard Pilgrim Health Care, Cambia Health Solutions and MedSavvy, United Healthcare, Kaiser Permanente, Premera Blue Cross, AstraZeneca, Genentech, GlaxoSmithKline, JohnsonJohnson, Merck, National Pharmaceutical Council, Sanofi, Alnylam, Novartis, HealthPartners, Blue Cross Blue Shield of Massachusetts, Health Care Services Corporation, Mallinkrodt Pharmaceuticals, Prime Therapeutics, Regeneron, National Institute for Health Care Management, Commonwealth Fund, Partners Healthcare, New England States Consortium Systems, Allergan, Biogen, Editas, LEO Pharma, and HealthFirst. ICER has also received grants from Kaiser Foundation Health Plan, California Health Care Foundation, and the Laura and John Arnold Foundation. Pearson and Rind are employees of ICER. Thokala and Stevenson have no potential conflicts of interest to disclose.

The effect of changing cloud cover on climate, based on cloud-aerosol interactions, is one of the major unknowns for climate forcing and climate sensitivity. It has two components: (1) the impact of aerosols on clouds and climate due to in situ interactions (i.e., rapid response) and (2) the effect of aerosols on the cloud feedback that arises as climate changes-climate feedback response. We examine both effects utilizing the NASA Goddard Institute for Space Studies ModelE2 to assess the indirect effect, with both mass-based and microphysical aerosol schemes, in transient twentieth century simulations. We separate the rapid response and climate feedback effects by making simulations with a coupled version of the model as well as one with no sea surface temperature or sea ice response ("atmosphere-only" simulations). We show that the indirect effect of aerosols on temperature is altered by the climate feedbacks following the ocean response, and this change differs depending upon which aerosol model is employed. Overall, the effective radiative forcing (ERF) for the "direct effect" of aerosol-radiation interaction (ERFari) ranges between -0.2 and -0.6 W m-2 for atmosphere-only experiments, while the total effective radiative forcing, including[C0]the indirect effect (ERFari+aci) varies between about -0.4 and -1.1 W m-2 for atmosphere-only simulations; both ranges are in agreement with those given in Intergovernmental Panel on Climate Change (2013). Including the full feedback of the climate system lowers these ranges to -0.2 to -0.5 W m-2 for ERFari and -0.3 to -0.74 W m-2 for ERFari+aci. With both aerosol schemes, the climate change feedbacks have reduced the global average indirect radiative effect of atmospheric aerosols relative to what the emission changes would have produced, at least partially due to its effect on tropical upper tropospheric clouds.

Funding for this summary was contributed by the Laura and John Arnold Foundation, Blue Shield of California, and California Health Care Foundation to the Institute for Clinical and Economic Review (ICER), an independent organization that evaluates the evidence on the value of health care interventions. ICER's annual policy summit is supported by dues from Aetna, AHIP, Anthem, Blue Shield of California, CVS Caremark, Express Scripts, Harvard Pilgrim Health Care, Cambia Health Solutions, United Healthcare, Kaiser Permanente, Premera Blue Cross, AstraZeneca, Genentech, GlaxoSmithKline, JohnsonJohnson, Merck, National Pharmaceutical Council, Prime Therapeutics, Sanofi, Spark Therapeutics, Health Care Service Corporation, Editas, Alnylam, Regeneron, Mallinkrodt, Biogen, HealthPartners, and Novartis. Synnott, Kumar, Adair, Rind, and Pearson are employees of ICER, which provided grants to the University of California, San Francisco, and the University of Colorado to perform work for these analyses. Tice and Walsh are employed by the University of California, San Francisco, and Campbell and Whittington are employed by the University of Colorado.

Moderate-to-severe atopic dermatitis can be difficult and costly to treat. The long-term health and economic outcomes of a new therapy, dupilumab, have yet to be evaluated. We aimed to identify the cost-effectiveness of dupilumab compared to usual care in moderate-to-severe atopic dermatitis.We compared dupilumab to usual care with emollients for adults with moderate-to-severe atopic dermatitis inadequately controlled with topical therapy, or for whom topical therapies were medically inadvisable. Subpopulations of moderate and severe patients were examined separately. We used a lifetime Markov model from a US payer perspective with health states categorized by the percent decrease in Eczema Area and Severity Index (EASI) score after a patient began an intervention: at least a 50% decrease (EASI 50), 75% decrease (EASI 75), 90% decrease (EASI 90), or no response.The expected lifetime cost for patients treated with dupilumab was $509,600, including $267,800 in dupilumab drug costs and $241,800 in other healthcare costs. Average lifetime cost for usual care was $271,500. Dupilumab provided an additional 1.91 quality-adjusted life years (QALYs) over the remaining lifetime of a patient, leading to an incremental cost-effectiveness ratio (ICER) of $124,500. The ICER was lower for patients with severe atopic dermatitis ($95,800) than those with moderate atopic dermatitis ($160,000). Key drivers of the model were utility values for quality-of-life for non-responders, and the price of dupilumab.This study was limited by data for health outcomes and costs over long time periods, particularly stratified by severity. We estimated that dupilumab improved health outcomes compared to usual care but with additional costs, with an ICER below commonly cited thresholds for cost-effectiveness. Dupilumab was projected to be more cost-effective in patients with severe atopic dermatitis, but even in patients with moderate atopic dermatitis, the ICER remained below the upper range of commonly cited thresholds. J Drugs Dermatol. 2018;17(7):750-756.

IntroductionUpToDate 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.ObjectivesOur objective was to document the strength of recommendations in UpToDate and assess the frequency and appropriateness of discordant recommendations.DesignAnalytical survey of all recommendations in UpToDate.MethodsWe 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.ResultsUpToDate 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.ConclusionThe 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.