This Viewpoint examines the appropriateness of FDA accelerated approval of novel gene therapies to treat boys with Duchenne muscular dystrophy following clinical trials with surrogate outcomes that ...did not demonstrate net benefits.
This bi‐polar analysis resolves ice edge changes on space/time scales relevant for investigating seasonal ice‐ocean feedbacks and focuses on spatio‐temporal changes in the timing of annual sea ice ...retreat and advance over 1979/80 to 2010/11. Where Arctic sea ice decrease is fastest, the sea ice retreat is now nearly 2 months earlier and subsequent advance more than 1 month later (compared to 1979/80), resulting in a 3‐month longer summer ice‐free season. In the Antarctic Peninsula and Bellingshausen Sea region, sea ice retreat is more than 1 month earlier and advance 2 months later, resulting in a more than 3‐month longer summer ice‐free season. In contrast, in the western Ross Sea (Antarctica) region, sea ice retreat and advance are more than 1 month later and earlier respectively, resulting in a more than 2 month shorter summer ice‐free season. Regardless of trend magnitude or direction, and at latitudes mostly poleward of 70° (N/S), there is strong correspondence between anomalies in the timings of sea ice retreat and subsequent advance, but little correspondence between advance and subsequent retreat. These results support a strong ocean thermal feedback in autumn in response to changes in spring sea ice retreat. Further, model calculations suggest different net ocean heat changes in the Arctic versus Antarctic where autumn sea ice advance is 1 versus 2 months later. Ocean‐atmosphere changes, particularly in boreal spring and austral autumn (i.e., during ∼March‐May), are discussed and compared, as well as possible inter‐hemispheric climate connections.
Key Points
In some regions the ice‐free season has increased by >3 months over the last 32 years
Anomalies in sea ice retreat & subsequent advance show strong correspondence
Results support a positive atmospheric‐ocean‐ice feedback over summer but not winter
To distinguish between simultaneous natural and anthropogenic impacts on surface temperature, regionally as well as globally, we perform a robust multivariate analysis using the best available ...estimates of each together with the observed surface temperature record from 1889 to 2006. The results enable us to compare, for the first time from observations, the geographical distributions of responses to individual influences consistent with their global impacts. We find a response to solar forcing quite different from that reported in several papers published recently in this journal, and zonally averaged responses to both natural and anthropogenic forcings that differ distinctly from those indicated by the Intergovernmental Panel on Climate Change, whose conclusions depended on model simulations. Anthropogenic warming estimated directly from the historical observations is more pronounced between 45°S and 50°N than at higher latitudes whereas the model‐simulated trends have minimum values in the tropics and increase steadily from 30 to 70°N.
Reliable forecasts of climate change in the immediate future are difficult, especially on regional scales, where natural climate variations may amplify or mitigate anthropogenic warming in ways that ...numerical models capture poorly. By decomposing recent observed surface temperatures into components associated with ENSO, volcanic and solar activity, and anthropogenic influences, we anticipate global and regional changes in the next two decades. From 2009 to 2014, projected rises in anthropogenic influences and solar irradiance will increase global surface temperature 0.15 ± 0.03°C, at a rate 50% greater than predicted by IPCC. But as a result of declining solar activity in the subsequent five years, average temperature in 2019 is only 0.03 ± 0.01°C warmer than in 2014. This lack of overall warming is analogous to the period from 2002 to 2008 when decreasing solar irradiance also countered much of the anthropogenic warming. We further illustrate how a major volcanic eruption and a super ENSO would modify our global and regional temperature projections.
Abstract Objective To clarify the GRADE (grading of recommendations assessment, development and evaluation) definition of certainty of evidence and suggest possible approaches to rating certainty of ...the evidence for systematic reviews, health technology assessments and guidelines. Study Design and Setting This work was carried out by a project group within the GRADE Working Group, through brainstorming and iterative refinement of ideas, using input from workshops, presentations, and discussions at GRADE Working Group meetings to produce this document, which constitutes official GRADE guidance. Results Certainty of evidence is best considered as the certainty that a true effect lies on one side of a specified threshold, or within a chosen range. We define possible approaches for choosing threshold or range. For guidelines, what we call a fully contextualized approach requires simultaneously considering all critical outcomes and their relative value. Less contextualized approaches, more appropriate for systematic reviews and health technology assessments, include using specified ranges of magnitude of effect, e.g. ranges of what we might consider no effect, trivial, small, moderate, or large effects. Conclusion It is desirable for systematic review authors, guideline panelists, and health technology assessors to specify the threshold or ranges they are using when rating the certainty in evidence.
This document updates the American Thoracic Society/European Respiratory Society/Japanese Respiratory Society/Latin American Thoracic Association guideline on idiopathic pulmonary fibrosis treatment.
...Systematic reviews and, when appropriate, meta-analyses were performed to summarize all available evidence pertinent to our questions. The evidence was assessed using the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach and then discussed by a multidisciplinary panel. Predetermined conflict-of-interest management strategies were applied, and recommendations were formulated, written, and graded exclusively by the nonconflicted panelists.
After considering the confidence in effect estimates, the importance of outcomes studied, desirable and undesirable consequences of treatment, cost, feasibility, acceptability of the intervention, and implications to health equity, recommendations were made for or against specific treatment interventions.
The panel formulated and provided the rationale for recommendations in favor of or against treatment interventions for idiopathic pulmonary fibrosis.
Abstract In the GRADE approach, the strength of a recommendation reflects the extent to which we can be confident that the composite desirable effects of a management strategy outweigh the composite ...undesirable effects. This article addresses GRADE's approach to determining the direction and strength of a recommendation. The GRADE describes the balance of desirable and undesirable outcomes of interest among alternative management strategies depending on four domains, namely estimates of effect for desirable and undesirable outcomes of interest, confidence in the estimates of effect, estimates of values and preferences, and resource use. Ultimately, guideline panels must use judgment in integrating these factors to make a strong or weak recommendation for or against an intervention.
Ample physical evidence shows that carbon dioxide (CO₂) is the single most important climate-relevant greenhouse gas in Earth's atmosphere. This is because CO₂, like ozone, N₂O, CH₄, and ...chlorofluorocarbons, does not condense and precipitate from the atmosphere at current climate temperatures, whereas water vapor can and does. Noncondensing greenhouse gases, which account for 25% of the total terrestrial greenhouse effect, thus serve to provide the stable temperature structure that sustains the current levels of atmospheric water vapor and clouds via feedback processes that account for the remaining 75% of the greenhouse effect. Without the radiative forcing supplied by CO₂ and the other noncondensing greenhouse gases, the terrestrial greenhouse would collapse, plunging the global climate into an icebound Earth state.
Abstract GRADE requires guideline developers to make an overall rating of confidence in estimates of effect (quality of evidence—high, moderate, low, or very low) for each important or critical ...outcome. GRADE suggests, for each outcome, the initial separate consideration of five domains of reasons for rating down the confidence in effect estimates, thereby allowing systematic review authors and guideline developers to arrive at an outcome-specific rating of confidence. Although this rating system represents discrete steps on an ordinal scale, it is helpful to view confidence in estimates as a continuum, and the final rating of confidence may differ from that suggested by separate consideration of each domain. An overall rating of confidence in estimates of effect is only relevant in settings when recommendations are being made. In general, it is based on the critical outcome that provides the lowest confidence.
This study aimed to estimate the cost-effectiveness of remdesivir, the first novel therapeutic to receive Emergency Use Authorization for the treatment of hospitalized patients with COVID-19, and ...identify key drivers of value to guide future pricing and reimbursement efforts.
A Markov model evaluated the cost-effectiveness of remdesivir in patients hospitalized with COVID-19 from a US healthcare sector perspective. A lifetime time horizon captured potential long-term costs and outcomes. Model outcomes included discounted total costs, life-years, and quality-adjusted life-years (QALYs). Remdesivir was modeled as an addition to standard of care and compared with standard of care alone, including dexamethasone for patients requiring respiratory support. COVID-19 hospitalizations were assumed to be reimbursed through a single payment based on the respiratory support received alongside a remdesivir carveout payment in the base case. Sensitivity and scenario analyses identified key drivers.
At a unit price of $520 per vial and assuming no survival benefit with remdesivir, the incremental cost-effectiveness was $298 200/QALY for patients with moderate to severe COVID-19 and $1 847 000/QALY for patients with mild COVID-19. Although current data do not support a survival benefit, if one was assumed, the cost-effectiveness estimate was $50 100/QALY for the moderate to severe population and $103 400/QALY for the mild population. Another key driver included the hospitalization payment structure (per diem vs bundled payment).
With the current evidence available, remdesivir’s price is too high to align with its expected health gains for hospitalized patients with COVID-19. Results from this study provide a rationale for iterative health technology assessment.
•The debate on how to assess the value of therapeutics for COVID-19 treatments continues as treatments (eg, remdesivir) gain regulatory approval and progress through clinical trials.•This article suggests the cost-effectiveness of remdesivir for hospitalized patients with COVID-19 and identifies key drivers of value to guide future pricing and reimbursement efforts.•With the current evidence available, remdesivir’s price is too high to align with its expected health gains. Results from this study provide a rationale for iterative health technology assessments in a pandemic.
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