Angiotensin receptor blockers and β blockers in Marfan syndrome: an individual patient data meta-analysis of randomised trials

Angiotensin receptor blockers; Marfan syndromeBloquejadors dels receptors d'angiotensina; Síndrome de MarfanBloqueadores de los receptores de angiotensina; Síndrome de MarfanBackground Angiotensin receptor blockers (ARBs) and β blockers are widely used in the treatment of Marfan syndrome to try to reduce the rate of progressive aortic root enlargement characteristic of this condition, but their separate and joint effects are uncertain. We aimed to determine these effects in a collaborative individual patient data meta-analysis of randomised trials of these treatments. Methods In this meta-analysis, we identified relevant trials of patients with Marfan syndrome by systematically searching MEDLINE, Embase, and CENTRAL from database inception to Nov 2, 2021. Trials were eligible if they involved a randomised comparison of an ARB versus control or an ARB versus β blocker. We used individual patient data from patients with no prior aortic surgery to estimate the effects of: ARB versus control (placebo or open control); ARB versus β blocker; and indirectly, β blocker versus control. The primary endpoint was the annual rate of change of body surface area-adjusted aortic root dimension Z score, measured at the sinuses of Valsalva. Findings We identified ten potentially eligible trials including 1836 patients from our search, from which seven trials and 1442 patients were eligible for inclusion in our main analyses. Four trials involving 676 eligible participants compared ARB with control. During a median follow-up of 3 years, allocation to ARB approximately halved the annual rate of change in the aortic root Z score (mean annual increase 0·07 [SE 0·02] ARB vs 0·13 [SE 0·02] control; absolute difference –0·07 [95% CI –0·12 to –0·01]; p=0·012). Prespecified secondary subgroup analyses showed that the effects of ARB were particularly large in those with pathogenic variants in fibrillin-1, compared with those without such variants (heterogeneity p=0·0050), and there was no evidence to suggest that the effect of ARB varied with β-blocker use (heterogeneity p=0·54). Three trials involving 766 eligible participants compared ARBs with β blockers. During a median follow-up of 3 years, the annual change in the aortic root Z score was similar in the two groups (annual increase –0·08 [SE 0·03] in ARB groups vs –0·11 [SE 0·02] in β-blocker groups; absolute difference 0·03 [95% CI –0·05 to 0·10]; p=0·48). Thus, indirectly, the difference in the annual change in the aortic root Z score between β blockers and control was –0·09 (95% CI –0·18 to 0·00; p=0·042). Interpretation In people with Marfan syndrome and no previous aortic surgery, ARBs reduced the rate of increase of the aortic root Z score by about one half, including among those taking a β blocker. The effects of β blockers were similar to those of ARBs. Assuming additivity, combination therapy with both ARBs and β blockers from the time of diagnosis would provide even greater reductions in the rate of aortic enlargement than either treatment alone, which, if maintained over a number of years, would be expected to lead to a delay in the need for aortic surgery.Marfan Foundation, the Oxford British Heart Foundation Centre for Research Excellence, and the UK Medical Research Council

New ozone-nitrogen model shows early senescence onset is the primary cause of ozone-induced reduction in grain quality of wheat

Ozone (O3) air pollution is well known to adversely affect both the grain and protein yield of wheat, an important staple crop. This study aims to identify and model the key plant processes influencing the effect of O3 on wheat protein. We modified the DO3SE-Crop model to incorporate nitrogen (N) processes, and parameterised the O3 effect on stem, leaf and grain N using O3 fumigation datasets spanning 3 years and 4 O3 treatments. Our results show the new model captures the O3 effect on grain N concentrations, and anthesis leaf and stem concentration, well. However, the O3 effect on harvest leaf and stem N is exaggerated. Further, a sensitivity analysis revealed that, irrespective of O3 treatment, accelerated senescence onset was the primary plant process affecting grain N. This modelling study therefore demonstrates the capability of the DO3SE-CropN model to simulate processes by which O3 affects N content, and thereby determines that senescence onset is the main driver of O3 reductions in grain protein yield. The implication of the sensitivity analysis is that breeders should focus their efforts on stay-green cultivars that do not experience a protein penalty when developing O3 tolerant lines, to maintain both wheat yield and nutritional quality under O3 exposure

New Insights into Leaf Physiological Responses to Ozone for Use in Crop Modelling

Estimating food production under future air pollution and climate conditions in scenario analysis depends on accurately modelling ozone (O₃) effects on yield. This study tests several assumptions that form part of published approaches for modelling O₃ effects on photosynthesis and leaf duration against experimental data. In 2015 and 2016, two wheat cultivars were exposed in eight hemispherical glasshouses to O₃ ranging from 22 to 57 ppb (24 h mean), with profiles ranging from raised background to high peak treatments. The stomatal O₃ flux (Phytotoxic Ozone Dose, POD) to leaves was simulated using a multiplicative stomatal conductance model. Leaf senescence occurred earlier as average POD increased according to a linear relationship, and the two cultivars showed very different senescence responses. Negative effects of O₃ on photosynthesis were only observed alongside O₃-induced leaf senescence, suggesting that O₃ does not impair photosynthesis in un-senesced flag leaves at the realistic O₃ concentrations applied here. Accelerated senescence is therefore likely to be the dominant O₃ effect influencing yield in most agricultural environments. POD was better than 24 h mean concentration and AOT40 (accumulated O₃ exceeding 40 ppb, daylight hours) at predicting physiological response to O₃, and flux also accounted for the difference in exposure resulting from peak and high background treatments

Combined impacts of climate and air pollution on human health and agricultural productivity

Climate change and air pollution can interact to amplify risks to human health and crop production. This has significant implications for our ability to reach the Sustainable Development Goals (e.g. SDGs 2, 3, 13, 15) and for the design of effective mitigation and adaptation policies and risk management. To be able to achieve the SDG targets, closer integration of climate change and air pollution both in terms of impact assessment for human health and agricultural productivity and respective policy development is needed. Currently, studies estimating the impacts of climate and air pollutants on human health and crops mostly treat these stressors separately, and the methods used by the health and agricultural science communities differ. Better insights into the methods applied in the different communities can help to improve existing and develop new methods to advance our knowledge about the combined impacts of climate change and air pollution on human health and crops. This topical review provides an overview of current methodologies applied in the two fields of human health and agricultural crop impact studies, ranging from empirical regression-based and experimental methods to more complex process-based models. The latter are reasonably well developed for estimating impacts on agricultural crops, but not for health impacts. We review available literature addressing the combined effects of climate and air pollution on human health or agricultural productivity to provide insights regarding state-of-the-art knowledge and currently available methods in the two fields. Challenges to assess the combined effect of climate and air pollution on human health and crops, and opportunities for both fields to learn from each other, are discussed

Global Air Quality and Health Co-benefits of Mitigating Near-Term Climate Change through Methane and Black Carbon Emission Controls

Background: Tropospheric ozone and black carbon (BC), a component of fine particulate matter (PM ≤ 2.5 µm in aerodynamic diameter; PM:2.5), are associated with premature mortality and they disrupt global and regional climate. Objectives: We examined the air quality and health benefits of 14 specific emission control measures targeting BC and methane, an ozone precursor, that were selected because of their potential to reduce the rate of climate change over the next 20–40 years.: Methods: We simulated the impacts of mitigation measures on outdoor concentrations of PM2.5 and ozone using two composition-climate models, and calculated associated changes in premature PM2.5- and ozone-related deaths using epidemiologically derived concentration–response functions. Results: We estimated that, for PM:2.5 and ozone, respectively, fully implementing these measures could reduce global population-weighted average surface concentrations by 23–34% and 7–17% and avoid 0.6–4.4 and 0.04–0.52 million annual premature deaths globally in 2030. More than 80% of the health benefits are estimated to occur in Asia. We estimated that BC mitigation measures would achieve approximately 98% of the deaths that would be avoided if all BC and methane mitigation measures were implemented, due to reduced BC and associated reductions of nonmethane ozone precursor and organic carbon emissions as well as stronger mortality relationships for PM2.5 relative to ozone. Although subject to large uncertainty, these estimates and conclusions are not strongly dependent on assumptions for the concentration–response function. Conclusions: In addition to climate benefits, our findings indicate that the methane and BC emission control measures would have substantial co-benefits for air quality and public health worldwide, potentially reversing trends of increasing air pollution concentrations and mortality in Africa and South, West, and Central Asia. These projected benefits are independent of carbon dioxide mitigation measures. Benefits of BC measures are underestimated because we did not account for benefits from reduced indoor exposures and because outdoor exposure estimates were limited by model spatial resolution.