Tree mortality submodels drive simulated long-term forest dynamics: assessing 15 models from the stand to global scale

Models are pivotal for assessing future forest dynamics under the impacts of changing climate and management practices, incorporating representations of tree growth, mortality, and regeneration. Quantitative studies on the importance of mortality submodels are scarce. We evaluated 15 dynamic vegetation models (DVMs) regarding their sensitivity to different formulations of tree mortality under different degrees of climate change. The set of models comprised eight DVMs at the stand scale, three at the landscape scale, and four typically applied at the continental to global scale. Some incorporate empirically derived mortality models, and others are based on experimental data, whereas still others are based on theoretical reasoning. Each DVM was run with at least two alternative mortality submodels. Model behavior was evaluated against empirical time series data, and then, the models were subjected to different scenarios of climate change. Most DVMs matched empirical data quite well, irrespective of the mortality submodel that was used. However, mortality submodels that performed in a very similar manner against past data often led to sharply different trajectories of forest dynamics under future climate change. Most DVMs featured high sensitivity to the mortality submodel, with deviations of basal area and stem numbers on the order of 10–40% per century under current climate and 20–170% under climate change. The sensitivity of a given DVM to scenarios of climate change, however, was typically lower by a factor of two to three. We conclude that (1) mortality is one of the most uncertain processes when it comes to assessing forest response to climate change, and (2) more data and a better process understanding of tree mortality are needed to improve the robustness of simulated future forest dynamics. Our study highlights that comparing several alternative mortality formulations in DVMs provides valuable insights into the effects of process uncertainties on simulated future forest dynamics

More than additive effects on liver triglyceride accumulation by combinations of steatotic and non-steatotic pesticides in HepaRG cells

The liver is constantly exposed to mixtures of hepatotoxic compounds, such as food contaminants and pesticides. Dose addition is regularly assumed for mixtures in risk assessment, which however might not be sufficiently protective in case of synergistic effects. Especially the prediction of combination effects of substances which do not share a common adverse outcome (AO) might be problematic. In this study, the focus was on the endpoint liver triglyceride accumulation in vitro, an indicator of hepatic fatty acid changes. The hepatotoxic compounds difenoconazole, propiconazole and tebuconazole were chosen which cause hepatic fatty acid changes in vivo, whereas fludioxonil was chosen as a hepatotoxic substance not causing fatty acid changes. Triglyceride accumulation was analyzed for combinations of steatotic and non-steatotic pesticides in human HepaRG hepatocarcinoma cells. Investigations revealed a potentiation of triglyceride accumulation by mixtures of the steatotic compounds with the non-steatotic fludioxonil, as compared to the single compounds. Mathematical modeling of combination effects indicated more than additive effects for the tested combinations if the method by Chou was applied, and a decrease in E

Efficacy and Safety of Vedolizumab in Ulcerative Colitis and Crohn’s Disease Patients Stratified by Age

Introduction: The efficacy and safety of vedolizumab, a gut-selective α4β7 integrin antibody, were demonstrated in the GEMINI 1 and GEMINI 2 clinical trials of adults aged 18–80 years. We investigated the efficacy and safety of vedolizumab in patients stratified by age from the GEMINI trials. Methods: Safety and efficacy, including clinical response, clinical remission, and corticosteroid-free remission, at week 6 and/or 52 were determined post hoc in patients aged <35, 35 to <55, and ≥55 years. Results: At baseline, 353, 412, and 130 ulcerative colitis (UC) and 582, 443, and 90 Crohn’s disease (CD) patients were aged <35, 35 to <55, and ≥55. Of these patients, 56 were aged ≥65 years (UC: 33, CD: 23). Trends favoring vedolizumab over placebo were observed for most efficacy endpoints irrespective of patient age; some variability between subgroups was observed. Safety profiles of vedolizumab and placebo were similar in all age groups. Vedolizumab-treated patients aged ≥55 had the lowest incidence of serious infections (0.9 per 100 person–years) and adverse events leading to hospitalization (14.8 per 100 person–years). There were no age-related differences in the incidence of adverse hematological events, malignancy, or death. Conclusions: The safety and efficacy of vedolizumab in patients with UC or CD were similar for all age groups. The number of patients in the oldest age group in these analyses was small; thus further studies of vedolizumab in larger cohorts of elderly patients are warranted. Funding Millennium Pharmaceuticals, Inc. (d/b/a Takeda Pharmaceuticals International Co.). Electronic supplementary material The online version of this article (doi:10.1007/s12325-016-0467-6) contains supplementary material, which is available to authorized users

Vedolizumab as Induction and Maintenance Therapy for Crohn's Disease in Patients Naive to or Who Have Failed Tumor Necrosis Factor Antagonist Therapy

BACKGROUND: Vedolizumab is a gut-selective α4β7 integrin antagonist for the treatment of moderately to severely active Crohn's disease (CD). Aims of this study were to characterize the efficacy and safety of vedolizumab induction and maintenance therapy in patients who were naïve to tumor necrosis factor-alpha (TNF-α) antagonist therapy (TNF-naïve) or who had discontinued TNF-α antagonist therapy because of inadequate response (i.e., primary nonresponse), loss of response, or intolerance (collectively classified as the TNF-failure population). METHODS: Post hoc analyses of the efficacy data for 516 TNF-naïve and 960 TNF-failure patients from the GEMINI 2 and GEMINI 3 trials were evaluated at weeks 6, 10, and 52 and included clinical remission (CD Activity Index [CDAI] score ≤150), enhanced clinical response (≥100-point decrease from baseline in CDAI score), durable clinical remission (remission at ≥80% of visits), and corticosteroid-free remission. Adverse events were summarized for the TNF-naïve and TNF-failure subgroups by treatment received. RESULTS: Among patients who responded to vedolizumab induction at week 6, 48.9% of TNF-naïve and 27.7% of TNF-failure patients were in remission with vedolizumab at week 52 (versus 26.8% and 12.8% with placebo). Clinical efficacy was similar between the different types of TNF-α antagonist failure or the number of prior TNF-α antagonists failed. Safety profiles were similar in both subpopulations. CONCLUSIONS: Vedolizumab had increased efficacy over placebo in CD patients irrespective of TNF-α antagonist treatment history. Overall, rates of response and remission were numerically higher in patients receiving vedolizumab as a first biologic than in patients who had experienced TNF failure.status: publishe

An eight-compound mixture but not corresponding concentrations of individual chemicals induces triglyceride accumulation in human liver cells

Lichtenstein D, Lasch A, Alarcan J, et al. An eight-compound mixture but not corresponding concentrations of individual chemicals induces triglyceride accumulation in human liver cells. Toxicology. 2021;459: 152857.In real life, organisms are exposed to complex mixtures of chemicals at low concentration levels, whereas research on toxicological effects is mostly focused on single compounds at comparably high doses. Mixture effects deviating from the assumption of additivity, especially synergistic effects, are of concern. In an adverse outcome pathway (AOP)-guided manner, we analyzed the accumulation of triglycerides in human HepaRG liver cells by a mixture of eight steatotic chemicals (amiodarone, benzoic acid, cyproconazole, flusilazole, imazalil, prochloraz, propiconazole and tebuconazole), each present below its individual effect concentration at 1-3 mu M. Pronounced and significantly enhanced triglyceride accumulation was observed with the mixture, and similar effects were seen at the level of pregnane-X-receptor activation, a molecular initiating event leading to hepatic steatosis. Transcript pattern analysis indicated subtle pro-steatotic changes at low compound concentrations, which did not exert measurable effects on cellular triglycerides. Mathematical modeling of mixture effects indicated potentially more than additive behavior using a model for compounds with similar modes of action. The present data underline the usefulness of AOP-guided in vitro testing for the identification of mixture effects and highlight the need for further research on chemical mixtures and harmonization of data interpretation of mixture effects

Combining multiple statistical methods to evaluate the performance of process-based vegetation models across three forest stands

Process-based vegetation models are crucial tools to better understand biosphere-atmosphere exchanges and eco-physiological responses to climate change. In this contribution the performance of two global dynamic vegetation models, i.e. CARAIB and ISBACC, and one stand-scale forest model, i.e. 4C, was compared to long-term observed net ecosystem carbon exchange (NEE) time series from eddy covariance monitoring stations at three old-grown European beech (Fagus sylvatica L.) forest stands. Residual analysis, wavelet analysis and singular spectrum analysis were used beside conventional scalar statistical measures to assess model performance with the aim of defining future targets for model improvement. We found that the most important errors for all three models occurred at the edges of the observed NEE distribution and the model errors were correlated with environmental variables on a daily scale. These observations point to possible projection issues under more extreme future climate conditions. Recurrent patterns in the residuals over the course of the year were linked to the approach to simulate phenology and physiological evolution during leaf development and senescence. Substantial model errors occurred on the multi-annual time scale, possibly caused by the lack of inclusion of management actions and disturbances. Other crucial processes defined were the forest structure and the vertical light partitioning through the canopy. Further, model errors were shown not to be transmitted from one time scale to another. We proved that models should be evaluated across multiple sites, preferably using multiple evaluation methods, to identify processes that request reconsideration

Combining multiple statistical methods to evaluate the performance of process-based vegetation models across three forest stands

Process-based vegetation models are crucial tools to better understand biosphere-atmosphere exchanges and ecophysiological responses to climate change. In this contribution the performance of two global dynamic vegetation models, i.e. CARAIB and ISBACC, and one stand-scale forest model, i.e. 4C, was compared to long-term observed net ecosystem carbon exchange (NEE) time series from eddy covariance monitoring stations at three old-grown European beech (Fagus sylvatica L.) forest stands. Residual analysis, wavelet analysis and singular spectrum analysis were used beside conventional scalar statistical measures to assess model performance with the aim of defining future targets for model improvement. We found that the most important errors for all three models occurred at the edges of the observed NEE distribution and the model errors were correlated with environmental variables on a daily scale. These observations point to possible projection issues under more extreme future climate conditions. Recurrent patterns in the residuals over the course of the year were linked to the approach to simulate phenology and physiological evolution during leaf development and senescence. Substantial model errors occurred on the multi-annual time scale, possibly caused by the lack of inclusion of management actions and disturbances. Other crucial processes defined were the forest structure and the vertical light partitioning through the canopy. Further, model errors were shown not to be transmitted from one time scale to another. We proved that models should be evaluated across multiple sites, preferably using multiple evaluation methods, to identify processes that request reconsideration.MAS

Roadmap for action on Risk Assessment of Combined Exposure to Multiple Chemicals (RACEMiC)

EFSA's aim by 2030, is that the Agency and its partners will be equipped for the routine implementation of human health risk assessment to multiple chemicals, across EFSA's domains of activity. To facilitate this effort, a roadmap for action has been developed by mapping the methods, data and tools that are currently available for mixture risk assessment and identifying current scientific gaps including challenges and blockers. The results shows that extensive methods, data and tools are available for dietary mixture risk assessment for pesticides, but that several scientific gaps still exist for the non-dietary mixture exposure to pesticides. For food additives and for certain contaminants, the regulatory readiness for mixture risk assessment was also found to be fairly high compared to food contact materials and cross-silo mixture risk assessment. The scientific gaps identified were prioritised according to their impact on the implementation of mixture risk assessment and, as a result, ten multi-annual project proposals were defined to address these scientific gaps on the short-term, mid-term and long-term. The roadmap also proposes and prioritises a number of working areas in the regulatory domains of pesticides, food contact materials, contaminants, food additives, as well as in the overarching domain of chemicals. Besides the scientific proposals, recommendations to improve stakeholder engagement and communication on mixture risk assessment was investigated. These included, among others, creating an online catalogue of tools, methods and data for mixture risk assessment, as well as the organisation of regular webinars/workshop to promote exchange of information between stakeholders and making more efficient use of national communication hubs for food safety in communicating with the general public