Evaluating the performance of a climate-driven mortality model during heat waves and cold spells in Europe.

The impact of climate change on human health is a serious concern. In particular, changes in the frequency and intensity of heat waves and cold spells are of high relevance in terms of mortality and morbidity. This demonstrates the urgent need for reliable early-warning systems to help authorities prepare and respond to emergency situations. In this study, we evaluate the performance of a climate-driven mortality model to provide probabilistic predictions of exceeding emergency mortality thresholds for heat wave and cold spell scenarios. Daily mortality data corresponding to 187 NUTS2 regions across 16 countries in Europe were obtained from 1998-2003. Data were aggregated to 54 larger regions in Europe, defined according to similarities in population structure and climate. Location-specific average mortality rates, at given temperature intervals over the time period, were modelled to account for the increased mortality observed during both high and low temperature extremes and differing comfort temperatures between regions. Model parameters were estimated in a Bayesian framework, in order to generate probabilistic simulations of mortality across Europe for time periods of interest. For the heat wave scenario (1-15 August 2003), the model was successfully able to anticipate the occurrence or non-occurrence of mortality rates exceeding the emergency threshold (75th percentile of the mortality distribution) for 89% of the 54 regions, given a probability decision threshold of 70%. For the cold spell scenario (1-15 January 2003), mortality events in 69% of the regions were correctly anticipated with a probability decision threshold of 70%. By using a more conservative decision threshold of 30%, this proportion increased to 87%. Overall, the model performed better for the heat wave scenario. By replacing observed temperature data in the model with forecast temperature, from state-of-the-art European forecasting systems, probabilistic mortality predictions could potentially be made several months ahead of imminent heat waves and cold spells

Evaluation of an Early-Warning System for Heat Wave-Related Mortality in Europe: Implications for Sub-seasonal to Seasonal Forecasting and Climate Services.

Heat waves have been responsible for more fatalities in Europe over the past decades than any other extreme weather event. However, temperature-related illnesses and deaths are largely preventable. Reliable sub-seasonal-to-seasonal (S2S) climate forecasts of extreme temperatures could allow for better short-to-medium-term resource management within heat-health action plans, to protect vulnerable populations and ensure access to preventive measures well in advance. The objective of this study is to assess the extent to which S2S climate forecasts could be incorporated into heat-health action plans, to support timely public health decision-making ahead of imminent heat wave events in Europe. Forecasts of apparent temperature at different lead times (e.g., 1 day, 4 days, 8 days, up to 3 months) were used in a mortality model to produce probabilistic mortality forecasts up to several months ahead of the 2003 heat wave event in Europe. Results were compared to mortality predictions, inferred using observed apparent temperature data in the mortality model. In general, we found a decreasing transition in skill between excellent predictions when using observed temperature, to predictions with no skill when using forecast temperature with lead times greater than one week. However, even at lead-times up to three months, there were some regions in Spain and the United Kingdom where excess mortality was detected with some certainty. This suggests that in some areas of Europe, there is potential for S2S climate forecasts to be incorporated in localised heat-health action plans. In general, these results show that the performance of this climate service framework is not limited by the mortality model itself, but rather by the predictability of the climate variables, at S2S time scales, over Europe

Olfactory Stem Cells, a New Cellular Model for Studying Molecular Mechanisms Underlying Familial Dysautonomia

International audienceBackground: Familial dysautonomia (FD) is a hereditary neuropathy caused by mutations in the IKBKAP gene, the most common of which results in variable tissue-specific mRNA splicing with skipping of exon 20. Defective splicing is especially severe in nervous tissue, leading to incomplete development and progressive degeneration of sensory and autonomic neurons. The specificity of neuron loss in FD is poorly understood due to the lack of an appropriate model system. To better understand and modelize the molecular mechanisms of IKBKAP mRNA splicing, we collected human olfactory ecto-mesenchymal stem cells (hOE-MSC) from FD patients. hOE-MSCs have a pluripotent ability to differentiate into various cell lineages, including neurons and glial cells.Methodology/Principal Findings: We confirmed IKBKAP mRNA alternative splicing in FD hOE-MSCs and identified 2 novel spliced isoforms also present in control cells. We observed a significant lower expression of both IKBKAP transcript and IKAP/hELP1 protein in FD cells resulting from the degradation of the transcript isoform skipping exon 20. We localized IKAP/hELP1 in different cell compartments, including the nucleus, which supports multiple roles for that protein. We also investigated cellular pathways altered in FD, at the genome-wide level, and confirmed that cell migration and cytoskeleton reorganization were among the processes altered in FD. Indeed, FD hOE-MSCs exhibit impaired migration compared to control cells. Moreover, we showed that kinetin improved exon 20 inclusion and restores a normal level of IKAP/hELP1 in FD hOE-MSCs. Furthermore, we were able to modify the IKBKAP splicing ratio in FD hOE-MSCs, increasing or reducing the WT (exon 20 inclusion):MU (exon 20 skipping) ratio respectively, either by producing free-floating spheres, or by inducing cells into neural differentiation.Conclusions/Significance: hOE-MSCs isolated from FD patients represent a new approach for modeling FD to better understand genetic expression and possible therapeutic approaches. This model could also be applied to other neurological genetic diseases

Long-term projections and acclimatization scenarios of temperature-related mortality in Europe

The steady increase in greenhouse gas concentrations is inducing a detectable rise in global temperatures. The sensitivity of human societies to warming temperatures is, however, a transcendental question not comprehensively addressed to date. Here we show the link between temperature, humidity and daily numbers of deaths in nearly 200 European regions, which are subsequently used to infer transient projections of mortality under state-of-the-art high-resolution greenhouse gas scenario simulations. Our analyses point to a change in the seasonality of mortality, with maximum monthly incidence progressively shifting from winter to summer. The results also show that the rise in heat-related mortality will start to completely compensate the reduction of deaths from cold during the second half of the century, amounting to an average drop in human lifespan of up 3-4 months in 2070-2100. Nevertheless, projections suggest that human lifespan might indeed increase if a substantial degree of adaptation to warm temperatures takes place

European seasonal mortality and influenza incidence due to winter temperature variability

International audienceRecent studies have vividly emphasized the lack of consensus on the degree of vulnerability (see ref. 1) of European societies to current and future winter temperatures. Here we consider several climate factors, influenza incidence and daily numbers of deaths to characterize the relationship between winter temperature and mortality in a very large ensemble of European regions representing more than 400 million people. Analyses highlight the strong association between the year-to-year fluctuations in winter mean temperature and mortality, with higher seasonal cases during harsh winters, in all of the countries except the United Kingdom, the Netherlands and Belgium. This spatial distribution contrasts with the well-documented latitudinal orientation of the dependency between daily temperature and mortality within the season. A theoretical framework is proposed to reconcile the apparent contradictions between recent studies, offering an interpretation to regional differences in the vulnerability to daily, seasonal and long-term winter temperature variability. Despite the lack of a strong year-to-year association between winter mean values in some countries, it can be concluded that warmer winters will contribute to the decrease in winter mortality everywhere in Europe

Validation of lipolysis product extraction from aqueous/biological samples, separation and quantification by thin-layer chromatography with flame ionization detection analysis using O-cholesteryl ethylene glycol as a new internal standard

International audienceA general and easily accessible method for the extraction followed by the simultaneous separation and quantitative determination of triacylglycerols, diacylglycerols, monoacylglycerols and free fatty acids has been improved and optimized based on existing protocols using liquid-phase extraction and thin-layer chromatography coupled to flame ionization detection (TLC/FID Iatroscan). After lipid extraction in the presence of a suitable new synthetic internal standard, namely CholE1, a single elution step using n-heptane/diethyl ether/formic acid (55:45:1, v/v/v) was applied. This method was validated in line with international bioanalytical method validation guidelines using two different matrix systems: purified water and human gastro-intestinal fluid. Overall, the assay was found to have high levels of precision with coefficients of variation ranging from 1.48% to 11.0% and accuracy ranging from −13.3% to +5.79% RE. The confidence limits of the lipid mean recovery rates varied between 89.9% and 104%. This method is therefore highly suitable for quantifying the lipolysis products generated in vitro during the hydrolysis of various fats and oils by digestive lipases, as well as those collected from the gastro-intestinal tract in the course of human clinical studies on lipid digestion

Copper-​Catalyzed Synthesis of 1,​3-​Butadienylphosphine Oxides and Chemoselective Phosphoryl Reduction to Stereodefined 1,​3-​Butadienylphosphines

International audienceCopper-​catalyzed C-​P cross-​coupling reactions between diphenylphosphine oxide and various 1-​bromo-​1,​3-​butadienes readily provided a set of functionalized 1,​3-​butadienyldiphenylphosphine oxides. Application of the latter to the synthesis of stereodefined 1,​3-​butadienyldiphenylphosphines was successfully achieved via chemoselective redn. of their phosphoryl moiety

Minimal Elements Required for the Formation of Respiratory Syncytial Virus Cytoplasmic Inclusion Bodies In Vivo and In Vitro

International audienceInfection of host cells by the respiratory syncytial virus (RSV) is characterized by the formation of spherical cytoplasmic inclusion bodies (IBs). These structures, which concentrate all the proteins of the polymerase complex as well as some cellular proteins, were initially considered aggresomes formed by viral dead-end products. However, recent studies revealed that IBs are viral factories where viral RNA synthesis, i.e., replication and transcription, occurs. The analysis of IBs by electron microscopy revealed that they are membrane-less structures, and accumulated data on their structure, organization, and kinetics of formation revealed that IBs share the characteristics of cellular organelles, such as P-bodies or stress granules, suggesting that their morphogenesis depends on a liquid-liquid phase separation mechanism. It was previously shown that expression of the RSV nucleoprotein N and phosphoprotein P of the polymerase complex is sufficient to induce the formation of pseudo-IBs. Here, using a series of truncated P proteins, we identified the domains of P required for IB formation and show that the oligomeric state of N, provided it can interact with RNA, is critical for their morphogenesis. We also show that pseudo-IBs can form in vitro when recombinant N and P proteins are mixed. Finally, using fluorescence recovery after photobleaching approaches, we reveal that in cellula and in vitro IBs are liquid organelles. Our results strongly support the liquid-liquid phase separation nature of IBs and pave the way for further characterization of their dynamics

Seasonality reversal of temperature attributable mortality projections due to previously unobserved extreme heat in Europe

In this Comment, we show for the first time the contribution of previously unobserved extreme heat to the trends and seasonality changes of temperature-attributable mortality (TAM) projections in 147 contiguous regions in 16 European countries.Acknowledgments MQ-Z, HA, DP, and JB gratefully acknowledge funding from the EU's Horizon 2020 research and innovation programme under grant agreement no 865564 (European Research Council Consolidator Grant EARLY-ADAPT). MQ-Z, ÈM-S, DP, and JB gratefully acknowledge funding from the EU's Horizon 2020 research and innovation programme under grant agreement no 727852 (project Blue-Action). HA gratefully acknowledges funding from the Secretariat for Universities and Research of the Ministry of Business and Knowledge of the Government of Catalonia (grant numbers B00391 [FI-2018], B100180 [FI-2019], and B200139 [FI-2020]). JB gratefully acknowledges funding from the EU's Horizon 2020 research and innovation programme under grant agreement no 956396 (project EDIPI), and from the Ministry of Science and Innovation (MCIU) under grant agreements no RYC2018-025446-I (programme Ramón y Cajal) and EUR2019-103822 (project EURO-ADAPT). JR gratefully acknowledges funding from the EU Community Action Program for Public Health (grant agreement no 2005114). ISGlobal acknowledges support from the Spanish Ministry of Science and Innovation through the Centro de Excelencia Severo Ochoa 2019–2023 Program (CEX2018-000806-S) and support from the Generalitat de Catalunya through the CERCA programme. The authors also acknowledge the E-OBS dataset from the EU-FP6 project UERRA and the Copernicus Climate Change Service, and the data providers in the ECA&D project. For their roles in producing, coordinating, and making available the Inter-Sectoral Impact Model Intercomparison Project (ISIMIP) input data and impact model output, the authors acknowledge the modelling groups, the ISIMIP sector coordinators, and the ISIMIP cross-sectoral science team for the health sector