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High-quality, long-term measurements of terrestrial trace gas emissions are important for investigations of atmospheric, geophysical and biological processes to help mitigate climate change and protect the environment and the health of citizens. High-frequency terrestrial fluxes of the radioactive noble gas 222Rn, in particular, are useful for validating radon flux maps and used to evaluate the performance of regional atmospheric models, to improve greenhouse gas emission inventories (by the radon tracer method) and to determine radon priority areas for radiation protection goals. A new automatic radon flux system (Autoflux) was developed as a transfer standard (TS) to assist with establishing a traceability chain for field-based radon flux measurements. The operational characteristics and features of the system were optimized based on a literature review of existing flux measurement systems. To characterize and calibrate Autoflux, a bespoke radon exhalation bed (EB) facility was also constructed with the intended purpose of providing a constant radon exhalation under a specific set of controlled laboratory conditions. The calibrated Autoflux was then used to transfer the derived calibration to a second continuous radon flux system under laboratory conditions; both instruments were then tested in the field and compared with modeled fluxes. This paper presents (i) a literature review of state-of-the-art radon flux systems and EB facilities; (ii) the design, characterization and calibration of a reference radon EB facility; (iii) the design, characterization and calibration of the Autoflux system; (iv) the calibration of a second radon flux system (INTE_Flux) using the EB and Autoflux, with a total uncertainty of 9 % (k = 1) for an average radon flux of ∼ 1800 mBq m−2 s−1 under controlled laboratory conditions; and (v)​​​​​​​ an example application of the calibrated TS and INTE_Flux systems for in situ radon flux measurements, which are then compared with simulated radon fluxes. Calibration of the TS under different environmental conditions and at lower reference fluxes will be the subject of a separate future investigation.

The Ebro River Delta, in the northwestern Mediterranean basin, has an extension of 320 km2 and is mainly covered by rice fields. Rice fields are known to be one of the main sources of anthropogenic methane emissions, and a better estimation of its temporal variability in relation to the different rice cultivation phases is important to help with the implementation of emission reduction strategies (Àgueda et al., 2017),In the framework of the ClimaDat network, an atmospheric station was installed in the middle of the Ebro Delta in 2012. A Picarro G2301 for greenhouse gases (GHG) atmospheric concentrations and an ARMON (Atmospheric Radon Monitor) for atmospheric 222Rn concentrations were collocated among other instruments. Nocturnal hourly atmospheric observations of CH4 and 222Rn measured between 2013 and 2019 were used to apply the Radon Tracer Method (RTM) for retrieving CH4 fluxes over the footprint area.The Ebro River Delta has a reduced dimension and a complex meteorological regime highly influenced by the Ebro channelled winds and the sea breezes, making it difficult to calculate GHG fluxes using global or regional inversion models. However, the use of high-resolution backtrajectories (model WRF-Flexpart) coupled with the traceRadon daily radon flux maps for Europe (Karsten et al., 2022), with a resolution of 0.05 degrees, has allowed the use of the RTM in this complex area.Methane fluxes estimated by RTM were compared with fluxes directly measured with chambers in past studies (Martínez-Eixarch et al., 2018) and with data obtained by the EDGAR inventory (Crippa et al., 2022). Results show a promising agreement between methane fluxes obtained with different methods, and a variability clearly governed by the rice crop cycle which is not reflected in the methane emissions values reported in EDGAR inventories.ReferencesÀgueda, A., Grossi, C., Pastor, E., Rioja, E., Sánchez-García, L., Batet, Ò., Curcoll, R., Ealo, M., Nofuentes, M., Occhipinti, P., Rodó, X. and Morguí, J.-A.: Temporal and spatial variability of ground level atmospheric methane concentrations in the Ebro River Delta, Atmos. Pollut. Res., 8(4), 741–753, doi:10.1016/j.apr.2017.01.009, 2017.Crippa, M., Guizzardi, D., Banja, M., Solazzo, E., Muntean, M., Schaaf, E., Pagani, F., Monforti-Ferrario, F., Olivier, J., Quadrelli, R., Risquez Martin, A., Taghavi-Moharamli, P., Grassi, G., Rossi, S., Jacome Felix Oom, D., Branco, A., San-Miguel-Ayanz, J. and Vignati, E., CO2 emissions of all world countries - 2022 Report, EUR 31182 EN, Publications Office of the European Union, Luxembourg, 2022, doi:10.2760/730164, JRC130363Karstens, U., Levin, I. (2022). traceRadon monthly radon flux map for Europe 2006-2022 (based on ERA5-Land soil moisture), Miscellaneous, https://hdl.handle.net/11676/XPxf8v5gfDWmi6BZ597euAJ7Martínez-Eixarch, M., Alcaraz, C., Viñas, M., Noguerol, J., Aranda, X., Prenafeta-Boldu, F. X., Saldaña-De la Vega, J. A., del Mar Catala, M. and Ibáñez, C.: Neglecting the fallow season can significantly underestimate annual methane emissions in Mediterranean rice fields, PLoS One, 13(5), doi:10.1371/journal.pone.0198081, 2018.

The noble and radioactive gas radon is well known to be the most important source of public exposure to natural environmental radioactivity in indoor environments (workplaces, homes, etc.). Consequently, it is important to identify radon-prone areas, where radon fluxes are high, and also to develop and apply mitigation measures when radon activity concentrations of indoor areas exceed guideline values.However, radon is also known by the climate and atmospheric research communities to be a useful environmental tracer and it is nowadays being used in several studies such as the improvement of atmospheric transport models or the indirect estimation of GHG fluxes by the Radon Tracer Method. These previous applications will benefit from the availability of radon flux maps.Stakeholders and scientists involved in radiation protection and climate analysis may benefit from reliable continuous radon flux measurements to validate and improve existing and future radon flux maps. In the framework of the project traceRadon (EMPIR reference 19ENV01) a full metrology chain has been designed and built for radon flux measurements.The work and the challenges related to this type of measurement will be presented here together with possible guidelines for carrying out continuous radon flux measurements in the field.

Soil CO2 emissions are one of the largest contributions to the global carbon cycle, and a full understanding of processes generating them and how climate change may modify them is needed and still uncertain. Thus, a dense spatial and temporal network of CO2 flux measurements from soil could help reduce uncertainty in the global carbon budgets. In the present study, the design, assembly, and calibration of low-cost air enquirer kits, including CO2 and environmental parameters sensors, is presented. Different types of calibrations for the CO2 sensors and their associated errors are calculated. In addition, for the first time, this type of sensor has been applied to design, develop, and test a new steady-state through-flow (SS-TF) chamber for simultaneous measurements of CO2 fluxes in soil and CO2 concentrations in air. The sensors' responses were corrected for temperature, relative humidity, and pressure conditions in order to reduce the uncertainty in the measured CO2 values and of the following calculated CO2 fluxes based on SS-TF. CO2 soil fluxes measured by the proposed SS-TF and by a standard closed non-steady-state non-through-flow (NSS-NTF) chamber were briefly compared to ensure the reliability of the results. The use of a multiparametric fitting reduced the total uncertainty of the CO2 concentration measurements by 62 %, compared with the uncertainty that occurred when a simple CO2 calibration was applied, and by 90 %, when compared to the uncertainty declared by the manufacturer. The new SS-TF system allows the continuous measurement of CO2 fluxes and CO2 ambient air with low cost (EUR ∼1200), low energy demand (

Beta-2 Glycoprotein I (β2-GPI) is the main target of anti-phospholipid antibodies (aPL) in the autoimmune anti-phospholipid syndrome, characterized by increased risk of stroke. We here investigated the antibody independent role of β2-GPI after ischemia/reperfusion, modeled in vivo by transient middle cerebral artery occlusion (tMCAo) in male C57Bl/6J mice; in vitro by subjecting immortalized human brain microvascular endothelial cells (ihBMEC) to 16 h hypoxia and 4 h re-oxygenation. ApoH (coding for β2-GPI) was upregulated selectively in the liver at 48 h after tMCAo. At the same time β2-GPI circulating levels increased. β2-GPI was detectable in brain parenchyma and endothelium at all time points after tMCAo. Parenchymal β2-GPI recognized apoptotic neurons (positive for annexin V, C3 and TUNEL) cleared by CD68+ brain macrophages. Hypoxic ihBMEC showed increased release of IL-6, over-expression of thrombomodulin and IL-1α after re-oxygenation with β2-GPI alone. β2-GPI interacted with mannose-binding lectin in mouse plasma and ihBMEC medium, potentially involved in formation of thrombi. We show for the first time that brain ischemia triggers the hepatic production of β2-GPI. β2-GPI is present in the ischemic endothelium, enhancing vascular inflammation, and extravasates binding stressed neurons before their clearance by phagocytosis. Thus β2-GPI may be a new mediator of brain injury following ischemic stroke.

In the framework of the EMPIR project 19ENV01 traceRadon(1) [1] stable atmospheres with low-level, activity concentrations of radon have to be produced for the calibration of radon detectors [2] capable of measuring the outdoor air activity concentration. The traceable calibration of these detectors at very low activity concentrations is of special interest, for the radiation protection community, as well as the climate observation community. Because radiation protection networks (like the EUropean Radiological Data Exchange Platform (EURDEP)) and climate observation networks (like the Integrated Carbon Observation System (ICOS)) need reliable, accurate radon activity concentration measurements, either for identification of Radon Priority Areas (RPA), for false alarm prevention or to apply the Radon Tracer Method (RTM) for the estimation of greenhouse gas (GHG) emissions.Radon gas is the largest source of public exposure to naturally occurring radioactivity, and concentration maps based on atmospheric measurements aid developers to comply with EU Safety Standard Regulations. Radon can also be used as a tracer to evaluate dispersal models important for supporting successful greenhouse gas (GHG) mitigation strategies. One of the recently most applied technique for this propose is the Radon Tracer Method (RTM). To reduce the uncertainty of both radiation protection measurements and those used for GHG modelling, traceability to SI units for radon exhalation rate from soil, its concentration in the atmosphere and validated models for its dispersal are needed. The project traceRadon started in 2020 to provide the necessary measurement infrastructure [3,4]. This is particularly important for GHG emission estimates that support national reporting under the Paris Agreement on climate change.As there is an overlapping need between the climate research and radiation protection communities for improved traceability at low-level outdoor radon and radon flux measurements the project traceRadon works on this aspect for the benefit of two large scientific communities. The results at midterm of the project are presented.[1] Röttger, A. et al: New metrology for radon at the environmental level 2021 Meas. Sci. Technol. 32, 124008, https://doi.org/10.1088/1361-6501/ac298d[2] Radulescu, I et al.: Inter-comparison of commercial continuous radon monitors responses, Nuclear Instruments and Methods in Physics Research Section A, Volume 1021, 2022, 165927, https://doi.org/10.1016/j.nima.2021.165927[3] Mertes, F et. al.: Approximate sequential Bayesian filtering to estimate Rn-222 emanation from Ra-226 sources from spectra, https://doi.org/10.5162/SMSI2021/D3.3[4] Mertes, F. et. al.: Ion implantation of 226Ra for a primary 222Rn emanation standard, Applied Radiation and Isotopes, Volume 181, March 2022, 110093, https://doi.org/10.1016/j.apradiso.2021.110093 (1) This project has received funding from the EMPIR programme co-financed by the Participating States and from the European Union's Horizon 2020 research and innovation programme. 19ENV01 traceRadon denotes the EMPIR project reference

Radon (222Rn) gas is the largest source of public exposure to naturally occurring radioactivity and the identification of radon priority areas is required by the Council Directive 2013/59/Euratom. Radon is also used as a tracer to improve atmospheric transport models and to indirectly estimate greenhouse gas (GHG) fluxes using the Radon Tracer Method (RTM). This method is based on the correlation between atmospheric concentrations of radon and GHG, together with information on the radon flux data. For radiological data, all European countries have installed networks of automatic gamma dose rate monitoring stations and report the real-time information gathered to the European Radiological Data Exchange Platform (EURDEP). So far, atmospheric radon activity concentrations and radon fluxes are not yet reported in EURDEP, nor routinely measured within the European radiological networks although these observations could help to avoid false positives results. Due to above applications, there is a need of building a metrological chain to ensure high quality radon activity concentrations and radon flux measurements. Both climate and radiation protection research communities underline the need for improved traceability in low-level atmospheric radon measurements (Khanbabaee et al., 2021). The EMPIR project 19ENV01 traceRadon1 is aimed towards providing the necessary measurement infrastructure and transfer standards to fulfil this need. Results of this project are particularly important for improving independent GHG emission estimates that support national reporting under the Paris Agreement on climate change and for the Council Directive 2013/59/Euratom, thus benefitting two large scientific communities. In this paper, early results, such as new activity standard developments and an overview of commercial and research radon monitors are presented and discussed. These results will feed into the traceRadon project with respect to radionuclide metrology in air and its potential for the improvement of the RTM.

The use of the noble gas radon ( 222Rn ) as a tracer for different research studies, for example observation-based estimation of greenhouse gas (GHG) fluxes, has led to the need of high-quality 222Rn activity concentration observations with high spatial and temporal resolution. So far a robust metrology chain for these measurements is not yet available. A portable direct atmospheric radon monitor (ARMON), based on electrostatic collection of 218Po , is now running at Spanish stations. This monitor has not yet been compared with other 222Rn and 222Rn progeny monitors commonly used at atmospheric stations. A 3-month intercomparison campaign of atmospheric 222Rn and 222Rn progeny monitors based on different measurement techniques was realized during the fall and winter of 2016–2017 to evaluate (i) calibration and correction factors between monitors necessary to harmonize the atmospheric radon observations and (ii) the dependence of each monitor's response in relation to the sampling height and meteorological and atmospheric aerosol conditions. Results of this study have shown the following. (i) All monitors were able to reproduce the atmospheric radon variability on a daily basis. (ii) Linear regression fits between the monitors exhibited slopes, representing the correction factors, between 0.62 and 1.17 and offsets ranging between −0.85 and −0.23 Bq m −3 when sampling 2 m above ground level (a.g.l.). Corresponding results at 100 m a.g.l. exhibited slopes of 0.94 and 1.03 with offsets of −0.13 and 0.01 Bq m −3 , respectively. (iii) No influence of atmospheric temperature and relative humidity on monitor responses was observed for unsaturated conditions at 100 m a.g.l., whereas slight influences (order of 10−2 ) of ambient temperature were observed at 2 m a.g.l. (iv) Changes in the ratio between 222Rn progeny and 222Rn monitor responses were observed under very low atmospheric aerosol concentrations. Results also show that the new ARMON could be useful at atmospheric radon monitoring stations with space restrictions or as a mobile reference instrument to calibrate in situ 222Rn progeny monitors and fixed radon monitors. In the near future a long-term comparison study between ARMON, HRM, and ANSTO monitors would be useful to better evaluate (i) the uncertainties of radon measurements in the range of a few hundred millibecquerels per cubic meter to a few becquerels per cubic meter and (ii) the response time correction of the ANSTO monitor for representing fast changes in the ambient radon concentrations.

International audience; An international intercomparison of continuous monitors measuring radon activity concentration was performed to validate the traceability of the European radon calibration facilities. It was carried out by comparison of the secondary standards, used by these previous facilities, in the range from 100 Bq·m-3 to 300 Bq·m-3. Secondary standards were individually compared to a secondary reference device previously calibrated in a reference radon atmosphere traceable to a primary standard. The intercomparison was organized by the National Institute for Nuclear, Chemical, and Biological Protection (SUJCHBO) in the period from October 2019 to April 2020 within the European Metrology Program for In-novation and Research (EMPIR), JRP-Contract 16ENV10 MetroRADON. Eight European laboratories participated in this study. The results of the experiment are presented and discussed.

Interlaboratory exercises are a good tool to compare the response of different systems to the same quantity and to identify possible inconsistencies between them. One of the main goals of the EMPIR 19ENV01 traceRadon project is to harmonize radon flux measurements based on different systems and methodologies. In the framework of the traceRadon Project, two radon flux intercomparison campaigns were carried out in October 2021 at high and at low radon source areas. Four institutions participated in the field intercomparison exercises with their own systems. Every system was based on a specific radon monitor (diffusion or pump mode) and an accumulation chamber (with manual or automatic opening). Radon fluxes were calculated by each participant using both exponential and linear fittings of the radon activity concentration measured over time within the accumulation chambers. The results of this study show mainly: (i) the exponential approach is not advisable due to the variability of the radon flux and the leakage of the systems during long-time measurements; (ii) the linear approach should be applied to minimize the measurement period in agreement with the time response and sensitivity of the monitors; (iii) radon flux measured at high radon source areas (radium content of about 800 Bq kg-¹) risks being underestimated because of the influence of dvective effects; (iv) radon flux measured at low radon source areas (radium content of about 30 Bq kg-¹) may present large uncertainties if sensitive radon monitors with pump mode are not used. Funding: This project 19ENV01 traceRadon has received funding from the EMPIR programme co-financed by the Participating States and from the European Union’s Horizon 2020 research and innovation programme. 19ENV01 traceRadon denotes the EMPIR project reference.

Indoor and outdoor (atmospheric) radon activity concentrations need to be measured as accurate as possible for radiation protection and for climate applications. Particularly radon concentrations below 100 Bq ⋅ m−3, useful for the retrieval of radon prone areas and for atmospheric studies, still need a robust metrological chain to ensure their quality. Ones of the most common used commercial continuous radon monitors were compared here under slightly different environmental conditions. The measured data set were divided into two groups ( ⋅ m−3 and ≥ 100 Bq ⋅ m−3) to assess the monitors responses and their associated uncertainties. Nevertheless, these results should also to point out if commercial monitors are suitable for monitoring low atmospheric radon concentrations with an associated uncertainty of 10% (k=1). This work, carried out within the EMPIR 19ENV01 traceRadon project, aims to offer a starting point for the development of a future radon monitor as transfer standard to increase the metrological capabilities of atmospheric radon monitoring.

Soil CO2 emissions are one of the largest contributions to the global carbon cycle, and a full understanding of processes generating them and how climate change may modify them is needed and still uncertain. Thus, a dense spatial and temporal network of CO2 flux measurements from soil could help reduce uncertainty in the global carbon budgets. In the present study, low cost Air Enquirer kits, including CO2 and environmental parameters sensors, have been designed, built and applied for the first time to design, develop and test a new Steady-State-Through-Flow (SS-TF) chamber for simultaneous measurements of CO2 fluxes in soil and CO2 concentrations in air. Sensor's responses were previously corrected for temperature, relative humidity, illumination and pressure conditions in order to reduce the uncertainty of measured CO2 values and of the following calculated CO2 fluxes. CO2 soil fluxes measured by the proposed SS-TF and by a standard closed Non-Steady-State-Non-Through-Flow (NSS-NTF) chamber were shortly compared. The use of a multi-parametric fitting reduced the total uncertainty of CO2 concentration measurements by 62 % compared with one where only a simple CO2 calibration was applied, and by a 90 % when compared to uncertainty declared by the manufacturer. The new SS-TF system allows continuous measurement of CO2 fluxes and CO2 ambient air with low cost (~1.2 k€), low energy demand (< 5 W) and low maintenance (twice per year due to sensor calibration requirements).

International audience; Radon gas is the largest source of public exposure to naturally occurring radioactivity. However, radon is also a useful tracer for understanding atmospheric processes, assessing the accuracy of chemical transport models, and enabling integrated emissions estimates of greenhouse gases. A sound metrological system for low level atmospheric radon observations is therefore needed for the benefit of the atmospheric, climate and radiation protection research communities. To this end, here we present a new calibration method for activity concentrations below 20 Bq m−3 and a prototype of the first portable radon monitor capable of achieving uncertainties of 5% (at k = 2) at these concentrations. Compliance checking of policy-driven regulations regarding greenhouse gas (GHG) emissions is an essential component of climate change mitigation efforts. Independent, reliable 'top down' methods that can be applied consistently for estimating local- to regional-scale GHG emissions (such as the radon tracer method (RTM)) are an essential part of this process. The RTM relies upon observed radon and GHG concentrations and measured or modeled radon fluxes. Reliable radon flux maps could also significantly aid EU member states comply with European COUNCIL DIRECTIVE 2013/59/EURATOM. This article also introduces the traceRadon project, key aims of which include outlining a standardized approach for application of the RTM, creating infrastructure with a traceability chain for radon concentration and radon flux measurements, and developing tools for the validation of radon flux models. Since radon progeny dominate the terrestrial gamma dose rate, the planned traceRadon activities are also expected to improve the sensitivity of radiation protection early warning networks because of the correlation known to exist between radon flux and ambient equivalent dose rates.

Radon gas is the largest source of public exposure to naturally occurring radioactivity, and concentration maps based on atmospheric measurements aid developers to comply with EU Safety Standard Regulations. Atmospheric radon can also be used as a tracer to evaluate transport models important for supporting successful greenhouse gas (GHG) mitigation strategies. One of the most common techniques currently applied for this propose is the Radon Tracer Method (RTM). To increase the accuracy of both radiation protection measurements and those used for GHG modelling, traceability to SI units for radon exhalation rates from soil, its concentration in the atmosphere and validated models for its dispersal are needed. Thus, atmospheric networks such as the Integrated Carbon Observation System (ICOS) are interested in integrating atmospheric radon concentration measurements. The EMPIR project 19ENV01 traceRadon[1] started to provide the necessary measurement infrastructure for atmospheric radon activity concentration and radon flux measurements, with benefits for both large scientific communities. This is particularly important for GHG emission estimates that support national reporting under the Paris Agreement on climate change.Compared to the large spatiotemporal heterogeneity of GHG fluxes, radon is emitted almost homogeneously over ice-free land and has a negligible flux from oceans. Atmospheric measurements of radon activity concentrations can be used for the assessment and improvement of atmospheric mixing and transport models.Similarly, for radiological data, all European countries have installed networks of automatic gamma dose rate and atmospheric concentration level monitoring stations and report the information gathered to the European Radiological Data Exchange Platform (EURDEP). Currently, EURDEP exchanges real-time monitoring information from 39 countries collected from more than 5500 automatic surveillance systems. Therefore, improving contamination detection requires greater accuracy in determining environmental radon concentrations and their movement in the atmosphere.An overlapping need exists between the climate research and radiation protection communities for improved traceable low-level outdoor radon measurements, combining the challenges of collating and modelling large datasets, with setting up new radiation protection services. The project traceRadon works on this aspect for the benefit of two large scientific communities. An overview will be presented, and first results with respect to radionuclide metrology will be discussed. [1] This project has received funding from the EMPIR programme co-financed by the Participating States and from the European Union's Horizon 2020 research and innovation programme. 19ENV01 traceRadon denotes the EMPIR project reference.

The natural radioactive noble gas radon (222Rn) is originated from the decay of radium into the soil and then continuously exhaled to the lower atmosphere. Its diffusion and exhalation rate depend both on the physical and environmental conditions of the soil layers and on the meteorological conditions. With a half-life of 3.8 days and a very limited chemical activity, the 222Rn is nowadays being used as an atmospheric tracer for: i) the improvement of atmospheric transport models used, among others, to identify greenhouse gas (GHG) emission sources; ii) for the indirect estimation of GHG fluxes by the Radon Tracer Method (RTM). These previous applications need high sensitivity and precision at low radon concentrations range (< 100 Bq m-3).A new monitor, based on alpha spectrometry of 218Po electrostatically collected on a PIPs detector, has been designed and developed at the Institute of Energy Technologies (INTE) of the Universitat Politecnica de Catlunya (UPC) in the mark of the project ‘High efficiency monitor of atmospheric radon concentration for radiation protection and environmental applications (MARE2EA), reference: 2019-LLAV-00035, funded by the Catalan Agency for Management of University and Research Grants. The aim is building an instrument able to measure atmospheric radon concentration activities with high precision in order to be running at GHG atmospheric networks for the RTM applications.The monitor is an improved version of a previous prototype instrument (Grossi et al., 2012, 2020). The new instrument will allow a higher efficiency, robustness and portability. In addition, it will have a GUI interface to be user friendly. Finally, in order to reduce the air sample humidity within the detection volume of the instrument which affects the 218Po collection, a portable drying system has also been built to keep the instrument ongoing without maintenance during several weeks. ReferencesGrossi, C., Arnold, D., Adame, J. A., López-Coto, I., Bolívar, J. P., De La Morena, B. A., & Vargas, A. (2012). Atmospheric 222Rn concentration and source term at El Arenosillo 100 m meteorological tower in southwest Spain. Radiation Measurements, 47(2), 149–162. https://doi.org/10.1016/j.radmeas.2011.11.006Grossi, C., Chambers, S. D., Llido, O., Vogel, F. R., Kazan, V., Capuana, A., Werczynski, S., Curcoll, R., Delmotte, M., Vargas, A., Morguí, J.-A., Levin, I., & Ramonet, M. (2020). Intercomparison study of atmospheric 222Rn and 222Rn progeny monitors. Atmospheric Measurement Techniques, 13(5). https://doi.org/10.5194/amt-13-2241-2020

Background Animal models and few clinical reports suggest the involvement of the complement system in the onset of severe manifestations of coronavirus disease-2019 (COVID-19). However, complement contribution to endotheliopathy and hypercoagulability has not been elucidated yet. Objective To evaluate the association among complement activation, endothelial damage and disease severity or activity in COVID-19 patients. Methods In this single-centre cohort study, 148 patients with COVID-19 of different severity were evaluated upon hospital admission and 30 days later. Markers of complement activation (SC5b-9 and C5a) and endothelial perturbation (von Willebrand factor [vWF], tissue-type plasminogen activator [t-PA], plasminogen activator inhibitor-1 [PAI-1], soluble thrombomodulin [sTM], and soluble endothelial selectin [sE-selectin]) were measured in plasma. Results The patients had high plasma levels of SC5b-9 and C5a (p = 0.0001 for both) and vWF, t-PA and PAI-1 (p = 0.0001 for all). Their SC5b-9 levels correlated with those of vWF (r = 0.517, p = 0.0001) and paralleled disease severity (severe vs mild p = 0.0001, severe vs moderate p = 0.026 and moderate vs mild p = 0.001). The levels of sE-selectin were significantly increased only in the patients with severe disease. After 30 days, plasma SC5b-9, C5a and vWF levels had significantly decreased (p = 0.0001 for all), and 43% of the evaluated patients had normal levels. Conclusions Complement activation is boosted during the progression of COVID-19 and dampened during remission, thus indicating its role in the pathophysiology of the disease. The association between complement activation and the biomarkers of endothelial damage suggests that complement may contribute to tissue injury and could be the target of specific therapy.

An interlaboratory comparison for European radon calibration facilities was conducted to evaluate the establishment of a harmonized quality level for the activity concentration of radon in air and to demonstrate the performance of the facilities when calibrating measurement instruments for radon. Fifteen calibration facilities from 13 different European countries participated. They represented different levels in the metrological hierarchy: national metrology institutes and designated institutes, national authorities for radiation protection and participants from universities. The interlaboratory comparison was conducted by the German Federal Office for Radiation Protection (BfS) and took place from 2018 to 2020. Participants were requested to measure radon in atmospheres of their own facilities according to their own procedures and requirements for metrological traceability. A measurement device with suitable properties was used to determine the comparison values. The results of the comparison showed that the radon activity concentrations that were determined by European calibration facilities complying with metrological traceability requirements were consistent with each other and had common mean values. The deviations from these values were normally distributed. The range of variation of the common mean value was a measure of the degree of agreement between the participants. For exposures above 1000 Bq/m3, the variation was about 4% for a level of confidence of approximately 95% (k=2). For lower exposure levels, the variation increased to about 6%.

β2-Glycoprotein I (β2-GPI) is an abundant plasma glycoprotein with unknown physiological function and is currently recognized as the main target of antiphospholipid Abs responsible for complement activation and vascular thrombosis in patients with antiphospholipid syndrome (APS). In this study, we provide evidence that mannose-binding lectin (MBL) binds to β2-GPI in Ca++ and a dose-dependent manner and that this interaction activates complement and promotes complement-dependent thrombin generation. Surprisingly, a significant binding was observed between MBL and isolated domains II and IV of β2-GPI, whereas the carbohydrate chains, domain I and domain V, were not involved in the interaction, documenting a noncanonical binding mode between MBL and β2-GPI. Importantly, this interaction may occur on endothelial cells because binding of MBL to β2-GPI was detected on the surface of HUVECs, and colocalization of MBL with β2-GPI was observed on the endothelium of a biopsy specimen of a femoral artery from an APS patient. Because β2-GPI–mediated MBL-dependent thrombin generation was increased after priming the endothelium with TNF-α, our data suggests that this mechanism could play an important yet unrecognized role under physiological conditions and may be upregulated in pathological situations. Moreover, the complement activation and the procoagulant effects of the β2-GPI/MBL complex may contribute to amplify similar activities of anti–β2-GPI Abs in APS and possibly act independently of Abs, raising the issue of developing appropriate therapies to avoid recurrences and disability in patients at risk for these clinical conditions.

A layer of phosphogypsum was placed at the bottom of two large volume boxes. This system allowed to measure the surface radon exhalation from phosphogypsum without altering the emitting material. The limits and optimal setup of the closed-circuit accumulation chamber technique were thoroughly studied. More precisely, the performance of different radon exhalation fitting methods was analyzed in the reference exhalation boxes, employing different measurement devices and three smaller operational accumulation chambers. As expected, the best approach to obtain the radon exhalation rate depends upon the effective decay constant of the measurement system and the time employed to perform the measurement. The time until the linear approximation can no longer be applied was scrutinized. Although this approximation is usually applied routinely in the literature, the effective time constant of the chamber is often not low enough for the linear fit to be applied safely, providing statistically acceptable measurements that can lead to significative underestimations of the radon exhalation rate.

Up to 40% of patients treated with tumor necrosis factor alpha inhibitors (TNFi) do not respond to therapy. Testing drug bioavailability and/or anti-drug antibody (ADAb) levels may justify dosage adjustment or switch to different drugs, enabling a personalized medicine approach. We report a multicenter cross-sectional study on different methods [ELISA and a cell based functional assay (reporter gene assay – RGA)] for drug/ADAb detection, and on the relationship between drug bioavailability and ADAb. 163 patients with rheumatoid arthritis (RA) treated with infliximab (IFX; n = 67), adalimumab (ADL; n = 49) or etanercept (ETA; n = 47) were tested for drug and ADAb levels. Furthermore, we report prospective data from additional 70 patients (59 RA and 11 juvenile idiopathic arthritis - JIA) tested for drug and ADAb levels at baseline (T0) and after 3 (T3) and 6 months (T6) of treatment with ADL or ETA only. IFX-treated patients were not included because of the increasing use of IFX biosimilars. Stringent inclusion criteria were used in order to avoid unwanted variables in both studies; none of the patients used TNFi before the study, and TNFi was used only in combination with methotrexate. Clinical response was defined according to EULAR response criteria. The two assays performed comparably in the comparison study. Accordingly, ELISA was selected for the prospective study because of its feasibility in the clinical setting. The cross-sectional study found ADAb in IFX and ADL treated groups only, that were associated with a decrease in pharmacological drug availability in the blood. Comparable results were found for the ADL-treated group in the prospective study which also showed a relationship between drug/ADAb levels and the loss of clinical response. Altogether our findings support drug and anti-drug Ab monitoring in the real-world clinical setting thus enabling individualized treatment and reducing disability in chronic inflammatory arthritis.

Clinical studies have reported different diagnostic/predictive values of antibodies to domain 1 or 4/5 of β2glycoproteinI in terms of risk of thrombosis and pregnancy complications in patients with antiphospholipid syndrome. To obtain direct evidence for the pathogenic role of anti-domain 1 or anti-domain 4/5 antibodies, we analyzed the in vivo pro-coagulant effect of two groups of 5 sera IgG each reacting selectively with domain 1 or domain 5 in lipopolysaccharide (LPS)-treated rats. Antibody-induced thrombus formation in mesenteric vessels was followed by intravital microscopy, and vascular deposition of β2glycoproteinI, human IgG and C3 was analyzed by immunofluorescence. Five serum IgG with undetectable anti-β2glycoproteinI antibodies served as controls. All the anti-domain 1-positive IgG exhibited potent pro-coagulant activity while the anti-domain 5-positive and the negative control IgG failed to promote blood clot and vessel occlusion. A stronger granular deposit of IgG/C3 was found on the mesenteric endothelium of rats treated with anti-domain 1 antibodies, as opposed to a mild linear IgG staining and absence of C3 observed in rats receiving anti-domain 5 antibodies. Purified anti-domain 5 IgG, unlike anti-domain 1 IgG, did not recognize cardiolipin-bound β2glycoproteinI while being able to interact with fluid-phase β2glycoproteinI. These findings may explain the failure of anti-domain 5 antibodies to exhibit a thrombogenic effect in vivo, and the interaction of these antibodies with circulating β2glycoproteinI suggests their potential competitive role with the pro-coagulant activity of anti-domain 1 antibodies. These data aim at better defining “really at risk” patients for more appropriate treatments to avoid recurrences and disability.

Antibodies against β2 glycoprotein I (anti-β2GPI) have been identified as the main pathogenic autoantibody subset in anti-phospholipid syndrome (APS); the most relevant epitope is a cryptic and conformation-dependent structure on β2GPI domain (D) 1. Anti-β2GPI domain profiling has been investigated in thrombotic APS, leading to the identification of antibodies targeting D1 as the main subpopulation. In contrast, scarce attention has been paid to obstetric APS, hence this study aimed at characterizing the domain reactivity with regards to pregnancy morbidity (PM). To this end, 135 women with persistently positive, medium/high titre anti-β2GPI IgG, without any associated systemic autoimmune diseases and at least one previous pregnancy were included: 27 asymptomatic carriers; 53 women with obstetric APS; 20 women with thrombotic APS; and 35 women with both thrombotic and obstetric complications. Anti-D1 and anti-D4/5 antibodies were tested using a chemiluminescent immunoassay and a research ELISA assay, respectively (QUANTA Flash® β2GPI Domain 1 IgG and QUANTA Lite® β2GPI D4/5 IgG, Inova Diagnostics). Positivity for anti-D1 antibodies, but not anti-D4/5 antibodies, was differently distributed across the 4 subgroups of patients (p As a whole, our data suggest that anti-D1 antibodies are significantly associated not only with thrombosis, but also with late PM, while positive anti-D4/5 antibodies are not predictive of thrombosis or PM.

The ClimaDat station at Gredos (GIC3) has been continuously measuring atmospheric (dry air) mixing ratios of carbon dioxide (CO2) and methane (CH4), as well as meteorological parameters, since November 2012. In this study we investigate the atmospheric variability of CH4 mixing ratios between 2013 and 2015 at GIC3 with the help of co-located observations of 222Rn concentrations, modelled 222Rn fluxes and modelled planetary boundary layer heights (PBLHs). Both daily and seasonal changes in atmospheric CH4 can be better understood with the help of atmospheric concentrations of 222Rn (and the corresponding fluxes). On a daily timescale, the variation in the PBLH is the main driver for 222Rn and CH4 variability while, on monthly timescales, their atmospheric variability seems to depend on emission changes. To understand (changing) CH4 emissions, nocturnal fluxes of CH4 were estimated using two methods: the radon tracer method (RTM) and a method based on the EDGARv4.2 bottom-up emission inventory, both using FLEXPARTv9.0.2 footprints. The mean value of RTM-based methane fluxes (FR_CH4) is 0.11 mg CH4 m−2 h−1 with a standard deviation of 0.09 or 0.29 mg CH4 m−2 h−1 with a standard deviation of 0.23 mg CH4 m−2 h−1 when using a rescaled 222Rn map (FR_CH4_rescale). For our observational period, the mean value of methane fluxes based on the bottom-up inventory (FE_CH4) is 0.33 mg CH4 m−2 h−1 with a standard deviation of 0.08 mg CH4 m−2 h−1. Monthly CH4 fluxes based on RTM (both FR_CH4 and FR_CH4_rescale) show a seasonality which is not observed for monthly FE_CH4 fluxes. During January–May, RTM-based CH4 fluxes present mean values 25 % lower than during June–December. This seasonal increase in methane fluxes calculated by RTM for the GIC3 area appears to coincide with the arrival of transhumant livestock at GIC3 in the second half of the year.

Retrospective studies reported a high incidence of maternal complications in pregnant women with lupus. In this paper we prospectively assessed the rate of risk and the risk factors of maternal outcome in women with stable lupus nephritis who received pre-pregnancy counseling. This prospective multicenter study includes 71 pregnancies in 61 women with lupus nephritis who became pregnant between 2006 and 2013. Complete renal remission was present before pregnancy in 56 cases (78.9%) and mild active nephritis in 15 cases. All women underwent a screening visit before pregnancy and were closely monitored by a multidisciplinary team. Lupus anticoagulant, serum C3 and C4 complement fractions, anti-DNA antibodies, anti-C1q antibodies, anticardiolipin IgG and IgM antibodies, anti-beta2 IgG and IgM antibodies were tested at screening visit, at first, second, third trimester of pregnancy, and one year after delivery. Renal flares of lupus during or after pregnancy, pre-eclampsia, and HELLP syndrome were defined as adverse maternal outcomes. Fourteen flares (19.7%), six cases of pre-eclampsia (8.4%) and two cases of HELLP (2.8%) occurred during the study period. All flares responded to therapy and the manifestations of pre-eclampsia and HELLP were promptly reversible. Low C3, high anti-DNA antibodies and predicted all renal flares. High anti-C1q antibodies and low C4 predicted early flares. The body mass index (BMI) was associated with increased risk of late flares. History of previous renal flares and the presence of clinically active lupus nephritis at conception did not increase the risk of renal flares during pregnancy. History of renal flares before pregnancy, arterial hypertension, and longer disease predicted pre-eclampsia/HELLP. In pregnant women with lupus nephritis adverse maternal outcomes were relatively common but proved to be reversible when promptly diagnosed and treated. Immunological activity, arterial hypertension and BMI may predispose to maternal complications.

Recurrent thrombosis and miscarriages are the main clinical manifestations of antiphospholipid syndrome (APS). Although most patients display both clinical signs, some patients can have isolated vascular or obstetric variants. Emerging data raise the question of whether obstetric and vascular APS are the same or different diseases. An important difference between the two conditions is that a thrombophilic state is a common feature in vascular APS, whereas clot occlusions of the decidual spiral arteries are seldom observed in obstetric APS, and infarctions are found in only one-third of APS placentae. Conversely, inflammation, which is undetectable in vascular APS, is frequently observed in the placentae of patients with obstetric APS and has been documented in the placentae of pregnant mice with fetal loss mediated by antiphospholipid antibodies. Attempts to identify different antibodies or epitopes responsible for the two clinical manifestations of APS have so far been unsuccessful. Possible mechanisms exist that might explain the development of the two clinical presentations, including the tissue distribution and expression level of the main target antigen of antiphospholipid antibodies, β2 glycoprotein I (β2GPI). The identification of the factors that promote the onset of either obstetric or vascular APS has important diagnostic and therapeutic implications.

Antiphospholipid antibodies (aPL) cause vascular thrombosis (VT) and/or pregnancy morbidity (PM). Differential mechanisms however, underlying the pathogenesis of these different manifestations of antiphospholipid syndrome (APS) are not fully understood. Therefore, we compared the effects of aPL from patients with thrombotic or obstetric APS on monocytes to identify different molecular pathways involved in the pathogenesis of APS subtypes. VT or PM IgG induced similar numbers of differentially expressed (DE) genes in monocytes. However, gene ontology (GO) analysis of DE genes revealed disease-specific genome signatures. Compared to PM, VT-IgG showed specific up regulation of genes associated with cell response to stress, regulation of MAPK signalling pathway and cell communication. In contrast, PM-IgG regulated genes involved in cell adhesion, extracellular matrix and embryonic and skeletal development. A novel gene expression analysis based on differential variability (DV) was also applied. This analysis identified similar GO categories compared to DE analysis but also uncovered novel pathways modulated solely by PM or VT-IgG. Gene expression analysis distinguished a differential effect of VT or PM-IgG upon monocytes supporting the hypothesis that they trigger distinctive physiological mechanisms. This finding contributes to our understanding of the pathology of APS and may lead to the development of different targeted therapies for VT or PM APS., Highlights • Gene expression analysis distinguished a differential effect of VT or PM IgG upon monocytes. • VT and PM trigger the expression of distinctive molecular pathways with functional relevance to these APS subtypes. • These pivotal findings could enable the design of therapies targeted to the pathogenesis of different APS subtypes.

Este artículo contiene 12 páginas, 1 tabla, 5 figuras., In order to improve the understanding of the carbon cycle in the Pyrenean region, two atmospheric monitoring mountain stations were set up within the Long-Term Ecological Research node of Aigüestortes i Estany de Sant Maurici at Central Pyrenees, Spain. The atmospheric concentration of carbon dioxide (CO2) was measured over 2008–2014 and 2010–2014 at Estany Llong (ELL) site and Centre de Recerca d’Alta Muntanya (CRAM), respectively. Measurements were carried out fortnightly off-line with high precision instrumentation at ELL and every minute online with a lower precision sensor at CRAM in conjunction with meteorological variables. The two datasets were analyzed in this study, quantifying whenever possible annual growth rates (AGR), seasonal variability, and diurnal amplitudes. Results were also compared with the NOAA Marine Boundary Layer (MBL) reference product and CO2 data from other background monitoring stations. Four-harmonics adjusted CO2 data from ELL showed a high correlation with the NOAA MBL reference product for the same latitude (Spearman’s rho ρ = 0.96). In addition, AGRs of CO2 at ELL correlated well with those observed at Mace Head (MHD) station (ρ = 0.94), suggesting that ELL can be considered a background station. Winter CRAM CO2 data was not statistically different from ELL data, while in summer, it was 5.5 ppm lower on average, suggesting a higher photosynthesis uptake. The amplitude of the CO2 diurnal cycle at CRAM was found to be exponentially related to the local mean daily temperature and dependent on forthcoming wind sector (N-NW or E-SE-S-SW).An increase in CRAM CO2 concentrations was observed under N-NW winds during daytime, which could be related to traffic emissions. This study demonstrates that the use of CO2 sensors with low precision but continuously corrected and periodically calibrated can be used for the study of local and regional CO2 sources and sinks., This work has been mainly funded by own resources of the LAO-Climadat Lab at IC3 and by the Fluxpyr project (POCTEFA Program EFA 34/08 - Interreg IV-A). Data is available through virtual access provided and funded in the frame of eLTER H2020 - European Long-Term Ecosystem and Socio-Ecological Research Infrastructure (EC project GA: 654359; INFRAIA; 2015– 2019).

BACKGROUND Hereditary spherocytosis (HS) is a congenital hemolytic anemia caused by defects in red blood cell (RBC) membrane proteins leading to premature RBC clearance in the spleen. The presence of RBC autoantibodies has never been extensively investigated in HS. STUDY DESIGN AND METHODS RBC antibody–bound immunoglobulin (Ig)G was investigated in 91 consecutive HS patients by mitogen-stimulated direct antiglobulin test (MS-DAT), a sensitive method able to magnify latent RBC antibody autoimmunity and related with hemolytic variables, previous splenectomy, and type of membrane defect. RESULTS A total of 61% of HS cases had RBC antibodies by MS-DAT (29 Band 3, 17 spectrin deficiency, and nine no defined defect). The amount of RBC-bound IgG was greater in HS compared with controls (236 ± 192 ng/mL vs. 52 ± 29 ng/mL, p

The thrombogenic effect of β2-glycoprotein I (β2GPI)-dependent anti-phospholipid antibodies (aPL) in animal models was found to be LPS dependent. Since β2GPI behaves as LPS scavenger, LPS/β2GPI complex was suggested to account for in vitro cell activation through LPS/TLR4 involvement being LPS the actual bridge ligand between β2GPI and TLR4 at least in monocytes/macrophages. However, no definite information is available on the interaction among β2GPI, LPS and endothelial TLR4 in spite of the main role of endothelial cells (EC) in clotting. To analyse at the endothelial level the need of LPS, we investigated the in vitro interaction of β2GPI with endothelial TLR4 and we assessed the role of LPS in such an interaction. To do this, we evaluated the direct binding and internalization of β2GPI by confocal microscopy in living TLR4-MD2 transfected CHO cells (CHO/TLR4-MD2) and β2GPI binding to CHO/TLR4-MD2 cells and human umbilical cord vein EC (HUVEC) by flow cytometry and cell-ELISA using anti-β2GPI monoclonal antibodies in the absence or presence of various concentrations of exogenous LPS. To further investigate the role of TLR4, we performed anti-β2GPI antibody binding and adhesion molecule up-regulation in TLR4-silenced HUVEC. Confocal microscopy studies show that β2GPI does interact with TLR4 at the cell membrane and is internalized in cytoplasmic granules in CHO/TLR4-MD2 cells. β2GPI binding to CHO/TLR4-MD2 cells and HUVEC is also confirmed by flow cytometry and cell-ELISA, respectively. The interaction between β2GPI and TLR4 is confirmed by the reduction of anti-β2GPI antibody binding and by the up-regulation of E-selectin or ICAM-1 by TLR4 silencing in HUVEC. β2GPI binding is not affected by LPS at concentrations comparable to those found in both β2GPI and antibody preparations. Only higher amount of LPS that can activate EC and up-regulate TLR4 expression are found to increase the binding. Our findings demonstrate that β2GPI interacts directly with TLR4 expressed on EC, and that such interaction may contribute to β2GPI-dependent aPL-mediated EC activation. At variance of monocytic cells, we also showed a threshold effect for the action of LPS, that is able to enhance anti-β2GPI antibody EC binding only at cell activating concentrations, shown to increase TLR4 expression. This in vitro model may explain why LPS behaves as a second hit increasing the expression of β2GPI in vascular tissues and triggering aPL-mediated thrombosis in experimental animals.

Atmospheric concentrations of the two main greenhouse gases (GHGs), carbon dioxide (CO 2 ) and methane (CH 4 ), are continuously measured since November 2012 at the Spanish rural station of Gredos (GIC3), within the climate network ClimaDat, together with atmospheric radon ( 222 Rn) tracer and meteorological parameters. The atmospheric variability of CH 4 concentrations measured from 2013 to 2015 at GIC3 has been analyzed in this study. It is interpreted in relation to the variability of measured 222 Rn concentrations, modelled 222 Rn fluxes and modelled heights of the planetary boundary layer (PBLH) in the same period. In addition, nocturnal fluxes of CH 4 were estimated using two methods: the Radon Tracer Method (RTM) and one based on the EDGARv4.2 bottom-up emission inventory. Both previous methods have been applied using the same footprints, calculated with the atmospheric transport model FLEXPARTv6.2. Results show that daily and seasonal changes in atmospheric concentrations of 222 Rn (and the corresponding fluxes) can help to understand the atmospheric CH 4 variability. On daily basis, the variation in the PBLH mainly drives changes in 222 Rn and CH 4 concentrations while, on monthly basis, their atmospheric variability seems to depend on changes in their emissions. The median value of RTM based methane fluxes (FR_CH 4 ) is 0.17 mg CH 4 m −2 h −1 with an absolute deviation of 0.08 mg CH 4 m −2 h −1 . Median methane fluxes based on bottom-up inventory (FE_CH 4 ) is of 0.32 mg CH 4 m −2 h −1 with an absolute deviation of 0.06 mg CH 4 m −2 h −1 . Monthly FR_CH 4 flux shows a seasonality which is not observed in the monthly FE_CH 4 flux. During January–May FR_CH 4 fluxes present a median value of 0.08 mg CH 4 m −2 h −1 with an absolute deviation of 0.05 mg CH 4 m −2 h −1 and a median value of 0.19 mg CH 4 m −2 h −1 with an absolute deviation of 0.06 mg CH 4 m −2 h −1 during June–December. This seasonal doubling of the median methane fluxes calculated by RTM at the GIC3 area seems to be mainly related to the alternate presence of transhumant livestock in the GIC3 area. The results obtained in this study highlight the benefit of applying independent RTM to improve the seasonality of the emission factors from bottom-up inventories.

Centenarians are rare and exceptional individuals characterized by a peculiar phenotype. They are the best example of healthy aging in humans as most of them have escaped or substantially delayed the onset of major age-related diseases. Within this scenario, the purpose of the present work was to understand if immune status is associated with survival and health status in centenarians. To this aim, 116 centenarians were concomitantly characterized for their immunological, health and functional status, and followed-up for five-year survival. On the basis of previous knowledge we focused on a core of fundamental and basic immune parameters (number of leukocytes, monocytes, total lymphocytes, CD3(+) T lymphocytes, CD4(+) helper T lymphocytes, CD8(+) cytotoxic T lymphocytes, CD19(+) B lymphocytes and plasma levels of IgM), and the most important findings can be summarized as follows: i. a hierarchical cluster analysis was able to define Cluster1 (88 centenarians) and Cluster2 (28 centenarians) characterized by low and high values of all these immune parameters, respectively; ii. centenarians of Cluster2 showed a statistically longer five-year survival and more favorable values of other important immune (naïve, activated/memory and effector/memory T cells) and metabolic (glycemia, insulin and HOMA-IR) parameters, in accord with previous observations that centenarians have a peculiar immune profile, a preserved insulin pathway and a lower incidence of type 2 diabetes; and iii. unexpectedly, parameters related to frailty, as well as functional and cognitive status, did not show any significant correlation with the immune clustering, despite being capable per se of predicting survival. In conclusion, high values of basic immunological parameters and important T cell subsets correlate with five-year survival in centenarians, independent of other phenotypic characteristics. This unexpected biological scenario is compatible with the general hypothesis that in centenarians a progressive disconnection and loss of biological coherence among the different functions of the body occur, where survival/mortality result from the failure of any of these domains which apparently follow an independent age-related trajectory.

The variability of the atmospheric concentration of the 7Be and 210Pb radionuclides is strongly linked to the origin of air masses, the strength of their sources and the processes of wet and dry deposition. It has been shown how these processes and their variability are strongly affected by climate change. Thus, a deeper knowledge of the relationship between the atmospheric radionuclides variability measured close to the ground and these atmospheric processes could help in the analysis of climate scenarios. In the present study, we analyze the atmospheric variability of a 14-year time series of 7Be and 210Pb in a Mediterranean coastal city using a synergy of different indicators and tools such as: the local meteorological conditions, global and regional climate indexes and a lagrangian atmospheric transport model. We particularly focus on the relationships between the main pathways of air masses and sun spots occurrence, the variability of the local relative humidity and temperature conditions, and the main modes of regional climate variability, such as the North Atlantic Oscillation (NAO) and the Western Mediterranean Oscillation (WeMO). The variability of the observed atmospheric concentrations of both 7Be and 210Pb radionuclides was found to be mainly positively associated to the local climate conditions of temperature and to the pathways of air masses arriving at the station. Measured radionuclide concentrations significantly increase when air masses travel at low tropospheric levels from central Europe and the western part of the Iberian Peninsula, while low concentrations are associated with westerly air masses. We found a significant negative correlation between the WeMO index and the atmospheric variability of both radionuclides and no significant association was observed for the NAO index.