Search

This paper describes a 16-year dataset of air pollution concentrations and air quality indicators over France. Using a kriging method that combines background air quality measurements and modeling with the CHIMERE chemistry transport model, hourly concentrations of NO2, O3, PM10 and PM2.5 are produced with a spatial resolution of about 4 km. Regulatory indicators (annual average, SOMO35 (sum of ozone means over 35 ppb), AOT40 (accumulated ozone exposure over a threshold of 40 ppb), etc.) are also calculated from these hourly data. The NO2 and O3 datasets cover the period 2000–2015, as well as the annual PM10 data. Hourly PM10 concentrations are not available from 2000 to 2007 due to known artifacts in PM10 measurements. PM2.5 data are only available from 2009 onwards due to the limited number of measuring stations available before this date. The overall dataset was evaluated over all years by a cross-validation process against background stations (rural, sub-urban and urban) to take into account the data fusion between measurement and models in the method. The results are very good for PM10, PM2.5 and O3. They show an overestimation of NO2 concentrations in rural areas, while NO2 background values in urban areas are well represented. Maps of the main indicators are presented over several years, and trends are calculated. Finally, exposure and trends are calculated for the three main health-related indicators: annual averages of PM2.5, NO2 and SOMO35. The DOI link for the dataset is https://doi.org/10.5281/zenodo.5043645 (Real et al., 2021). We hope that the publication of this open dataset will facilitate further studies on the impacts of air pollution.

This paper describes the pre-operational analysis and forecasting system developed during MACC (Monitoring Atmospheric Composition and Climate) and continued in the MACC-II (Monitoring Atmospheric Composition and Climate: Interim Implementation) European projects to provide air quality services for the European continent. This system is based on seven state-of-the art models developed and run in Europe (CHIMERE, EMEP, EURAD-IM, LOTOS-EUROS, MATCH, MOCAGE and SILAM). These models are used to calculate multi-model ensemble products. The paper gives an overall picture of its status at the end of MACC-II (summer 2014) and analyses the performance of the multi-model ensemble. The MACC-II system provides daily 96 h forecasts with hourly outputs of 10 chemical species/aerosols (O3, NO2, SO2, CO, PM10, PM2.5, NO, NH3, total NMVOCs (non-methane volatile organic compounds) and PAN+PAN precursors) over eight vertical levels from the surface to 5 km height. The hourly analysis at the surface is done a posteriori for the past day using a selection of representative air quality data from European monitoring stations. The performance of the system is assessed daily, weekly and every 3 months (seasonally) through statistical indicators calculated using the available representative air quality data from European monitoring stations. Results for a case study show the ability of the ensemble median to forecast regional ozone pollution events. The seasonal performances of the individual models and of the multi-model ensemble have been monitored since September 2009 for ozone, NO2 and PM10. The statistical indicators for ozone in summer 2014 show that the ensemble median gives on average the best performances compared to the seven models. There is very little degradation of the scores with the forecast day but there is a marked diurnal cycle, similarly to the individual models, that can be related partly to the prescribed diurnal variations of anthropogenic emissions in the models. During summer 2014, the diurnal ozone maximum is underestimated by the ensemble median by about 4 μg m−3 on average. Locally, during the studied ozone episodes, the maxima from the ensemble median are often lower than observations by 30–50 μg m−3. Overall, ozone scores are generally good with average values for the normalised indicators of 0.14 for the modified normalised mean bias and of 0.30 for the fractional gross error. Tests have also shown that the ensemble median is robust to reduction of ensemble size by one, that is, if predictions are unavailable from one model. Scores are also discussed for PM10 for winter 2013–1014. There is an underestimation of most models leading the ensemble median to a mean bias of −4.5 μg m−3. The ensemble median fractional gross error is larger for PM10 (~ 0.52) than for ozone and the correlation is lower (~ 0.35 for PM10 and ~ 0.54 for ozone). This is related to a larger spread of the seven model scores for PM10 than for ozone linked to different levels of complexity of aerosol representation in the individual models. In parallel, a scientific analysis of the results of the seven models and of the ensemble is also done over the Mediterranean area because of the specificity of its meteorology and emissions. The system is robust in terms of the production availability. Major efforts have been done in MACC-II towards the operationalisation of all its components. Foreseen developments and research for improving its performances are discussed in the conclusion.

Newborn bloodspot screening (NBS) began in the early 1960s based on the work of Dr. Robert “Bob” Guthrie in Buffalo, NY, USA. His development of a screening test for phenylketonuria on blood absorbed onto a special filter paper and transported to a remote testing laboratory began it all. Expansion of NBS to large numbers of asymptomatic congenital conditions flourishes in many settings while it has not yet been realized in others. The need for NBS as an efficient and effective public health prevention strategy that contributes to lowered morbidity and mortality wherever it is sustained is well known in the medical field but not necessarily by political policy makers. Acknowledging the value of national NBS reports published in 2007, the authors collaborated to create a worldwide NBS update in 2015. In a continuing attempt to review the progress of NBS globally, and to move towards a more harmonized and equitable screening system, we have updated our 2015 report with information available at the beginning of 2024. Reports on sub-Saharan Africa and the Caribbean, missing in 2015, have been included. Tables popular in the previous report have been updated with an eye towards harmonized comparisons. To emphasize areas needing attention globally, we have used regional tables containing similar listings of conditions screened, numbers of screening laboratories, and time at which specimen collection is recommended. Discussions are limited to bloodspot screening.

The phenylpropanoid pathway is one of the plant metabolic pathways most prominently linked to the transition to terrestrial life, but its evolution and early functions remain elusive. Here, we show that activity of the t-cinnamic acid 4-hydroxylase (C4H), the first plant-specific step in the pathway, emerged concomitantly with the CYP73 gene family in a common ancestor of embryophytes. Through structural studies, we identify conserved CYP73 residues, including a crucial arginine, that have supported C4H activity since the early stages of its evolution. We further demonstrate that impairing C4H function via CYP73 gene inactivation or inhibitor treatment in three bryophyte species-the moss Physcomitrium patens, the liverwort Marchantia polymorpha and the hornwort Anthoceros agrestis-consistently resulted in a shortage of phenylpropanoids and abnormal plant development. The latter could be rescued in the moss by exogenous supply of p-coumaric acid, the product of C4H. Our findings establish the emergence of the CYP73 gene family as a foundational event in the development of the plant phenylpropanoid pathway, and underscore the deep-rooted function of the C4H enzyme in embryophyte biology., (© 2024. The Author(s).)

Immunotoxicology/immunosafety science is rapidly evolving, with novel modalities and immuno-oncology among the primary drivers of new tools and technologies. The Immunosafety Working Group of IQ/DruSafe sought to better understand some of the key challenges in immunosafety evaluation, gaps in the science, and current limitations in methods and data interpretation. A survey was developed to provide a baseline understanding of the needs and challenges faced in immunosafety assessments, the tools currently being applied across the industry, and the impact of feedback received from regulatory agencies. This survey also focused on current practices and challenges in conducting the T-cell-dependent antibody response (TDAR) and the cytokine release assay (CRA). Respondents indicated that ICH S8 guidance was insufficient for the current needs of the industry portfolio of immunomodulators and novel modalities and should be updated. Other challenges/gaps identified included translation of nonclinical immunosafety assessments to the clinic, and lack of relevant nonclinical species and models in some cases. Key areas of emerging science that will add future value to immunotoxicity assessments include development of additional in vitro and microphysiological system models, as well as application of humanized mouse models. Efforts are ongoing in individual companies and consortia to address some of these gaps and emerging science., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

T-cell dependent antibody responses to biotherapeutics remain a challenge to the optimal clinical application of biotherapeutics because of their capacity to impair drug efficacy and their potential to cause safety issues. To minimize this clinical immunogenicity risk, preclinical assays measuring the capacity of biotherapeutics to elicit CD4 T cell response in vitro are commonly used. However, there is considerable variability in assay formats and a general poor understanding of their respective predictive value. In this study, we evaluated the performance of three different CD4 T cell proliferation assays in their capacity to predict clinical immunogenicity: a CD8 T cell depleted peripheral blood mononuclear cells (PBMC) assay and two co-culture-based assays between dendritic cells (DCs) and autologous CD4 T cells with or without restimulation with monocytes. A panel of 10 antibodies with a wide range of clinical immunogenicity was selected. The CD8 T cell depleted PBMC assay predicted the clinical immunogenicity in four of the eight highly immunogenic antibodies included in the panel. Similarly, five antibodies with high clinical immunogenicity triggered a response in the DC: CD4 T cell assay but the responses were of lower magnitude than the ones observed in the PBMC assay. Remarkably, three antibodies with high clinical immunogenicity did not trigger any response in either platform. The addition of a monocyte restimulation step to the DC: CD4 T cell assay did not further improve its predictive value. Overall, these results indicate that there are no CD4 T cell assay formats that can predict the clinical immunogenicity of all biotherapeutics and reinforce the need to combine results from various preclinical assays assessing antigen uptake and presentation to fully mitigate the immunogenicity risk of biotherapeutics., Competing Interests: RW, AN, and LM are employees of Eli Lilly and Company and own stock in Eli Lilly and Company. CA, AM, JS, and SP are employed with ImmunXperts, a Q2 Solutions Company., (Copyright © 2024 Walsh, Nix, Ackaert, Mazy, Schockaert, Pattyn and Malherbe.)

Biologics have revolutionized disease management in many therapeutic areas by addressing unmet medical needs and overcoming resistance to standard-of-care treatment in numerous patients. However, the development of unwanted immune responses directed against these drugs, humoral and/or cellular, can hinder their efficacy and have safety consequences with various degrees of severity. Health authorities ask that a thorough immunogenicity risk assessment be conducted during drug development to incorporate an appropriate monitoring and mitigation plan in clinical studies. With the rapid diversification and complexification of biologics, which today include modalities such as multi-domain antibodies, cell-based products, AAV delivery vectors, and nucleic acids, developers are faced with the challenge of establishing a risk assessment strategy sometimes in the absence of specific regulatory guidelines. The European Immunogenicity Platform (EIP) Open Symposium on Immunogenicity of Biopharmaceuticals and its one-day training course gives experts and newcomers across academia, industry, and regulatory agencies an opportunity to share experience and knowledge to overcome these challenges. Here, we report the discussions that took place at the EIP's 14 th Symposium, held in April 2023. The topics covered included immunogenicity monitoring and clinical relevance, non-clinical immunogenicity risk assessment, regulatory aspects of immunogenicity assessment and reporting, and the challenges associated with new modalities, which were discussed in a dedicated session.

Background and Purpose: Chronic heart failure, a progressive disease with limited treatment options currently available, especially in heart failure with preserved ejection fraction (HFpEF), represents an unmet medical need as well as an economic burden. The development of a novel therapeutic to slow or reverse disease progression would be highly impactful to patients and society. Relaxin-2 (relaxin) is a human hormone regulating cardiovascular, renal, and pulmonary adaptations during pregnancy. A short-acting recombinant relaxin, Serelaxin, demonstrated short-term heart failure symptom relief and biomarker improvement in acute heart failure trials. Here, we present the development of a long-acting relaxin analogue to be tested in the treatment of chronic heart failure., Experimental Approach: LY3540378 is a long-acting protein therapeutic composed of a human relaxin analogue and a serum albumin-binding VHH domain., Key Results: LY3540378 is a potent agonist of the relaxin family peptide receptor 1 (RXFP1) and maintains selectivity against RXFP2/3/4 comparable to native relaxin. The half-life of LY3540378 in preclinical species is extended through high affinity binding of the albumin-binding VHH domain to serum albumin. When tested in a single dose administration, LY3540378 elicited relaxin-mediated pharmacodynamic responses, such as reduced serum osmolality and increased renal blood flow in rats. In an isoproterenol-induced cardiac hypertrophy mouse model, treatment with LY3540378 significantly reduced cardiac hypertrophy and improved isovolumetric relaxation time. In a monkey cardiovascular safety study, there were no adverse observations from administration of LY3540378., Conclusion and Implications: LY3540378 demonstrated to be a suitable clinical development candidate, and is progressing in clinical trials., (© 2023 Eli Lilly and Company. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

A survey conducted by the Therapeutic Product Immunogenicity (TPI) community within the American Association of Pharmaceutical Scientists (AAPS) posed questions to the participants on their immunogenicity risk assessment strategies prior to clinical development. The survey was conducted in 2 phases spanning 5 years, and queried information about in silico algorithms and in vitro assay formats for immunogenicity risk assessments and how the data were used to inform early developability effort in discovery, chemistry, manufacturing and control (CMC), and non-clinical stages of development. The key findings representing the trends from a majority of the participants included the use of high throughput in silico algorithms, human immune cell-based assays, and proteomics based outputs, as well as specialized assays when therapeutic mechanism of action could impact risk assessment. Additional insights into the CMC-related risks could also be gathered with the same tools to inform future process development and de-risk critical quality attributes with uncertain and unknown risks. The use of the outputs beyond supporting early development activities was also noted with participants utilizing the risk assessments to drive their clinical strategy and streamline bioanalysis., (© 2023. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.)

Background: The aim of this study was to use an integrated exposure assessment approach, combining spatiotemporal modeling of environmental exposure and fate of the chemical to assess the exposure of vulnerable populations. In this study, chlorpyrifos exposure of pregnant women in Picardy was evaluated at a regional scale during 1 year. This approach provided a mapping of exposure indicators of pregnant women to chlorpyrifos over fine spatial and temporal resolutions using a GIS environment., Methods: Fate and transport models (emission, atmospheric dispersion, multimedia exposure, PBPK) were combined with environmental databases in a GIS environment. Quantities spread over agricultural fields were simulated and integrated into a modeling chain coupling models. The fate and transport of chlorpyrifos was characterized by an atmospheric dispersion statistical metamodel and the dynamiCROP model. Then, the multimedia model Modul'ERS was used to predict chlorpyrifos daily exposure doses which were integrated in a PBPK model to compute biomarker of exposure (TCPy urinary concentrations). For the concentration predictions, two scenarios (lower bound and upper bound) were built., Results: At fine spatio-temporal resolutions, the cartography of biomarkers in the lower bound scenario clearly highlights agricultural areas. In these maps, some specific areas and hotspots appear as potentially more exposed specifically during application period. Overall, predictions were close to biomonitoring data and ingestion route was the main contributor to chlorpyrifos exposure., Conclusions: This study demonstrated the feasibility of an integrated approach for the evaluation of chlorpyrifos exposure which allows the comparison between modeled predictions and biomonitoring data., (© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: Studies have reported associations between maternal exposure to atmospheric pollution and lower birth weight. However, the evidence is not consistent and uncertainties remain. We used advanced statistical approaches to robustly estimate the association of atmospheric pollutant exposure during specific pregnancy time windows with term birth weight (TBW) in a nationwide study., Methods: Among 13,334 women from the French Longitudinal Study of Children (ELFE) cohort, exposures to PM 2.5 , PM 10 (particles < 2.5 µm and <10 µm) and NO 2 (nitrogen dioxide) were estimated using a fine spatio-temporal exposure model. We used inverse probability scores and doubly robust methods in generalized additive models accounting for spatial autocorrelation to study the association of such exposures with TBW., Results: First trimester exposures were associated with an increased TBW. Second trimester exposures were associated with a decreased TBW by 17.1 g (95% CI, -26.8, -7.3) and by 18.0 g (-26.6, -9.4) for each 5 µg/m 3 increase in PM 2.5 and PM 10 , respectively, and by 15.9 g (-27.6, -4.2) for each 10 µg/m 3 increase in NO 2 . Third trimester exposures (truncated at 37 gestational weeks) were associated with a decreased TBW by 48.1 g (-58.1, -38.0) for PM 2.5 , 38.1 g (-46.7, -29.6) for PM 10 and 14.7 g (-25.3, -4.0) for NO 2 . Effects of pollutants on TBW were larger in rural areas., Conclusions: Our results support an adverse effect of air pollutant exposure on TBW. We highlighted a larger effect of air pollutants on TBW among women living in rural areas compared to women living in urban areas.

Background: At a regional or continental scale, the characterization of environmental health inequities (EHI) expresses the idea that populations are not equal in the face of pollution. It implies an analysis be conducted in order to identify and manage the areas at risk of overexposure where an increasing risk to human health is suspected. The development of methods is a prerequisite for implementing public health activities aimed at protecting populations., Methods: This paper presents the methodological framework developed by INERIS (French National Institute for Industrial Environment and Risks) to identify a common framework for a structured and operationalized assessment of human exposure. An integrated exposure assessment approach has been developed to integrate the multiplicity of exposure pathways from various sources, through a series of models enabling the final exposure of a population to be defined., Results: Measured data from environmental networks reflecting the actual contamination of the environment are used to gauge the population's exposure. Sophisticated methods of spatial analysis are applied to include additional information and take benefit of spatial and inter-variable correlation to improve data representativeness and characterize the associated uncertainty. Integrated approaches bring together all the information available for assessing the source-to-human-dose continuum using a Geographic Information System, multimedia exposure and toxicokinetic model., Discussion: One of the objectives of the integrated approach was to demonstrate the feasibility of building complex realistic exposure scenarios satisfying the needs of stakeholders and the accuracy of the modelling predictions at a fine spatial-temporal resolution. A case study is presented to provide a specific application of the proposed framework and how the results could be used to identify an overexposed population., Conclusion: This framework could be used for many purposes, such as mapping EHI, identifying vulnerable populations and providing determinants of exposure to manage and plan remedial actions and to assess the spatial relationships between health and the environment to identify factors that influence the variability of disease patterns.

Microbacterium sp. strain Nx66 was isolated from waters contaminated by petrochemical effluents collected in Algeria. Its genome was sequenced using Illumina MiSeq (2 × 150-bp read pairs) and Oxford Nanopore (long reads) technologies and was assembled using Unicycler. It is composed of one chromosome of 3.42 Mb and one plasmid of 34.22 kb., (Copyright © 2020 Chéraiti et al.)

Background: Porphyromonas gingivalis strain W83, one of the most widely investigated, is considered virulent in the context of periodontitis. The recently isolated P. gingivalis TDC60 has been reported to be highly pathogenic, although it has not yet been investigated in a mouse periodontitis model by oral gavage. Aim: Our aim was to compare the virulence of both strains by evaluating their impact on alveolar bone loss and the composition of oral microbiota. Methods: We inoculated by oral gavage C57BL/6 mice with either one of the two P. gingivalis strains and compared to a sham-treated group, without antibiotics pre-treatment. The mandibular alveolar bone of treated mice and controls were assessed, one month after the final inoculation, by microCT measurements. Moreover, at this time, we characterized their oral microbiota by 16S rRNA gene sequencing. Results: While P. gingivalis W83 successfully initiated periodontitis, TDC60-treated mice only experienced moderate lesions. Furthermore, only W83-treated mice exhibited a specific distinct microbiota, with significantly lower richness and evenness than other samples, and decreased proportions of taxa usually found in healthy individuals. Conclusion: This association between alveolar bone loss and a major persistent shift of the oral microbiota gives insights into virulence discrepancies among these bacterial strains., Competing Interests: No potential conflict of interest was reported by the authors., (© 2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

In Nantes, low-cost sensors were installed in the city center and deployed on driving school cars, ambulances and service vehicles to measure PM 10 concentrations. This work aims to use the large amount of observations provided by the sensors for air quality mapping at the urban scale in order to show the potential added-value with respect to the dispersion model (ADMS-Urban) calculations. A preprocessing is applied to the raw sensor dataset to remove the unreliable observations based on an outlier detection technique and to compensate for the measurement drift by adjusting the estimated daily variation of the underlying background PM 10 concentrations with the reference stations. Then, data fusion is performed by combining the preprocessed fixed and mobile low-cost sensor observations and the 2016 annual average of the ADMS-Urban outputs. The measurement uncertainty related to the low-cost sensors and the dispersion of the data are considered in data fusion as the Variance of Measurement Error (VME). The spatial interpolation is achieved at hourly resolution and results are presented for November 29th, 2018 from 7 am to 7 pm. Hourly fused maps show disparate responses to data fusion mainly depending on the variability of the sensor data and the correlation between the sensor observations and the drift. The data fusion performance has been investigated by comparing the daily average of the estimated concentrations, the reference observations and the hourly model outputs at each station of the Air Pays de la Loire network. Results show that considering the model alone implies 8% bias whereas including the LCS observations reduces the bias to 2.5%. However, the concentration distributions related to the data fusion are characterized by a lower dispersion than the reference observations and the model estimation. Thus, the fusion smooths the PM 10 peaks. In addition, the effect of the measurement uncertainty has been investigated by doubling it or reducing it to the reference station measurement uncertainty. The sensitivity study demonstrates that the performance is increasing by reducing the uncertainty. This highlights the importance to estimate accurately the measurement uncertainty of the devices to ensure relevant air quality mapping. The method efficiency is also quite limited by the low correlation between the sensor observations and the model used as external drift in the kriging that may be explained by the remaining bias on LCS data. Efforts on this issue might increase the performance of the spatial interpolation., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Cause of complex dyskinesia remains elusive in some patients. A homozygous missense variant leading to drastic decrease of PDE2A enzymatic activity was reported in one patient with childhood-onset choreodystonia preceded by paroxysmal dyskinesia and associated with cognitive impairment and interictal EEG abnormalities. Here, we report three new cases with biallelic PDE2A variants identified by trio whole-exome sequencing. Mitochondria network was analyzed after Mitotracker™ Red staining in control and mutated primary fibroblasts. Analysis of retrospective video of patients' movement disorder and refinement of phenotype was carried out. We identified a homozygous gain of stop codon variant c.1180C>T; p.(Gln394*) in PDE2A in siblings and compound heterozygous variants in young adult: a missense c.446C>T; p.(Pro149Leu) and splice-site variant c.1922+5G>A predicted and shown to produce an out of frame transcript lacking exon 22. All three patients had cognitive impairment or developmental delay. The phenotype of the two oldest patients, aged 9 and 26, was characterized by childhood-onset refractory paroxysmal dyskinesia initially misdiagnosed as epilepsy due to interictal EEG abnormalities. The youngest patient showed a proven epilepsy at the age of 4 months and no paroxysmal dyskinesia at 15 months. Interestingly, analysis of the fibroblasts with the biallelic variants in PDE2A variants revealed mitochondria network morphology changes. Together with previously reported case, our three patients confirm that biallelic PDE2A variants are a cause of childhood-onset refractory paroxysmal dyskinesia with cognitive impairment, sometimes associated with choreodystonia and interictal baseline EEG abnormalities or epilepsy.

Treatment-emergent antidrug antibodies (TE-ADA) pose a major challenge to the development of biotherapeutics. The antidrug antibody responses are highly orchestrated and involve many types of immune cells and biological processes. Biological drug internalization and processing by antigen-presenting cells (APCs) are two initial and critical steps in the cascade of events leading to T cell-dependent ADA production. The assays thus far described in literature to evaluate immunogenicity potential/risk as a function of APC activity mainly focus on internalization of labeled drug candidates in vitro. Herein, we describe a high-throughput Förster Resonance Energy Transfer (FRET)-based assay for assessing both internalization and processing using CD14+ monocyte-derived dendritic cells (DCs) as APCs. Antigen-binding fragment F(ab')2 against IgG fragment crystallizable gamma (Fcγ) was labeled with the activatable FRET pair TAMRA-QSY7 as a universal probe for antibodies and proteins with a fragment crystallizable (Fc) domain. The assay was qualified using six mAbs of known clinical immunogenicity and one IgG1 isotype antibody using Design of Experiment (DoE). Correlation analysis of internalization and clinical immunogenicity data showed that this FRET-based internalization assay was able to detect clinically immunogenic antibodies. This method provides a tool for analyzing/screening the immunogenicity risk of biological candidates by assessing one of the critical components of the ADA formation process within the broader context of an immunogenicity risk assessment strategy.

Many autoimmune diseases are characterized by the production of autoantibodies. The current view is that CD4 + T follicular helper (Tfh) cells are the main subset regulating autoreactive B cells. Here we report a CXCR5 + PD1 + Tfh subset of CD8 + T cells whose development and function are negatively modulated by Stat5. These CD8 + Tfh cells regulate the germinal center B cell response and control autoantibody production, as deficiency of Stat5 in CD8 T cells leads to an increase of CD8 + Tfh cells, resulting in the breakdown of B cell tolerance and concomitant autoantibody production. CD8 + Tfh cells share similar gene signatures with CD4 + Tfh, and require CD40L/CD40 and TCR/MHCI interactions to deliver help to B cells. Our study thus highlights the diversity of follicular T cell subsets that contribute to the breakdown of B-cell tolerance.

Reducing environmental health inequalities has become a major focus of public health efforts in France, as evidenced by the French action plans for health and the environment. To evaluate environmental inequalities, routine monitoring networks provide a valuable source of data on environmental contamination, which can be used in integrated assessments, to identify overexposed populations and prioritize actions. However, available databases generally do not meet sufficient spatial representativeness to characterize population exposure, as they are usually not assembled for this specific purpose. The aim of this study was to develop geoprocessing procedures and statistical methods to build spatial environmental variables (water, air, soil, and food pollutant concentrations) at a fine resolution, and provide appropriate input for the exposure modelling. Those methods were designed to combine in situ monitoring data with correlated auxiliary information (for example, atmospheric emissions, population, and altitude), in order to better represent the variability of the environmental compartment quality. The MODUL'ERS multimedia exposure model developed by INERIS (French Institute for industrial Environment and Risks) was then used to assess the transfer of substances from the environment to humans, through inhalation and ingestion pathway characterization. We applied the methodology to a carcinogenic Polycyclic Aromatic Hydrocarbon substance, benzo[a]pyrene(B[a]P), to map spatialized exposure indicators, at the national scale. The largest environmental contribution corresponded to the ingestion pathway. Data processing algorithms and calculation of exposure will be integrated into the French coordinated integrated environment and health platform PLAINE (PLteforme intégrée d'Analyse des INégalités Environnementales) which has been developed to map and analyze environmental health inequalities.

The European legislation on ambient air quality introduces the concepts of spatial representativeness of a monitoring station and spatial extent of an exceedance zone. Spatial representativeness is an essential macro-scale siting criterion which should be evaluated before the setting-up and during the life of a monitoring point. As for the exceedance area, it has to be defined each time an environmental objective is exceeded in an assessment zone. No specific approach is prescribed to delimit such areas. A probabilistic methodology is presented, based on a preliminary kriging estimation of atmospheric concentrations at each point of the domain. It is applied to NO 2 pollution on the urban scale. In the proposed approach, a point belongs to the area of representativeness of a station if its concentration differs from the station measurement by less than a given threshold. To take the estimation uncertainty into account, the standard deviation of the kriging error is used in a probabilistic framework. The choice of the criteria used to deal with overlapping areas is first tested on NO 2 annual mean concentration maps of France, built by combining surface monitoring observations and outputs from the CHIMERE chemistry transport model. At the local scale, data from passive sampling surveys and high -resolution auxiliary variables are used to provide a more precise estimation of the background pollution in different French cities. The traffic-related pollution can also be accounted for in the map by additional predictors such as distance to the road, and traffic-related NO x emissions. Similarly, the proposed approach is implemented to identify the points, at a given statistical risk, where the NO 2 concentration is above the annual limit value.

Unfortunately, after publication of this article [1], it was noticed that corrections to the legends of Figs. 1 and 2 were not correctly incorporated. The correct legends can be seen below.

Background: Modulation of the PD-1/PD-L1 axis through antagonist antibodies that block either receptor or ligand has been shown to reinvigorate the function of tumor-specific T cells and unleash potent anti-tumor immunity, leading to durable objective responses in a subset of patients across multiple tumor types., Results: Here we describe the discovery and preclinical characterization of LY3300054, a fully human IgG1λ monoclonal antibody that binds to human PD-L1 with high affinity and inhibits interactions of PD-L1 with its two cognate receptors PD-1 and CD80. The functional activity of LY3300054 on primary human T cells is evaluated using a series of in vitro T cell functional assays and in vivo models using human-immune reconstituted mice. LY3300054 is shown to induce primary T cell activation in vitro, increase T cell activation in combination with anti-CTLA4 antibody, and to potently enhance anti-tumor alloreactivity in several xenograft mouse tumor models with reconstituted human immune cells. High-content molecular analysis of tumor and peripheral tissues from animals treated with LY3300054 reveals distinct adaptive immune activation signatures, and also previously not described modulation of innate immune pathways., Conclusions: LY3300054 is currently being evaluated in phase I clinical trials for oncology indications.

Background: The increasing number of people with dementia (PwD) drives research exploring Web-based support interventions to provide effective care for larger populations. In this concept, a Web-based platform (CAREGIVERSPRO-MMD, 620911) was designed to (1) improve the quality of life for PwD, (2) reduce caregiver burden, (3) reduce the financial costs for care, and (4) reduce administration time for health and social care professionals., Objective: The objective of this study was to evaluate the usability and usefulness of CAREGIVERSPRO-MMD platform for PwD or mild cognitive impairment (MCI), informal caregivers, and health and social care professionals with respect to a wider strategy followed by the project to enhance the user-centered approach. A secondary aim of the study was to collect recommendations to improve the platform before the future pilot study., Methods: A mixed methods design was employed for recruiting PwD or MCI (N=24), informal caregivers (N=24), and professionals (N=10). Participants were asked to rate their satisfaction, the perceived usefulness, and ease of use of each function of the platform. Qualitative questions about the improvement of the platform were asked when participants provided low scores for a function. Testing occurred at baseline and 1 week after participants used the platform. The dropout rate from baseline to the follow-up was approximately 10% (6/58)., Results: After 1 week of platform use, the system was useful for 90% (20.75/23) of the caregivers and for 89% (5.36/6) of the professionals. When users responded to more than 1 question per platform function, the mean of satisfied users per function was calculated. These user groups also provided positive evaluations for the ease of use (caregivers: 82%, 18.75/23; professionals: 97%, 5.82/6) and their satisfaction with the platform (caregivers: 79%, 18.08/23; professionals: 73%, 4.36/6). Ratings from PwD were lower than the other groups for usefulness (57%, 13/23), ease of use (41%, 9.4/23), and overall satisfaction (47%, 11/23) with the platform (P<.05). Qualitative comments related to both improvements for functionality and the platform interface., Conclusions: Although caregivers and professionals were overall satisfied with the platform, further adaptations were recommended by PwD. This reiterates the importance of the involvement of end users in the development of Web-based interventions. Recommendations from users in this paper apply for the interface and functionality of a wider range of Web-based support interventions., (©Paraskevi Zafeiridi, Kevin Paulson, Rosie Dunn, Emma Wolverson, Caroline White, Jonathan Adrian Thorpe, Marco Antomarini, Francesca Cesaroni, Francesca Scocchera, Isabelle Landrin-Dutot, Laëtitia Malherbe, Hendi Lingiah, Marie Bérard, Xavier Gironès, Maria Quintana, Ulises Cortés, Cristian Barrué, Atia Cortés, Ioannis Paliokas, Konstantinos Votis, Dimitrios Tzovaras. Originally published in JMIR Formative Research (http://formative.jmir.org), 12.03.2018.)

Background: Exposure to atmospheric pollutants is a danger for the health of pregnant mother and children. Our objective was to identify individual (socioeconomic and behavioural) and contextual factors associated with atmospheric pollution pregnancy exposure at the nationwide level., Method: Among 14 921 women from the French nationwide ELFE (French Longitudinal Study of Children) mother-child cohort recruited in 2011, outdoor exposure levels of PM 2.5 , PM 10 (particulate matter <2.5 µm and <10 µm in diameter) and NO 2 (nitrogen dioxide) were estimated at the pregnancy home address from a dispersion model with 1 km resolution. We used classification and regression trees (CART) and linear regression to characterise the association of atmospheric pollutants with individual (maternal age, body mass index, parity, education level, relationship status, smoking status) and contextual (European Deprivation Index, urbanisation level) factors., Results: Patterns of associations were globally similar across pollutants. For the CART approach, the highest tertile of exposure included mainly women not in a relationship living in urban and socially deprived areas, with lower education level. Linear regression models identified different determinants of atmospheric pollutants exposure according to the residential urbanisation level. In urban areas, atmospheric pollutants exposure increased with social deprivation, while in rural areas a U-shaped relationship was observed., Conclusion: We highlighted social inequalities in atmospheric pollutants exposure according to contextual characteristics such as urbanisation level and social deprivation and also according to individual characteristics such as education, being in a relationship and smoking status. In French urban areas, pregnant women from the most deprived neighbourhoods were those most exposed to health-threatening atmospheric pollutants., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

An irreversible loss in lung function limits the long-term success in lung transplantation. We evaluated the role of chronic exposure to ambient air pollution on lung function levels in lung transplant recipients (LTRs).The lung function of 520 LTRs from the Cohort in Lung Transplantation (COLT) study was measured every 6 months. The levels of air pollutants (nitrogen dioxide (NO 2 ), particulate matter with an aerodynamic cut-off diameter of x µm (PM x ) and ozone (O 3 )) at the patients' home address were averaged in the 12 months before each spirometry test. The effects of air pollutants on forced expiratory volume in 1 s (FEV 1 ) and forced vital capacity (FVC) in % predicted were estimated using mixed linear regressions. We assessed the effect modification of macrolide antibiotics in this relationship.Increased 12-month levels of pollutants were associated with lower levels of FVC % pred (-2.56%, 95% CI -3.86--1.25 for 5 µg·m -3 of PM 10 ; -0.75%, 95% CI -1.38--0.12 for 2 µg·m -3 of PM 2.5 and -2.58%, 95% CI -4.63--0.53 for 10 µg·m -3 of NO 2 ). In patients not taking macrolides, the deleterious association between PM and FVC tended to be stronger and PM 10 was associated with lower FEV 1 Our study suggests a deleterious effect of chronic exposure to air pollutants on lung function levels in LTRs, which might be modified with macrolides., (Copyright ©ERS 2017.)

The glycine receptor (GlyR) is a pentameric ligand-gated ion channel (pLGIC) mediating inhibitory transmission in the nervous system. Its transmembrane domain (TMD) is the target of allosteric modulators such as general anesthetics and ethanol and is a major locus for hyperekplexic congenital mutations altering the allosteric transitions of activation or desensitization. We previously showed that the TMD of the human α1GlyR could be fused to the extracellular domain of GLIC, a bacterial pLGIC, to form a functional chimera called Lily. Here, we overexpress Lily in Schneider 2 insect cells and solve its structure by X-ray crystallography at 3.5 Å resolution. The TMD of the α1GlyR adopts a closed-channel conformation involving a single ring of hydrophobic residues at the center of the pore. Electrophysiological recordings show that the phenotypes of key allosteric mutations of the α1GlyR, scattered all along the pore, are qualitatively preserved in this chimera, including those that confer decreased sensitivity to agonists, constitutive activity, decreased activation kinetics, or increased desensitization kinetics. Combined structural and functional data indicate a pore-opening mechanism for the α1GlyR, suggesting a structural explanation for the effect of some key hyperekplexic allosteric mutations. The first X-ray structure of the TMD of the α1GlyR solved here using GLIC as a scaffold paves the way for mechanistic investigation and design of allosteric modulators of a human receptor.

To understand the molecular mechanism of ion permeation in pentameric ligand-gated ion channels (pLGIC), we solved the structure of an open form of GLIC, a prokaryotic pLGIC, at 2.4 Å. Anomalous diffraction data were used to place bound anions and cations. This reveals ordered water molecules at the level of two rings of hydroxylated residues (named Ser6' and Thr2') that contribute to the ion selectivity filter. Two water pentagons are observed, a self-stabilized ice-like water pentagon and a second wider water pentagon, with one sodium ion between them. Single-channel electrophysiology shows that the side-chain hydroxyl of Ser6' is crucial for ion translocation. Simulations and electrostatics calculations complemented the description of hydration in the pore and suggest that the water pentagons observed in the crystal are important for the ion to cross hydrophobic constriction barriers. Simulations that pull a cation through the pore reveal that residue Ser6' actively contributes to ion translocation by reorienting its side chain when the ion is going through the pore. Generalization of these findings to the pLGIC family is proposed.