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Abstract Wetlands are crucial components of the Earth's system, interacting with various processes such as the hydrological cycle, energy exchanges with the atmosphere, and global nitrogen and carbon cycles. The future trajectory of wetlands is anticipated to be influenced not only by direct human activities, but also by climate change. Here we present our assessment of climate‐driven global changes in wetlands extent, focusing on the main wetland complexes. We used an approach based on the Topographic Hydrological model (TOPMODEL) and soil liquid water content projections from 14 models of the Coupled Model Intercomparison Project Phase 6 (CMIP6). Our analysis reveals a consistent decrease in wetlands extent in the Mediterranean, Central America, and northern South America, with a substantial loss of 28% in the western Amazon Basin for the end of the 21st century (2081–2100) under the SSP370 scenario. Conversely, Central Africa exhibits an increase in wetlands extent, except in the Congo Basin. Nevertheless, most of the areas studied (80%) present uncertain results, due to conflicting projections of changes between the models. Notably, we show that there is significant uncertainty among CMIP6 models regarding liquid soil water content in high latitudes. By narrowing our focus to 10 models, which seem to better represent the thawing of permafrost, we obtain a better inter‐model agreement. We then find a modest declines in the overall global area (

Global estimates of the land carbon sink are often based on simulations by terrestrial biosphere models (TBMs). The use of a large number of models that differ in their underlying hypotheses, structure and parameters is one way to assess the uncertainty in the historical land carbon sink. Here we show that the atmospheric forcing datasets used to drive these TBMs represent a significant source of uncertainty that is currently not systematically accounted for in land carbon cycle evaluations. We present results from three TBMs each forced with three different historical atmospheric forcing reconstructions over the period 1850-2015. We perform an analysis of variance to quantify the relative uncertainty in carbon fluxes arising from the models themselves, atmospheric forcing, and model-forcing interactions. We find that atmospheric forcing in this set of simulations plays a dominant role on uncertainties in global gross primary productivity (GPP) (75% of variability) and autotrophic respiration (90%), and a significant but reduced role on net primary productivity and heterotrophic respiration (30%). Atmospheric forcing is the dominant driver (52%) of variability for the net ecosystem exchange flux, defined as the difference between GPP and respiration (both autotrophic and heterotrophic respiration). In contrast, for wildfire-driven carbon emissions model uncertainties dominate and, as a result, model uncertainties dominate for net ecosystem productivity. At regional scales, the contribution of atmospheric forcing to uncertainty shows a very heterogeneous pattern and is smaller on average than at the global scale. We find that this difference in the relative importance of forcing uncertainty between global and regional scales is related to large differences in regional model flux estimates, which partially offset each other when integrated globally, while the flux differences driven by forcing are mainly consistent across the world and therefore add up to a larger fractional contribution to global uncertainty.

Phylogeographic studies have been conducted on many different mammal species in order to track their recent demographic histories. The climatic fluctuations associated with the Last Glacial Maximum (LGM) appear to have had a profound influence on the geographic patterning of genetic diversity in mammals. However, most phylogenetic studies have focused on single species. Few have used a holistic approach covering multiple taxa to explore common patterns. Here, we conducted meta-analyses of mitochondrial DNA control region sequences, identifying haplotype diversity and private allelic richness patterns in a geographic context. Four general patterns emerged among European mammals: an east–west decline in variation, a Western-Central belt of the highest diversity, southern richness, and homogeneity with no geographic pattern. These patterns likely reflect the refugial origins of modern populations. The east–west variation decline suggests species with eastern LGM refugia; the Western-Central belt of the highest diversity may harbor taxa with cryptic northern refugia, while southern richness may correspond to traditional southern refugia. Species with homogeneity and no geographic pattern may have been panmictic without a specific refugium or may reflect the occurrence of both southern and cryptic northern refugia. Surprisingly, the “no pattern” phenomenon is seldom discussed and may frequently have been discounted. Our study emphasizes the importance of considering multiple taxa, providing valuable insights into the responses of European mammals to past climatic changes.

Previously, we pointed out in P. aeruginosa PAO1 biofilm cells the accumulation of a hypothetical protein named PA3731 and showed that the deletion of the corresponding gene impacted its biofilm formation capacity. PA3731 belongs to a cluster of 4 genes (pa3732 to pa3729) that we named bac for “Biofilm Associated Cluster.” The present study focuses on the PA14_16140 protein, i.e., the PA3732 (BacA) homolog in the PA14 strain. The role of BacA in rhamnolipid secretion, biofilm formation and virulence, was confirmed by phenotypic experiments with a bacA mutant. Additional investigations allow to advance that the bac system involves in fact 6 genes organized in operon, i.e., bacA to bacF. At a molecular level, quantitative proteomic studies revealed an accumulation of the BAC cognate partners by the bacA sessile mutant, suggesting a negative control of BacA toward the bac operon. Finally, a first crystallographic structure of BacA was obtained revealing a structure homologous to chaperones or/and regulatory proteins.

IntroductionHyperkalaemia is a common electrolyte disorder and can be life-threatening. In the emergency room (ER), interventions aim to protect patients from the immediate dangers of elevated serum potassium by redistributing potassium ions from the bloodstream into the cells via intravenous insulin or nebulised beta2-agonists. However, to date, evidence for acute management of hyperkalaemia is limited. The aim of this randomised controlled trial is therefore to compare three strategies, namely insulin/glucose intravenous infusion, nebulised salbutamol or a combination of nebulised salbutamol and insulin/glucose intravenous infusion to reduce serum potassium concentration at 60 min as a first-line treatment in patients admitted to the ER with serum potassium concentrations superior or equal to 6 mmol/L.Methods and analysisINSAKA is a prospective, multicentre, controlled, open-label, parallel-group, randomised in a 1:1:1 ratio clinical trial. Patients will be eligible for randomisation if they have serum potassium concentrations superior or equal to 6 mmol/L measured in the ER. Patients will receive either: (1) 10 mg of nebulised salbutamol, (2) 10 units of short-acting insulin in an intravenous bolus with 500 mL of 10% glucose or (3) 10 units of short-acting insulin in an intravenous bolus with 500 mL of 10% glucose combined with 10 mg of nebulised salbutamol. The primary endpoint will be the mean change in the absolute serum potassium level from baseline to 60 min measured in mmol/L. We plan to include 525 patients.Ethics and disseminationThe INSAKA trial will be conducted in accordance with the International Council on Harmonization Good Clinical Practices. All trial documents and procedures have been reviewed and approved by the Ethics Committee Sud Méditerranée III (approval ID number: 19.07.16.36428). The results will be actively disseminated through peer-reviewed journals, conference presentations, social media, broadcast media, print media and the internet.Trial registrationEudraCT number: 2019-002710-39, Clinicaltrials.gov identifier: NCT04012138.

Abstract Background In emergency medicine, pain is a frequent reason for consultation. However, there is a great variation in its management which is often insufficient. The use intravenous morphine alone or multimodal analgesia with paracetamol is recommended for severe pain. But robust data are lacking to justify the association of paracetamol with morphine versus morphine alone for pain management in the emergency room (ER). The aim of our study is therefore to assess if in patients with acute pain of moderate to severe intensity with a numerical verbal scale (NVS) ≥5 in the ER, the intravenous administration of morphine alone is not inferior to the administration of intravenous morphine combined with paracetamol at 30 min from the first administration of the study drug. Methods ADAMOPA is a prospective, non-inferiority, multicenter, placebo-controlled, parallel-group, randomized (1:1), double-blind trial. Subjects will be enrolled in the ER if they experience moderate to severe, acute, non-traumatic, and traumatic pain, defined as an NVS ≥5. The primary endpoint will be the between-group difference in mean change in NVS pain scores among patients receiving the combination of intravenous morphine plus paracetamol or intravenous morphine given alone, measured from the time before administration of the study medication to 30 min later. Discussion This trial will determine the clinical utility of the association of paracetamol with morphine for pain management in the emergency room. The ADAMOPA trial will be conducted in accordance with the International Council on Harmonization Good Clinical Practices. Trial registration EudraCT number: 2019-002149-39. ClinicalTrials.gov identifier: NCT04148495. Date of trial registration: November 1, 2019.

Based on the existing research work on the modeling and control of cyclically operated high-throughput screening systems, this paper presents the scheduling and control of high-throughput screening systems with uncertainties and disturbances. Different definitions of disturbance decoupling problems are considered in order to achieve the optimal scheduling of high-throughput screening systems. Online scheduling was achieved by computing optimal prefilters and output feedback controllers, which can be computed using residuation theory. The control strategies achieved by the controllers are optimal in the sense of the just-in-time criterion commonly used in industrial schedule practice.

The cell wall and cytoplasmic MreB polymers are important for bacterial cell shape. However, Spiroplasma cells lack a cell wall and still display a helical shape and kink-based motility, which is thought to rely on five MreB isoforms and a fibril protein. Here, Lartigue et al. show that heterologous expression of a single Spiroplasma MreB isoform confers helical shape and kinking ability to Mycoplasma cells, which are naturally spherical and non-motile.

Antoniou and colleagues used base editing to generate a variety of mutations inducing γ-globin and rescue the β-hemoglobinopathy phenotype. This strategy was safe and effective in long-term repopulating hematopoietic stem/progenitor cells.

Abstract Background The Posttraumatic growth inventory (PTGI) aims to assess the positive psychological changes that individuals can perceive after a traumatic life event such as a cancer diagnosis. Several French translations of the PTGI have been proposed, but comprehensive data on their psychometric properties are lacking. This study aimed to provide a more complete assessment of the psychometric properties of one of the most used PTGI translations in early-stage breast cancer and melanoma patients. Methods A sample of 379 patients completed the PTGI two years after their cancer diagnosis. A confirmatory analysis was first performed to determine whether the initial five-factor structure of the PTGI was adequate for this French version. As issues were identified in the translation and in the questionnaire structure, we performed an exploratory analysis to determine the most suitable structure for this questionnaire. Validity and reliability of the evidenced structured were then assessed. Results The exploratory analysis evidenced a four-factor structure close to the initial structure: four of the five initial domains were recovered, and items from the unrecovered domain were split into the other domains. This new structure showed good internal consistency and acceptable validity. Conclusions This study highlights that the process of translation and cross-cultural validation of questionnaires is crucial to obtain valid and reliable psychometric instruments. We advise French psycho-oncology researchers and psychotherapists to (i) use the revised translation of Lelorain et al. (2010) proposed in this manuscript and (ii) use the four scores newly evidenced with a grouping of two response categories.

When analyzing patient-reported outcome (PRO) data, sources of differential item functioning (DIF) can be multiple and there may be more than one covariate of interest. Hence, it could be of great interest to disentangle their effects. Yet, in the literature on PRO measures, there are many studies where DIF detection is applied separately and independently for each covariate under examination. With such an approach, the covariates under investigation are not introduced together in the analysis, preventing from simultaneously studying their potential DIF effects on the questionnaire items. One issue, among others, is that it may lead to the detection of false-positive effects when covariates are correlated. To overcome this issue, we developed two new algorithms (namely ROSALI-DIF FORWARD and ROSALI-DIF BACKWARD). Our aim was to obtain an iterative item-by-item DIF detection method based on Rasch family models that enable to adjust group comparisons for DIF in presence of two binary covariates. Both algorithms were evaluated through a simulation study under various conditions aiming to be representative of health research contexts. The performance of the algorithms was assessed using: (i) the rates of false and correct detection of DIF, (ii) the DIF size and form recovery, and (iii) the bias in the latent variable level estimation. We compared the performance of the ROSALI-DIF algorithms to the one of another approach based on likelihood penalization. For both algorithms, the rate of false detection of DIF was close to 5%. The DIF size and form influenced the rates of correct detection of DIF. Rates of correct detection was higher with increasing DIF size. Besides, the algorithm fairly identified homogeneous differences in the item threshold parameters, but had more difficulties identifying non-homogeneous differences. Over all, the ROSALI-DIF algorithms performed better than the penalized likelihood approach. Integrating several covariates during the DIF detection process may allow a better assessment and understanding of DIF. This study provides valuable insights regarding the performance of different approaches that could be undertaken to fulfill this aim.

Abstract Background Meaningfully interpreting patient-reported outcomes (PRO) results from randomized clinical trials requires that the PRO scores obtained in the trial have the same meaning across patients and previous applications of the PRO instrument. Calibration of PRO instruments warrants this property. In the Rasch measurement theory (RMT) framework, calibration is performed by fixing the item parameter estimates when measuring the targeted concept for each individual of the trial. The item parameter estimates used for this purpose are typically obtained from a previous “calibration” study. But imposing this constraint on item parameters, instead of freely estimating them directly in the specific sample of the trial, may hamper the ability to detect a treatment effect. The objective of this simulation study was to explore the potential negative impact of calibration of PRO instruments that were developed using RMT on the comparison of results between treatment groups, using different analysis methods. Methods PRO results were simulated following a polytomous Rasch model, for a calibration and a trial sample. Scenarios included varying sample sizes, with instrument of varying number of items and modalities, and varying item parameters distributions. Different treatment effect sizes and distributions of the two patient samples were also explored. Cross-sectional comparison of treatment groups was performed using different methods based on a random effect Rasch model. Calibrated and non-calibrated approaches were compared based on type-I error, power, bias, and variance of the estimates for the difference between groups. Results There was no impact of the calibration approach on type-I error, power, bias, and dispersion of the estimates. Among other findings, mistargeting between the PRO instrument and patients from the trial sample (regarding the level of measured concept) resulted in a lower power and higher position bias than appropriate targeting. Conclusions Calibration does not compromise the ability to accurately assess a treatment effect using a PRO instrument developed within the RMT paradigm in randomized clinical trials. Thus, given its essential role in producing interpretable results, calibration should always be performed when using a PRO instrument developed using RMT as an endpoint in a randomized clinical trial.

Abstract Anthropogenic atmospheric pollution and immune response regularly expose bacteria to toxic nitrogen oxides such as NO• and NO2. These reactive molecules can damage a wide variety of biomolecules such as DNA, proteins and lipids. Several components of the bacterial envelope are susceptible to be damaged by reactive nitrogen species. Furthermore, the hydrophobic core of the membranes favors the reactivity of nitrogen oxides with other molecules, making membranes an important factor in the chemistry of nitrosative stress. Since bacteria are often exposed to endogenous or exogenous nitrogen oxides, they have acquired protection mechanisms against the deleterious effects of these molecules. By exposing bacteria to gaseous NO2, this work aims to analyze the physiological effects of NO2 on the cell envelope of the airborne bacterium Pseudomonas fluorescens MFAF76a and its potential adaptive responses. Electron microscopy showed that exposure to NO2 leads to morphological alterations of the cell envelope. Furthermore, the proteomic profiling data revealed that these cell envelope alterations might be partly explained by modifications of the synthesis pathways of multiple cell envelope components, such as peptidoglycan, lipid A, and phospholipids. Together these results provide important insights into the potential adaptive responses to NO2 exposure in P. fluorescens MFAF76a needing further investigations.

Abstract Background The resurgence of heroin use and the misuse of pharmaceutical opioids are some of the reasons for a worldwide increase in opioid dependence. Opioid Medication Therapies (OMT) have amply demonstrated their efficacy. From a medical point of view, the main objectives of OMT concern medical and social outcomes, centred on risk reduction and the cessation of opioid use. But patient points of view can differ and few studies have explored opioid-dependent patient viewpoints on their OMT. This variable seems important to consider in a patient-centred approach. The aim of our study was to explore points of view of people who use drugs (PWUD) treated with OMT, in a large multicentre sample. Method A cross-sectional multicentre study explored the points of view of PWUD with Opioid Use Disorder following OMT. Data regarding the patients’ points of view were collected using a self-administered questionnaire developed by the scientific committee of the study. A descriptive analysis and an exploratory factor analysis were performed to explore the structure of items exploring patient viewpoints. Results 263 opioid dependent PWUD were included, a majority were men consuming heroin prior to being prescribed OMT. 68% were on methadone, 32% were on buprenorphine. Most PWUD identified a positive impact on their lives, with 92.8% agreeing or strongly agreeing that OMT had changed a lot of things in their lives. The exploratory factor analysis identified three factors: (F1) items related to points of views concerning the objectives and efficacy of OMT; (F2) items related to the legitimacy of OMT as a treatment compared to a drug, (F3) items related to experiences and relationships with OMT. Conclusion Patient viewpoints on efficacy were correlated with the pharmacological benefits of OMT and with the associated psychosocial measures. The implications of OMT in relationships, such as the feeling of being judged, concerned a majority. Points of view were ambivalent concerning the role of OMT as a treatment or as a drug. Involving patient points of view in therapeutic strategies decisions could help enhance positive views among PWUD on OMT and help PWUD towards their recovery. Trial registration: OPAL study was registered: (NCT01847729).

Abstract Background To validate the ability of PROS (vitamin K-dependent protein S) and CO7 (complement component C7) to predict response to the methotrexate (MTX)/etanercept (ETA) combination in rheumatoid arthritis (RA) patients who received this therapeutic combination in a well-documented cohort. Method From the ESPOIR cohort, RA patients having received the MTX/ETA or MTX/adalimumab (ADA) combination as a first-line biologic treatment were included. Serum concentrations of PROS and CO7 were measured by ELISA prior to the initiation of ETA or ADA, at a time where the disease was active (DAS28 ESR > 3.2). The clinical efficacy (response/non-response) of both combinations has been evaluated after at least 6 months of treatment, according to the EULAR response criteria with some modifications. Results Thirty-two were treated by MTX/ETA; the numbers of responders and non-responders were 24 and 8, respectively. Thirty-three patients received the MTX/ADA combination; 27 and 5 patients were respectively responders and non-responders. While there were no differences for demographic, clinical, biological, and X-rays data, as well as for CO7, serum levels of PROS tended to be significantly higher in responders to the MTX/ETA combination (p = 0.08) while no difference was observed in the group receiving MTX/ADA. For PROS, the best concentration threshold to differentiate both groups was calculated at 40 μg/ml using ROC curve. The theranostic performances of PROS appeared better for the ETA/MTX combination. When considering the response to this combination, analysis of pooled data from ESPOIR and SATRAPE (initially used to validate PROS and CO7 as potential theranostic biomarkers) cohorts led to a higher theranostic value of PROS that became significant (p = 0.009). Conclusion PROS might be one candidate of a combination of biomarkers capable of predicting the response to MTX/ETA combination in RA patients refractory to MTX. Trial registration ClinicalTrials.gov identifiers: NCT03666091 and NCT00234234 .

The TGFβ family member NODAL, repeatedly required during embryonic development, has also been associated with tumour progression. Our aim was to clarify the controversy surrounding its involvement in melanoma tumour progression. We found that the deletion of the NODAL exon 2 in a metastatic melanoma cell line impairs its ability to form tumours and colonize distant tissues. However, we show that this phenotype does not result from the absence of NODAL, but from a defect in the expression of a natural antisense transcript of NODAL, here called LADON. We show that LADON expression is specifically activated in metastatic melanoma cell lines, that its transcript is packaged in exosomes secreted by melanoma cells, and that, via its differential impact on the expression of oncogenes and tumour suppressors, it promotes the mesenchymal to amoeboid transition that is critical for melanoma cell invasiveness. LADON is, therefore, a new player in the regulatory network governing tumour progression in melanoma and possibly in other types of cancer.