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Abstract The cloud parameterizations of the LMDZ6A climate model (the atmospheric component of the IPSL‐CM6 Earth system model) are entirely described, and the global cloud distribution and cloud radiative effects are evaluated against the CALIPSO‐CloudSat and CERES observations. The cloud parameterizations in recent versions of LMDZ favor an object‐oriented approach for convection, with two distinct parameterizations for shallow and deep convection and a coupling between convection and cloud description through the specification of the subgrid‐scale distribution of water. Compared to the previous version of the model (LMDZ5A), LMDZ6A better represents the low‐level cloud distribution in the tropical belt, and low‐level cloud reflectance and cover are closer to the PARASOL and CALIPSO‐GOCCP observations. Mid‐level clouds, which were mostly missing in LMDZ5A, are now better represented globally. The distribution of cloud liquid and ice in mixed‐phase clouds is also in better agreement with the observations. Among identified deficiencies, low‐level cloud covers are too high in mid‐latitude to high‐latitude regions, and high‐level cloud covers are biased low globally. However, the cloud global distribution is significantly improved, and progress has been made in the tuning of the model, resulting in a radiative balance in close agreement with the CERES observations. Improved tuning also revealed structural biases in LMDZ6A, which are currently being addressed through a series of new physical and radiative parameterizations for the next version of LMDZ.

Abstract The Radiative‐Convective Equilibrium Model Intercomparison Project (RCEMIP) is an intercomparison of multiple types of numerical models configured in radiative‐convective equilibrium (RCE). RCE is an idealization of the tropical atmosphere that has long been used to study basic questions in climate science. Here, we employ RCE to investigate the role that clouds and convective activity play in determining cloud feedbacks, climate sensitivity, the state of convective aggregation, and the equilibrium climate. RCEMIP is unique among intercomparisons in its inclusion of a wide range of model types, including atmospheric general circulation models (GCMs), single column models (SCMs), cloud‐resolving models (CRMs), large eddy simulations (LES), and global cloud‐resolving models (GCRMs). The first results are presented from the RCEMIP ensemble of more than 30 models. While there are large differences across the RCEMIP ensemble in the representation of mean profiles of temperature, humidity, and cloudiness, in a majority of models anvil clouds rise, warm, and decrease in area coverage in response to an increase in sea surface temperature (SST). Nearly all models exhibit self‐aggregation in large domains and agree that self‐aggregation acts to dry and warm the troposphere, reduce high cloudiness, and increase cooling to space. The degree of self‐aggregation exhibits no clear tendency with warming. There is a wide range of climate sensitivities, but models with parameterized convection tend to have lower climate sensitivities than models with explicit convection. In models with parameterized convection, aggregated simulations have lower climate sensitivities than unaggregated simulations.

Background: PRR (Pattern Recognition Receptor) agonists have been widely tested as potent vaccine adjuvants. TLR7 (Toll-Like Receptor 7) and NOD2 (nucleotide-binding oligomerization domain 2) are key innate receptors widely expressed at mucosal levels. Methods: Here, we evaluated the immunostimulatory properties of a novel hybrid chemical compound designed to stimulate both TLR7 and NOD2 receptors. Finding: The combined TLR7/NOD2 agonist showed increase efficacy than TLR7L or NOD2L agonists alone or combined in different in vitro models. Dual TLR7/NOD2 agonist efficiently stimulates TLR7 and NOD2, and promotes the maturation and reprogramming of human dendritic cells, as well as the secretion of pro-inflammatory or adaptive cytokines. This molecule also strongly induces autophagy in human cells which is a major intracellular degradation system that delivers cytoplasmic constituents to lysosomes in both MHC class I and II-restricted antigen presentation. In vivo, TLR7/NOD2L agonist is a potent adjuvant after intranasal administration with NP-p24 HIV vaccine, inducing high-quality humoral and adaptive responses both in systemic and mucosal compartments. Use of TLR7/NOD2L adjuvant improves very significantly the protection of mice against an intranasal challenge with a vaccinia virus expressing the p24. Interpretation: Dual TLR7/NOD2L agonist is a very potent and versatile vaccine adjuvant and promote very efficiently both systemic and mucosal immunity. Funding: This work was supported by Sidaction.

Objectives Presently, those outcomes that should be prioritised for chronic obstructive pulmonary disease (COPD) exacerbation studies remain unclear. In order to coordinate multicentre studies on eosinophilia-driven corticosteroid therapy for patients hospitalised for acute exacerbation of COPD (AECOPD), we aimed to find consensus among experts in the domain regarding the prioritisation of outcomes.Design A modified Delphi study was proposed to recognised COPD experts. Two brainstorming questionnaires were used to collect potential outcomes. Four subsequent rounds of questionnaires were used to rank items according to a six-point Likert scale for their importance in the protocol, as well as for being the primary outcome. Priority outcome criteria were predefined as those for which ≥70% of experts indicated that the outcome was essential for interpreting study results.Setting COPD exacerbation management in France.Participants 34 experts recommended by the French Language Pulmonology Society were invited to participate. Of the latter, 21 experts participated in brainstorming, and 19 participated in all four ranking rounds.Results 105 outcomes were ranked. Two achieved consensus as candidate primary outcomes: (1) treatment failure defined as death from any cause or the need for intubation and mechanical ventilation, readmission because of COPD or intensification of pharmacologic therapy, and (2) the time required to meet predefined discharge criteria. The 10 secondary priority outcomes included survival, time with no sign of improvement, episodes of hospitalisation, exacerbation, pneumonia, mechanical or non-invasive ventilation and oxygen use, as well as comorbidities during the initial hospitalisation.Conclusions This Delphi consensus project generated and prioritised a great many outcomes, documenting current expert views concerning a diversity of COPD endpoints. Among the latter, 12 reached consensus as priority outcomes for evaluating the efficacy of eosinophil-driven corticosteroid therapy in AECOPD inpatients.Study registration The eo-Delphi project/protocol was registered on 23 January 2018 at https://osf.io/4ahqw/.

Abstract This study presents the version of the LMDZ global atmospheric model used as the atmospheric component of the Institut Pierre Simon Laplace coupled model (IPSL‐CM6A‐LR) to contribute to the 6th phase of the international Coupled Model Intercomparison Project (CMIP6). This LMDZ6A version includes original convective parameterizations that define the LMDZ “New Physics”: a mass flux parameterization of the organized structures of the convective boundary layer, the “thermal plume model,” and a parameterization of the cold pools created by reevaporation of convective rainfall. The vertical velocity associated with thermal plumes and gust fronts of cold pools are used to control the triggering and intensity of deep convection. Because of several shortcomings, the early version 5B of this New Physics was worse than the previous “Standard Physics” version 5A regarding several classical climate metrics. To overcome these deficiencies, version 6A includes new developments: a stochastic triggering of deep convection, a modification of the thermal plume model that allows the representation of stratocumulus and cumulus clouds in a unified framework, an improved parameterization of very stable boundary layers, and the modification of the gravity waves scheme targeting the quasi‐biennal oscillation in the stratosphere. These improvements to the physical content and a more well‐defined tuning strategy led to major improvements in the LMDZ6A version model climatology. Beyond the presentation of this particular model version and documentation of its climatology, the present paper underlines possible methodological pathways toward model improvement that can be shared across modeling groups.

Abstract This study presents the global climate model IPSL‐CM6A‐LR developed at Institut Pierre‐Simon Laplace (IPSL) to study natural climate variability and climate response to natural and anthropogenic forcings as part of the sixth phase of the Coupled Model Intercomparison Project (CMIP6). This article describes the different model components, their coupling, and the simulated climate in comparison to previous model versions. We focus here on the representation of the physical climate along with the main characteristics of the global carbon cycle. The model's climatology, as assessed from a range of metrics (related in particular to radiation, temperature, precipitation, and wind), is strongly improved in comparison to previous model versions. Although they are reduced, a number of known biases and shortcomings (e.g., double Intertropical Convergence Zone [ITCZ], frequency of midlatitude wintertime blockings, and El Niño–Southern Oscillation [ENSO] dynamics) persist. The equilibrium climate sensitivity and transient climate response have both increased from the previous climate model IPSL‐CM5A‐LR used in CMIP5. A large ensemble of more than 30 members for the historical period (1850–2018) and a smaller ensemble for a range of emissions scenarios (until 2100 and 2300) are also presented and discussed.

Options to achieve oral corticosteroid (OCS)-sparing have been triggering increasing interest since the 1970s because of the side-effects of OCSs, and this has now become achievable with biologics. The Société de Pneumologie de Langue Française workshop on OCSs aimed to conduct a comprehensive review of the basics for OCS use in asthma and issue key research questions. Pharmacology and definition of regular use were reviewed by the first working group (WG1). WG2 examined whether regular OCS use is associated with T2 endotype. WG3 reported on the specificities of the paediatric area. Key “research statement proposals” were suggested by WG4. It was found that the benefits of regular OCS use in asthma outside episodes of exacerbations are poorly supported by the existing evidence. However, complete OCS elimination couldn’t be achieved in any available studies for all patients and the panel felt that it was too early to conclude that regular OCS use could be declared criminal. Repeated or prolonged need for OCS beyond 1 g·year−1 should indicate the need for referral to secondary/tertiary care. A strategic sequential plan aiming at reducing overall exposure to OCS in severe asthma was then held as a conclusion of the workshop.

Since bacterial consortia involved in conventional wastewater treatment processes are not efficient in removing diclofenac (DCF), an emerging pollutant frequently detected in water bodies, the identification of microorganisms able to metabolise this pharmaceutical compound is relevant. Thus, DCF removal was investigated using bacteria isolated from aqueous stock solutions of this micropollutant and identified as Bacillus and Brevibacillus species using 16S rRNA gene sequencing. A 100% DCF removal was achieved after 17 hours of experiment at 20°C in a nutrient medium; the biodegradation kinetic followed a pseudo-first order (kbiol = 11 L·gSS−1·d−1). Quantitative assessment of DCF removal showed that its main route was biotic degradation. The main degradation product of DCF, 4′-hydroxy-diclofenac (4′-OH-DCF), was identified using liquid chromatography-electrospray ionisation high-resolution mass spectrometry. Since the ecotoxicological impact of 4′-hydroxy-diclofenac was not reported in the literature, the ecotoxicity of DCF and its metabolite were tentatively evaluated using Vibrio fischeri bioassays. Results from these tests showed that this metabolite is not more toxic than its parent compound and may hopefully be an intermediate product in the DCF transformation. Indeed, no significant difference in ecotoxicity was observed after 30 min between DCF (50 should be writtten in subscript all along the manuscript in EC50 = 23 ± 4 mg·L−1) and 4′-hydroxy-diclofenac (EC50 = 19 ± 2 mg·L−1). Besides, the study highlighted a limit of the Microtox® bioassay, which is largely used to assess ecotoxicity. The bioluminescence of Vibrio fischeri was impacted due to the production of microbial activity and the occurrence of some carbon source in the studied medium.

Abstract Background After stroke, spasticity of the rectus femoris (RF) and triceps surae (TS) muscles frequently alters the gait pattern. Knee flexion and ankle dorsiflexion in swing are often reduced, respectively called Stiff Knee Gait (SKG) and equinus. A preliminary uncontrolled study suggested that botulinum toxin type A (BTX-A) injections could improve muscle length and force generated during gait, improving inter-segmental coordination. The aim of this randomised controlled study is thus to evaluate changes in the length of the RF and TS muscles during gait 1 month after either BTX-A or placebo injection in patients with chronic stroke, SKG and spastic equinus. The secondary aims are to evaluate peak length and peak force generated during gait, as well inter-segmental coordination assessed using the continuous relative phase method initially described by Barela et al. in patients with stroke. Methods This is a prospective, three-centre, randomised, placebo-controlled, triple blind study over 3 months with 4 visits. Forty patients will be included. During visits V1, V3 and V4, length and force generated by RF and TS during gait will be assessed using musculoskeletal models (MSM). Muscle force will also be assessed using an isokinetic dynamometer. Inter segmental coordination will be evaluated using 3D gait analysis and functional tests will be performed. During V2, patients will receive either an injection of BTX-A in the RF and TS muscles or a placebo injection of saline solution. Discussion We expect an increase in peak length and a decrease in peak force generated by the RF and TS muscles in the BTX-A group 1 month post injection. Moreover, we expect these parameters to be more improved in the BTX-A than the Control group. This is the first study to assess these parameters in a randomised, controlled trial using instrumented methods (isokinetic evaluation and 3D gait analysis). The results should help to improve understanding of the mechanism(s) underlying improvements in inter-segmental coordination that have been found in many previous uncontrolled studies. Trial registration ClinicalTrials.gov: NCT01821573, First received: March 27, 2013 Last updated: September 14, 2016 Last verified: September 2016 Other Study ID Numbers: P110136 AOM11223.

Abstract Background Incorrect inhaler technique is a common cause of poor asthma control. This two-phase pragmatic study evaluated inhaler technique mastery and maintenance of mastery with DuoResp® (budesonide-formoterol [BF]) Spiromax® compared with Symbicort® (BF) Turbuhaler® in patients with asthma who were receiving inhaled corticosteroids/long-acting β2-agonists. Methods In the initial cross-sectional phase, patients were randomized to a 6-step training protocol with empty Spiromax and Turbuhaler devices. Patients initially demonstrating ≥1 error with their current device, and then achieving mastery with both Spiromax and Turbuhaler (absence of healthcare professional [HCP]-observed errors), were eligible for the longitudinal phase. In the longitudinal phase, patients were randomized to BF Spiromax or BF Turbuhaler. Co-primary endpoints were the proportions of patients achieving device mastery after three training steps and maintaining device mastery (defined as the absence of HCP-observed errors after 12 weeks of use). Secondary endpoints included device preference, handling error frequency, asthma control, and safety. Exploratory endpoints included assessment of device mastery by an independent external expert reviewing video recordings of a subset of patients. Results Four hundred ninety-three patients participated in the cross-sectional phase, and 395 patients in the longitudinal phase. In the cross-sectional phase, more patients achieved device mastery after three training steps with Spiromax (94%) versus Turbuhaler (87%) (odds ratio [OR] 3.77 [95% confidence interval (CI) 2.05–6.95], p

Abstract Background Anticipating the future burden of chronic obstructive pulmonary disease (COPD) is required to develop adequate public health policies. Methods A dynamic population model was built to estimate COPD prevalence by 2025 using data collected during the most recent large general population study on COPD prevalence in France (2005) as baseline values. Sensitivity analyses were performed to test the effect of variations in key input variables. Results The model predicted a steady increase in crude COPD prevalence among subjects aged≥45 years from 2005 (prevalence estimate: 84.51‰) to 2025 (projected prevalence: 95.76‰, + 0.56‰/yr). There was a 4-fold increase in the prevalence of GOLD grade 3–4 cases, a 23% relative increase in women and a 21% relative increase in subjects ≥75 years. In sensitivity analyses, these temporal trends were robust. Factors associated with > 5% relative variations in projected 2025 prevalence estimates were baseline prevalence and severity distribution, incidence in women and severity of incident cases, transition rates between severity grades, and mortality. Conclusions Projections of future COPD epidemiology consistently predict an increase in the prevalence of moderate-to-very severe COPD, especially due to increases among women and subjects aged ≥75 years. Developing robust prediction models requires collecting reliable data on current COPD epidemiology.

Abstract Background External validations and comparisons of prognostic models or scores are a prerequisite for their use in routine clinical care but are lacking in most medical fields including chronic obstructive pulmonary disease (COPD). Our aim was to externally validate and concurrently compare prognostic scores for 3-year all-cause mortality in mostly multimorbid patients with COPD. Methods We relied on 24 cohort studies of the COPD Cohorts Collaborative International Assessment consortium, corresponding to primary, secondary, and tertiary care in Europe, the Americas, and Japan. These studies include globally 15,762 patients with COPD (1871 deaths and 42,203 person years of follow-up). We used network meta-analysis adapted to multiple score comparison (MSC), following a frequentist two-stage approach; thus, we were able to compare all scores in a single analytical framework accounting for correlations among scores within cohorts. We assessed transitivity, heterogeneity, and inconsistency and provided a performance ranking of the prognostic scores. Results Depending on data availability, between two and nine prognostic scores could be calculated for each cohort. The BODE score (body mass index, airflow obstruction, dyspnea, and exercise capacity) had a median area under the curve (AUC) of 0.679 [1st quartile–3rd quartile = 0.655–0.733] across cohorts. The ADO score (age, dyspnea, and airflow obstruction) showed the best performance for predicting mortality (difference AUCADO – AUCBODE = 0.015 [95% confidence interval (CI) = −0.002 to 0.032]; p = 0.08) followed by the updated BODE (AUCBODE updated – AUCBODE = 0.008 [95% CI = −0.005 to +0.022]; p = 0.23). The assumption of transitivity was not violated. Heterogeneity across direct comparisons was small, and we did not identify any local or global inconsistency. Conclusions Our analyses showed best discriminatory performance for the ADO and updated BODE scores in patients with COPD. A limitation to be addressed in future studies is the extension of MSC network meta-analysis to measures of calibration. MSC network meta-analysis can be applied to prognostic scores in any medical field to identify the best scores, possibly paving the way for stratified medicine, public health, and research.

Objective: To assess temporal congruence (the difference in performance-time and time to imagine) between the sub-tasks of the Expanded Timed Up and Go (ETUG) and imagined ETUG (iETUG) tests in patients with hemiparesis following unilateral hemispheric stroke, and to compare the results with those for with healthy subjects. Design: Case-controlled study. Subject/patients: Twenty patients with chronic stroke and 20 healthy subjects. Methods: TUG, ETUG and iETUG test performance times were recorded for all participants. Temporal congruence was calculated with the following formula: (ETUG-iETUG)/[(ETUG+iETUG)/2]*100. Results: Patients’ performances were slower than those of healthy subjects for all 5 sub-tasks of the TUG, ETUG and iETUG tests. However, there was no significant difference in temporal congruence between healthy subjects and patients. Intragroup analysis showed significant differences between the executed and the imagined conditions for both groups for the “walking”, “turn around” and “sitting” phases (healthy subjects p = 0.01, p = 0.03, p = 0.03, and patients p = 0.01, p = 0.003, p = 0.003, respectively). Conclusion: Temporal congruence was similar for healthy subjects and patients for all sub-tasks of the ETUG test. Moreover, temporal congruence was reduced for the same sub-tasks of the ETUG test in patients and healthy subjects. This suggests that the motor imagery involved the same cerebral structures in both groups, probably including the cerebellum, since it was intact in all patients.

Abstract Clinical practice guidelines are ubiquitous and are developed to provide recommendations for the management of many diseases, including chronic obstructive pulmonary disease. The development of these guidelines is burdensome, demanding a significant investment of time and money. In Europe, the majority of countries develop their own national guidelines, despite the potential for overlap or duplication of effort. A concerted effort and consolidation of resources between countries may alleviate the resource-intensity of maintaining individual national guidelines. Despite significant resource investment into the development and maintenance of clinical practice guidelines, their implementation is suboptimal. Effective strategies of guideline dissemination must be given more consideration, to ensure adequate implementation and improved patient care management in the future.

Located in a semi-arid to arid region, Morocco is confronting increasing water scarcity challenges. In the circular economy paradigm, the reuse of treated wastewater in agriculture is currently considered a possible solution to mitigate water shortage and pollution problems. In recent years, Morocco has made significative progress in urban wastewater treatment under the National Wastewater Program (PNA). However, rural sanitation has undergone significant delays. Therefore, an alternative technology for wastewater treatment and reuse in rural areas is investigated in this review, considering the region’s economic, social, and regulatory characteristics. Constructed wetlands (CWs) are a simple, sustainable, and cost-effective technology that has yet to be fully explored in Morocco. CWs, indeed, appear to be suitable for the treatment and reuse of wastewater in remote rural areas if they can produce effluent that meets the standards of agricultural irrigation. In this review, 29 studies covering 16 countries and different types of wastewater were collected and studied to assess the treatment efficiency of different types of CWs under different design and operational parameters, as well as their potential application in agricultural reuse. The results demonstrated that the removal efficiency of conventional contamination such as organic matter and suspended solids is generally high. CWs also demonstrated a remarkable capacity to remove heavy metals and emerging contaminants such as pharmaceuticals, care products, etc. The removal of microbial contamination, on the other hand, is challenging, and does not satisfy the standards all the time. However, it can be improved using hybrid constructed wetlands or by adding polishing treatment. In addition, several studies reported that CWs managed to produce effluent that met the requirements of wastewater reuse in agriculture of different countries or organisations including Morocco.

This experimental paper deals with the development of a hybrid biological reactor for the treatment of a synthetic oilfield produced water under an increase in total dissolved solids (TDS) concentration. To comply with strengthening regulations concerning produced water discharge and peculiar produced water compositions, a moving bed biofilm reactor (MBBR) consisting in a combination of free activated sludge and moving biofilm supports was compared to a fixed bed hybrid biological reactor (FBHBR) consisting in a combination of free activated sludge and a fixed biofilm support. After a 216 days experimental period, the MBBR and the FBHBR were efficient to treat a synthetic produced water with chemical oxygen demand (COD) removal rate above 90% under an increase in TDS concentrations from 1.5 to 20 g·L−1. Ecotoxicity measurements on freshwater and marine microorganisms revealed an absence of toxicity on treated waters. A decrease in bacterial diversity indices with respect to the inoculum was observed in both bioreactors. This suggests that the increase in TDS concentrations caused the predominance of a low number of bacterial species.

Abstract Background This study assessed the cost-effectiveness of indacaterol/glycopyrronium (IND/GLY) versus salmeterol/fluticasone (SFC) in chronic obstructive pulmonary disease (COPD) patients with moderate to very severe airflow limitation and ≥1 exacerbation in the preceding year. Methods A previously published and validated patient-level simulation model was adapted using clinical data from the FLAME trial and real-world cost data from the ARCTIC study. Costs (total monetary costs comprising drug, maintenance, exacerbation, and pneumonia costs) and health outcomes (life-years (LYs), quality-adjusted life-years (QALYs)) were projected over various time horizons (1, 5, 10 years, and lifetime) from the Swedish payer’s perspective and were discounted at 3% annually. Uncertainty in model input values was studied through one-way and probabilistic sensitivity analyses. Subgroup analyses were also performed. Results IND/GLY was associated with lower costs and better outcomes compared with SFC over all the analysed time horizons. Use of IND/GLY resulted in additional 0.192 LYs and 0.134 QALYs with cost savings of €1211 compared with SFC over lifetime. The net monetary benefit (NMB) was estimated to be €8560 based on a willingness-to-pay threshold of €55,000/QALY. The NMB was higher in the following subgroups: severe (GOLD 3), high risk and more symptoms (GOLD D), females, and current smokers. Conclusion IND/GLY is a cost-effective treatment compared with SFC in COPD patients with mMRC dyspnea grade ≥ 2, moderate to very severe airflow limitation, and ≥1 exacerbation in the preceding year.

Abstract  We have used an electromigration technique to fabricate a C60 single-molecule transistor (SMT). Besides describing our electromigration procedure, we focus and present an experimental study of a single molecule quantum dot containing an even number of electrons, revealing, for two different samples, a clear out-of-equilibrium Kondo effect. Low temperature magneto-transport studies are provided, which demonstrates a Zeeman splitting of the finite bias anomaly. [ABSTRACT FROM AUTHOR]

Pharmaceutical products have become a necessary part of life. Several studies have demonstrated that indirect exposure of humans to pharmaceuticals through the water could cause negative effects. Raw sewage and wastewater effluents are the major sources of pharmaceuticals found in surface waters and drinking water. Therefore, it is important to consider and characterize the efficiency of pharmaceutical removal during wastewater and drinking-water treatment processes. Various treatment options have been investigated for the removal/reduction of drugs (e.g., antibiotics, NSAIDs, analgesics) using conventional or biological treatments, such as activated sludge processes or bio-filtration, respectively. The efficiency of these processes ranges from 20–90%. Comparatively, advanced wastewater treatment processes, such as reverse osmosis, ozonation and advanced oxidation technologies, can achieve higher removal rates for drugs. Pharmaceuticals and their metabolites undergo natural attenuation by adsorption and solar oxidation. Therefore, pharmaceuticals in water sources even at trace concentrations would have undergone removal through biological processes and, if applicable, combined adsorption and photocatalytic degradation wastewater treatment processes. This review provides an overview of the conventional and advanced technologies for the removal of pharmaceutical compounds from water sources. It also sheds light on the key points behind adsorption and photocatalysis.

Objective: We aimed to investigate the prognostic performances of oxidative stress (OS), inflammatory and cell activation biomarkers measured at admission in COVID-19 patients. Design: retrospective monocentric study. Setting: patients with suspected SARS-CoV-2 infection (COVID-19) admitted to the hospital. Patients: One hundred and sixty documented and unselected COVID-19-patients. Disease severity (from mild to critical) was scored according to NIH’s classification. Interventions: none. Measurements and main results: We measured OS biomarkers (thiol, advanced oxidation protein products (AOPP), ischemia-modified albumin (IMA)), inflammation biomarkers (interleukin-6 (IL-6), presepsin) and cellular activation biomarkers (calprotectin) in plasma at admission. Thiol concentrations decreased while IMA, IL-6, calprotectin and PSEP increased with disease severity in COVID-19 patients and were associated with increased O2 needs and ICU admission. The best area under the receiver-operating-characteristics curve (AUC) for the prediction of ICU admission was for thiol (AUC = 0.762). A thiol concentration

Objective: Fatigue and fatigability are common problems in patients with multiple sclerosis, which might be improved by rehabilitation. The aim of this pilot study was to assess changes in the fatigue and fatigability of knee extensors in patients with multiple sclerosis after a short intensive, combined rehabilitation programme (including physiotherapy primarily focused on gait and balance, endurance and resistance training). Methods: Twenty-three patients with multiple sclerosis (10 men, 13 women) underwent isokinetic evaluations of fatigability of the knee extensor muscles during concentric contractions and rated a self-reported fatigue scale (Modified Fatigue Impact Scale; MFIS) before and after a rehabilitation programme. Patients performed rehabilitation for 150 min, 4 days per week for 4 weeks, with physiotherapy focused primarily on gait and balance, endurance training and resistance training. Results: After rehabilitation, perception of fatigue decreased significantly (median MFIS scores [1st; 3rd quartiles], pre: 44 [33; 53] vs post: 33.5 [16; 43];

Abstract Background Dry powder inhalers (DPIs) are often used in asthma and chronic obstructive pulmonary disease (COPD) therapies. Using the discrete choice experiment (DCE) methodology, this study conducted in France was designed to assess patients’ preferences for different attributes of DPIs. Methods Attributes of DPIs were defined based on a literature review, patient focus group discussions and interviews with healthcare professionals (qualitative phase of the study). An online survey was then conducted among French patients with asthma or COPD to elicit patient preferences and willingness to pay (WTP) for these attributes using the DCE methodology (quantitative phase). A fractional factorial design including three blocks of 12 choice sets was created. Each choice set comprised three alternatives: two fictitious inhalers and the patient’s current inhaler. Marginal utilities were estimated using a ranked ordered logit model. Interactions between attributes and disease (asthma or COPD) were tested. Results Six DPI attributes were defined based on the qualitative phase: ease of use/fool-proof priming; accurate and easy-to-read dose counter; dose confirmation; hygiene of the mouthpiece; flexibility of the device handling; ability to use the inhaler with breathing difficulties. Overall, 201 patients with asthma and 93 with COPD were included in the online survey. Patients with asthma placed most value on an inhaler that requires one step for dose preparation (WTP €4.83 [95% CI: €3.77–€5.90], relative to an inhaler requiring four steps) and one that could be used during episodes of breathing difficulties (WTP €4.49 [95% CI: €2.95–€6.02]). Patients with COPD placed most value on an inhaler that could be used during episodes of breathing difficulties (WTP €7.70 [95% CI: €5.65–€9.76]) and on the accuracy of the dose counter (WTP €5.87 [95% CI: €3.98–€ 7.77]). Conclusion This study suggests that asthma and COPD patients would be willing to change their inhaler if they were offered the option of a new inhaler with improved characteristics and they place a high value on an inhaler with ease of use during breathing difficulty episodes.

Abstract Background Long-term multicentre studies are subject to numerous factors that may affect the integrity of their conclusions. Quality control and standardization of data collection are crucial to minimise the biases induced by these factors. Nevertheless, tools implemented to manage biases are rarely described in publications about population-based cohorts. This report aims to describe the processes implemented to control biases in the Constances cohort taking lung function results as an example. Methods Constances is a general-purpose population-based cohort of 200,000 participants. Volunteers attend physical examinations at baseline and then every 5 years at selected study sites. Medical device specifications and measurement methods have to comply with Standard Operating Procedures developed by experts. Protocol deviations are assessed by on-site inspections and database controls. In February 2016, more than 94,000 participants yielding around 30 million readings from physical exams, had been covered by our quality program. Results Participating centres accepted to revise their practices in accordance with the study research specifications. Distributors of medical devices were asked to comply with international guidelines and Constances requirements. Close monitoring enhanced the quality of measurements and recordings of the physical exams. Regarding lung function testing, spirometry acceptability rates per operator doubled in some sites within a few months and global repeatability reached 96.7 % for 29,772 acceptable maneuvers. Conclusions Despite Constances volunteers being followed in multiple sites with heterogeneous materials, the investment of significant resources to set up and maintain a continuous quality management process has proved effective in preventing drifts and improving accuracy of collected data.

Cytomegalovirus (CMV) infects approximately 40% of adults in France and persists lifelong as a latent agent in different organs, including gut. A close relationship is observed between inflammation that favors viral expression and viral replication that exacerbates inflammation. In this context, CMV colitis may impact the prognosis of patients suffering from inflammatory bowel diseases (IBDs), and notably those with ulcerative colitis (UC). In UC, the mucosal inflammation and T helper cell (TH) 2 cytokines, together with immunomodulatory drugs used for controlling flare-ups, favor viral reactivation within the gut, which, in turn, increases mucosal inflammation, impairs corticoid and immunosuppressor efficacy (the probability of steroid resistance is multiplied by more than 20 in the case of CMV colitis), and enhances the risk for colectomy. This review emphasizes the virological tools that are recommended for exploring CMV colitis during inflammatory bowel diseases (IBD) and underlines the interest of using ganciclovir for treating flare-ups associated to CMV colitis in UC patients.

Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity, mortality and resource use worldwide. The goal of this official American Thoracic Society (ATS)/European Respiratory Society (ERS) Research Statement is to describe evidence related to diagnosis, assessment, and management; identify gaps in knowledge; and make recommendations for future research. It is not intended to provide clinical practice recommendations on COPD diagnosis and management. Clinicians, researchers and patient advocates with expertise in COPD were invited to participate. A literature search of Medline was performed, and studies deemed relevant were selected. The search was not a systematic review of the evidence. Existing evidence was appraised and summarised, and then salient knowledge gaps were identified. Recommendations for research that addresses important gaps in the evidence in all areas of COPD were formulated via discussion and consensus. Great strides have been made in the diagnosis, assessment and management of COPD, as well as understanding its pathogenesis. Despite this, many important questions remain unanswered. This ATS/ERS research statement highlights the types of research that leading clinicians, researchers and patient advocates believe will have the greatest impact on patient-centred outcomes.

A hybrid membrane bioreactor (HMBR) comprises activated sludge (free biomass), a biofilm (supported biomass), and a membrane separation. A laboratory pilot-scale HMBR was operated for seven months with high organic loads of both carbonic and nitrogen pollutants. Several experiments were conducted to investigate the influence of the height of the packing bed (27 cm, 50 cm, and 0 cm) and the effect of the concentration of dissolved oxygen (DO) on the organic removal rate, total nitrogen removal rate (TN), and ammonium removal. The organic removal rate was always >95% and mostly >98%. The NH4+-N and TN removal rates were directly related to DO. NH4+-N removal rate reached 100% and was mostly >99% with a concentration of DO > 0.1 mg/L, whereas the NO3--N removal rate was differentially affected depending on the level of DO. The removal rate increased when the concentration of DO was optimal for simultaneous nitrification and denitrification, which was between 0.1 and 0.5 mg/l, and the TN removal rate was consequently high. The removal rate decreased when DO was high and denitrification was consequently low thereby reducing the TN removal rate. This implies that high levels of DO (>1 mg/L) limit the denitrification process and low levels of DO (

This study aimed to identify and qualify grasp-types used by patients with stroke and determine the clinical parameters that could explain the use of each grasp. Thirty-eight patients with chronic stroke-related hemiparesis and a range of motor and functional capacities (17 females and 21 males, aged 25-78), and 10 healthy subjects were included. Four objects were used (tissue packet, teaspoon, bottle and tennis ball). Participants were instructed to "grasp the object as if you are going to use it". Three trials were video-recorded for each object. A total of 456 grasps were analysed and rated using a custom-designed Functional Grasp Scale. Eight grasp-types were identified from the analysis: healthy subjects used Multi-pulpar, Pluri-digital, Lateral-pinch and Palmar grasps (Standard Grasps). Patients used the same grasps with in addition Digito-palmar, Raking, Ulnar and Interdigital grasps (Alternative Grasps). Only patients with a moderate or relatively good functional ability used Standard grasps. The correlation and regression analyses showed this was conditioned by sufficient finger and elbow extensor strength (Pluri-digital grasp); thumb extensor and wrist flexor strength (Lateral pinch) or in forearm supinator strength (Palmar grasp). By contrast, the patients who had severe impairment used Alternative grasps that did not involve the thumb. These strategies likely compensate specific impairments. Regression and correlation analyses suggested that weakness had a greater influence over grasp strategy than spasticity. This would imply that treatment should focus on improving hand strength and control although reducing spasticity may be useful in some cases.

Motor imagery (MI) capacity may be altered following stroke. MI is evaluated by measuring temporal congruence between the timed performance of an imagined and an executed task. Temporal congruence between imagined and physical gait-related activities has not been evaluated following stroke. Moreover, the effect of cognitive dysfunction on temporal congruence is not known.To assess temporal congruence between the Timed Up and Go test (TUG) and the imagined TUG (iTUG) tests in patients with stroke and to investigate the role played by cognitive dysfunctions in changes in temporal congruence.TUG and iTUG performance were recorded and compared in twenty patients with chronic stroke and 20 controls. Cognitive function was measured using the Montreal Cognitive Assessment (MOCA), the Frontal Assessment Battery at Bedside (FAB) and the Bells Test.The temporal congruence of the patients with stroke was significantly altered compared to the controls, indicating a loss of MI capacity (respectively 45.11 ±35.11 vs 24.36 ±17.91, p = 0.02). Furthermore, iTUG test results were positively correlated with pathological scores on the Bells Test (r = 0.085, p = 0.013), likely suggesting that impairment of attention was a contributing factor.These results highlight the importance of evaluating potential attention disorder in patients with stroke to optimise the use of MI for rehabilitation and recovery. However further study is needed to determine how MI should be used in the case of cognitive dysfunction.

This review is the summary of a workshop on small airways disease, which took place in Porquerolles, France in November 2011. The purpose of this workshop was to review the evidence on small airways (bronchiolar) involvement under various pathophysiological circumstances, excluding asthma and chronic obstructive pulmonary disease. Histopathological patterns associated with small airways disease were reviewed, including cellular and obliterative bronchiolitis. Many pathophysiological conditions have been associated with small airways disease including airway infections, connective tissue diseases and inflammatory bowel diseases, bone marrow and lung transplantation, common variable immunodeficiency disorders, diffuse panbronchiolitis, and diseases related to environmental exposures to pollutants, allergens and drugs. Pathogenesis, clinical presentation, a computed tomography scan and pulmonary function test findings are reviewed, and therapeutic options are described with the objective of providing an integrative approach to these disorders.

Asthma management guidelines recommend adding a long-acting β2-agonist (LABA) or increasing the dose of inhaled corticosteroid (ICS) as step-up therapy for patients with uncontrolled asthma on ICS monotherapy. However, it is uncertain which option works best, which ICS particle size is most effective, and whether LABA should be administered by separate or combination inhalers. This historical, matched cohort study compared asthma-related outcomes for patients (aged 12–80 years) prescribed step-up therapy as a ≥50% extrafine ICS dose increase or add-on LABA, via either a separate inhaler or a fine-particle ICS/LABA fixed-dose combination (FDC) inhaler. Risk-domain asthma control was the primary end-point in comparisons of cohorts matched for asthma severity and control during the baseline year. After 1:2 cohort matching, the increased extrafine ICS versus separate ICS+LABA cohorts included 3232 and 6464 patients, respectively, and the fine-particle ICS/LABA FDC versus separate ICS+LABA cohorts included 7529 and 15 058 patients, respectively (overall mean age 42 years; 61–62% females). Over one outcome year, adjusted OR (95% CI) for achieving asthma control were 1.25 (1.13–1.38) for increased ICS versus separate ICS+LABA and 1.06 (1.05–1.09) for ICS/LABA FDC versus separate ICS+LABA. For patients with asthma, increased dose of extrafine-particle ICS, or add-on LABA via ICS/LABA combination inhaler, is associated with significantly better outcomes than ICS+LABA via separate inhalers.

BACKGROUND:The Timed Up and Go (TUG) test is widely used to assess locomotion in patients with stroke and is considered to predict the risk of falls. The analysis of locomotor trajectories during the TUG appears pertinent in stroke patients. The aims of this study were i) to analyze locomotor trajectories in patients with stroke during the walking and turning sub-tasks of the TUG, and to compare them with healthy subjects, ii) to determine whether trajectory parameters provide additional information to that provided by the conventional measure (performance time), iii) to compare the trajectory parameters of fallers and non-fallers with stroke and of patients with right and left hemisphere stroke, and iv) to evaluate correlations between trajectory parameters and Berg Balance Scale scores. METHODS:29 patients with stroke (mean age 54.2±12.2 years, 18 men, 8 fallers) and 25 healthy subjects (mean age 51.6±8.7 years, 11 men) underwent three-dimensional analysis of the TUG. The trajectory of the center of mass was analyzed by calculation of the global trajectory length, Hausdorff distance and Dynamic Time Warping. The parameters were compared with a reference trajectory during the total task and each sub-task (Go, Turn, Return) of the TUG. RESULTS:Values of trajectory parameters were significantly higher for the stroke group during the total TUG and the Go and Turn sub-tasks (p

BACKGROUND:Coactivation of agonist and antagonist lower limb muscles during gait stiffens joints and ensures stability. In patients with multiple sclerosis, coactivation of lower limb muscles might be a compensatory mechanism to cope with impairments of balance and gait. OBJECTIVE:The aim of this study was to assess coactivation of agonist and antagonist muscles at the knee and ankle joints during gait in patients with multiple sclerosis, and to evaluate the relationship between muscle coactivation and disability, gait performance, dynamic ankle strength measured during gait, and postural stability. METHODS:The magnitude and duration of coactivation of agonist-antagonist muscle pairs at the knee and ankle were determined for both lower limbs (more and less-affected) in 14 patients with multiple sclerosis and 11 healthy subjects walking at a spontaneous speed, using 3D-gait analysis. RESULTS:In the patient group, coactivation was increased in the knee muscles during single support (proximal strategy) and in the ankle muscles during double support (distal strategy). The magnitude of coactivation was highest in the patients with the slowest gait, the greatest motor impairment and the most instability. CONCLUSION:Increased muscle coactivation is likely a compensatory mechanism to limit the number of degrees of freedom during gait in patients with multiple sclerosis, particularly when postural stability is impaired.

BackgroundThe timed up and go test (TUG) is a functional test which is increasingly used to evaluate patients with stroke. The outcome measured is usually global TUG performance-time. Assessment of spatiotemporal and kinematic parameters during the Oriented gait and Turn sub-tasks of the TUG would provide a better understanding of the mechanisms underlying patients' performance and therefore may help to guide rehabilitation. The aim of this study was thus to determine the spatiotemporal and kinematic parameters which were most related to the walking and turning sub-tasks of TUG performance in stroke patients.Methods29 stroke patients carried out the TUG test which was recorded using an optoelectronic system in two conditions: spontaneous and standardized condition (standardized foot position and instructed to turn towards the paretic side). They also underwent a clinical assessment. Stepwise regression was used to determine the parameters most related to Oriented gait and Turn sub-tasks. Relationships between explanatory parameters of Oriented gait and Turn performance and clinical scales were evaluated using Spearman correlations.ResultsStep length and cadence explained 82% to 95% of the variance for the walking sub-tasks in both conditions. Percentage single support phase and contralateral swing phase (depending on the condition) respectively explained 27% and 56% of the variance during the turning sub-task in the spontaneous and standardized conditions.Discussion and conclusionStep length, cadence, percentage of paretic single support phase and non-paretic swing phase, as well as dynamic stability were the main parameters related to TUG performance and they should be targeted in rehabilitation.

The Timed Up and Go (TUG) test is often used to estimate risk of falls. Foot clearance and displacement of the center of mass (COM), which are related to risk of tripping and dynamic stability have never been evaluated during the TUG. Accurate assessment of these parameters using instrumented measurements would provide a comprehensive assessment of risk of falls in hemiparetic patients. The aims of this study were to analyze correlations between TUG performance time and displacement of the COM and foot clearance in patients with stroke-related hemiparesis and healthy subjects during the walking and turning sub-tasks of the TUG and to compare these parameters between fallers and non-fallers.29 hemiparetic patients and 25 healthy subjects underwent three-dimensional gait analysis during the TUG test. COM and foot clearance were analyzed during the walking and turning sub-tasks of the TUG.Lateral displacement of the COM was greater and faster during the walking sub-tasks and vertical displacement of the COM was greater during the turn in the patients compared to the healthy subjects (respectively p

Introducción. Entre mayo y julio de 2004 ocurrió en la comunidad Embera de Birrinchao de cuenca del río Purricha, Bajo Baudó, Chocó un brote de rabia humana con 14 víctimas. En enero de 2005 otro brote similar ocurrió en las comunidades negras de Pató y Nauca, Alto Baudó, Chocó, con tres nuevas víctimas. Objetivos. Describir los brotes de rabia humana transmitida por vampiros de mayor magnitud hasta ahora reportados en Colombia. Describir las técnicas diagnósticas utilizadas y las acciones de control de foco aplicadas. Discutir sobre el significado epidemiológico de estos brotes y sus implicaciones en salud pública. Materiales y métodos. Los casos se diagnosticaron por inmunofluorescencia directa, prueba biológica en ratones e inmunohistoquímica. Los virus se tipificaron por inmunofluorescencia indirecta utilizando anticuerpos monoclonales. Las acciones de control de foco en Bajo Baudó consistieron en un censo poblacional, aplicación de vacuna y tratamientos antirrábicos a los pobladores, vacunación canina y felina y aplicación de anticoagulante a murciélagos. Resultados. Cuatro casos humanos fueron confirmados positivos para rabia de ambos brotes. Otros 13 se dedujeron por nexos epidemiológicos. La variante antigénica 3 fue caracterizada en dichos casos. Se llevaron a cabo acciones en Bajo Baudó diseñadas para el control de foco de rabia humana transmitida por vampiros. Conclusiones. El brote de rabia humana en Bajo Baudó 2004 ha sido el de mayor magnitud reportado en Colombia. Este fue causado por vampiros, demostrando la amenaza que representa la rabia de especies silvestres para la salud pública, y la necesidad de implementar acciones para evitar su impacto en humanos. Se desconoce si existen vínculos entre este brote y el reportado en Alto Baudó seis meses después.

The relationship between neuromuscular fatigue and locomotion has never been investigated in hemiparetic patients despite the fact that, in the clinical context, patients report to be more spastic or stiffer after walking a long distance or after a rehabilitation session. The aim of this study was to evaluate the effects of quadriceps muscle fatigue on the biomechanical gait parameters of patients with a stiff-knee gait (SKG). Thirteen patients and eleven healthy controls performed one gait analysis before a protocol of isokinetic quadriceps fatigue and two after (immediately after and after 10 minutes of rest). Spatiotemporal parameters, sagittal knee and hip kinematics, rectus femoris (RF) and vastus lateralis (VL) kinematics and electromyographic (EMG) activity were analyzed. The results showed that quadriceps muscle weakness, produced by repetitive concentric contractions of the knee extensors, induced an improvement of spatiotemporal parameters for patients and healthy subjects. For the patient group, the increase in gait velocity and step length was associated with i) an increase of sagittal hip and knee flexion during the swing phase, ii) an increase of the maximal normalized length of the RF and VL and of the maximal VL lengthening velocity during the pre-swing and swing phases, and iii) a decrease in EMG activity of the RF muscle during the initial pre-swing phase and during the latter 2/3 of the initial swing phase. These results suggest that quadriceps fatigue did not alter the gait of patients with hemiparesis walking with a SKG and that neuromuscular fatigue may play the same functional role as an anti-spastic treatment such as botulinum toxin-A injection. Strength training of knee extensors, although commonly performed in rehabilitation, does not seem to be a priority to improve gait of these patients.

BACKGROUND: Hypothesizing that nutritional status, systemic inflammation and tumoral immune microenvironment play a role as determinants of lung cancer evolution, the purpose of this study was to assess their respective impact on long-term survival in resected non-small cell lung cancers (NSCLC). METHODS AND FINDINGS: Clinical, pathological and laboratory data of 303 patients surgically treated for NSCLC were retrospectively analyzed. C-reactive protein (CRP) and prealbumin levels were recorded, and tumoral infiltration by CD8+ lymphocytes and mature dendritic cells was assessed. We observed that factors related to nutritional status, systemic inflammation and tumoral immune microenvironment were correlated; significant correlations were also found between these factors and other relevant clinical-pathological parameters. With respect to outcome, at univariate analysis we found statistically significant associations between survival and the following variables: Karnofsky index, American Society of Anesthesiologists (ASA) class, CRP levels, prealbumin concentrations, extent of resection, pathologic stage, pT and pN parameters, presence of vascular emboli, and tumoral infiltration by either CD8+ lymphocytes or mature dendritic cells and, among adenocarcinoma type, tumor grade (all p285 mg/L) prealbumin levels and high (>96/mm2) CD8+ cell count had a 5-year survival rate of 80% [60.9-91.1] as compared to 18% [7.9-35.6] in patients with an opposite pattern of values. When stages I-II were considered alone, the prognostic significance of these factors was even more pronounced. CONCLUSIONS: Our data show that nutrition, systemic inflammation and tumoral immune contexture are prognostic determinants that, taken together, may predict outcome.

Intestinal microfold (M) cells possess a high transcytosis capacity and are able to transport a broad range of materials including particulate antigens, soluble macromolecules, and pathogens from the intestinal lumen to inductive sites of the mucosal immune system. M cells are also the primary pathway for delivery of secretory IgA (SIgA) to the gut-associated lymphoid tissue. However, although the consequences of SIgA uptake by M cells are now well known and described, the mechanisms whereby SIgA is selectively bound and taken up remain poorly understood. Here we first demonstrate that both the Cα1 region and glycosylation, more particularly sialic acid residues, are involved in M cell-mediated reverse transcytosis. Second, we found that SIgA is taken up by M cells via the Dectin-1 receptor, with the possible involvement of Siglec-5 acting as a co-receptor. Third, we establish that transcytosed SIgA is taken up by mucosal CX3CR1⁺ dendritic cells (DCs) via the DC-SIGN receptor. Fourth, we show that mucosal and systemic antibody responses against the HIV p24-SIgA complexes administered orally is strictly dependent on the expression of Dectin-1. Having deciphered the mechanisms leading to specific targeting of SIgA-based Ag complexes paves the way to the use of such a vehicle for mucosal vaccination against various infectious diseases.

In addition to changes in spatio-temporal and kinematic parameters, patients with stroke exhibit fear of falling as well as fatigability during gait. These changes could compromise interpretation of data from gait analysis. The aim of this study was to determine if the gait of hemiplegic patients changes significantly over successive gait trials. Forty two stroke patients and twenty healthy subjects performed 9 gait trials during a gait analysis session. The mean and variability of spatio-temporal and kinematic joint parameters were analyzed during 3 groups of consecutive gait trials (1-3, 4-6 and 7-9). Principal component analysis was used to reduce the number of variables from the joint kinematic waveforms and to identify the parts of the gait cycle which changed during the gait analysis session. The results showed that i) spontaneous gait velocity and the other spatio-temporal parameters significantly increased, and ii) gait variability decreased, over the last 6 gait trials compared to the first 3, for hemiplegic patients but not healthy subjects. Principal component analysis revealed changes in the sagittal waveforms of the hip, knee and ankle for hemiplegic patients after the first 3 gait trials. These results suggest that at the beginning of the gait analysis session, stroke patients exhibited phase of adaptation,characterized by a "cautious gait" but no fatigue was observed.

RationaleIn COPD patients, mortality risk is influenced by age, severity of respiratory disease, and comorbidities. With an unbiased statistical approach we sought to identify clusters of COPD patients and to examine their mortality risk.MethodsStable COPD subjects (n = 527) were classified using hierarchical cluster analysis of clinical, functional and imaging data. The relevance of this classification was validated using prospective follow-up of mortality.ResultsThe most relevant patient classification was that based on three clusters (phenotypes). Phenotype 1 included subjects at very low risk of mortality, who had mild respiratory disease and low rates of comorbidities. Phenotype 2 and 3 were at high risk of mortality. Phenotype 2 included younger subjects with severe airflow limitation, emphysema and hyperinflation, low body mass index, and low rates of cardiovascular comorbidities. Phenotype 3 included older subjects with less severe respiratory disease, but higher rates of obesity and cardiovascular comorbidities. Mortality was associated with the severity of airflow limitation in Phenotype 2 but not in Phenotype 3 subjects, and subjects in Phenotype 2 died at younger age.ConclusionsWe identified three COPD phenotypes, including two phenotypes with high risk of mortality. Subjects within these phenotypes may require different therapeutic interventions to improve their outcome.

BACKGROUND: The development of mucosal vaccines is crucial to efficiently control infectious agents for which mucosae are the primary site of entry. Major drawbacks of these protective strategies are the lack of effective mucosal adjuvant. Synthetic oligodeoxynucleotides that contain several unmethylated cytosine-guanine dinucleotide (CpG-ODN) motifs are now recognized as promising adjuvants displaying mucosal adjuvant activity through direct activation of TLR9-expressing cells. However, little is known about the efficacy of these molecules in stimulating the intestinal immune system in neonates. METHODOLOGY/PRINCIPAL FINDINGS: First, newborn mice received CpG-ODN orally, and the intestinal cytokine and chemokine response was measured. We observed that oral administration of CpG-ODN induces CXC and CC chemokine responses and a cellular infiltration in the intestine of neonates as detected by immunohistochemistry. We next compared the efficiency of the oral route to intraperitoneal administration in stimulating the intestinal immune responses of both adults and neonates. Neonates were more responsive to TLR9-stimulation than adults whatever the CpG-ODN administration route. Their intestinal epithelial cells (IECs) indirectly responded to TLR9 stimulation and contributed to the CXC chemokine response, whereas other TLR9-bearing cells of the lamina-propria produced CC chemokines and Th1-type cytokines. Moreover, we showed that the intestine of adult exhibited a significantly higher level of IL10 at homeostasis than neonates, which might be responsible for the unresponsiveness to TLR9-stimulation, as confirmed by our findings in IL10-deficient mice. CONCLUSIONS/SIGNIFICANCE: This is the first report that deciphers the role played by CpG-ODN in the intestine of neonates. This work clearly demonstrates that an intraperitoneal administration of CpG-ODN is more efficient in neonates than in adults to stimulate an intestinal chemokine response due to their lower IL-10 intestinal level. In addition we report the efficiency of the oral route at inducing intestinal chemokine responses in neonate that might be taken into consideration for further vaccine development against neonatal diseases.