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Encoding quantum information in quantum states with disjoint wave-function support and noise-insensitive energies is the key behind the idea of qubit protection. While fully protected qubits are expected to offer exponential protection against both energy relaxation and pure dephasing, simpler circuits may grant partial protection with currently achievable parameters. Here, we study a fluxonium circuit in which the wave functions are engineered to minimize their overlap while benefiting from a first-order-insensitive flux sweet spot. Taking advantage of a large superinductance (L∼1 μH), our circuit incorporates a resonant tunneling mechanism at zero external flux that couples states with the same fluxon parity, thus enabling bifluxon tunneling. The states |0⟩ and |1⟩ are encoded in wave functions with parities 0 and 1, respectively, ensuring a minimal form of protection against relaxation. Two-tone spectroscopy reveals the energy-level structure of the circuit and the presence of 4π quantum-phase slips between different potential wells corresponding to m=±1 fluxons, which can be precisely described by a simple fluxonium Hamiltonian or by an effective bifluxon Hamiltonian. Despite suboptimal fabrication, the measured relaxation (T_{1}=177±3 μs) and dephasing (T_{2}^{E}=75±5 μs) times not only demonstrate the relevance of our approach but also open an alternative direction toward quantum computing using partially protected fluxonium qubits.

Demonstration of phase matching mechanism in Josephson traveling wave parametric amplifiers involving in-situ sign reversal of Kerr nonlinearity opens up experimental possibilities in the framework of microwave quantum optics.

In recent decades, the laws of thermodynamics have been pushed down to smaller and smaller scales, within the theoretical field of stochastic thermodynamics and state-of-the-art experiments performed on microfabricated mesoscopic systems. These measurements concern thermal properties of electrons, photons, and mesoscopic mechanical objects. Here we report on the measurements of thermal fluctuations of a single mechanical mode in equilibrium with a heat reservoir. The device under study is a nanomechanical beam with a first flexural mode resonating at 3.8MHz, cooled down to temperatures in the range from 100 to 400mK. The technique is constructed around a microwave optomechanical setup using a cryogenic high electron mobility transistor, and is based on two parametric amplifications implemented in series: an in-built optomechanical “blue detuned” pumping plus a traveling wave parametric amplifier stage. We demonstrate our ability to resolve energy fluctuations of the mechanical mode in real time up to the fastest relevant speed given by the mechanical relaxation rate. The energy probability distribution is then exponential, matching the expected Boltzmann distribution. The variance of fluctuations is found to be (k_{B}T)^{2} with no free parameters. Our microwave detection floor is about three times the standard quantum limit at 6GHz; the resolution of our fastest acquisition tracks reached about 100phonons, and is directly related to the rather poor optomechanical coupling of the device (g_{0}/2π≈0.5Hz). This result is deeply in the classical regime, but shall be extended to the quantum case in the future with systems presenting a much larger g_{0} (up to 2π×250Hz), potentially reaching the resolution of a single mechanical quantum. We believe that it will open an experimental field, phonon-based quantum stochastic thermodynamics, with fundamental implications for quantum heat transport and macroscopic mechanical quantum coherence.

Advances in the design and fabrication of superconducting devices enable physicists to design and monitor quantum electronic systems in synthetic environments. Here the authors observe how many-body effects influence the zero-point motion of a Josephson junction coupled to a high impedance transmission line.

A microwave amplifier combining noise performances as close as possible to the quantum limit with large bandwidth and high saturation power is highly desirable for many solid-state quantum technologies. Here, we introduce a new traveling-wave parametric amplifier based on superconducting quantum interference devices. It displays a 3-GHz bandwidth, a -100-dBm saturation (1-dB compression) point and added noise near the quantum limit. Compared to the previous state of the art, it is an order of magnitude more compact, its characteristic impedance is in situ tunable, and its fabrication process requires only two lithography steps. The key is the engineering of a gap in the dispersion relation of the transmission line. This is obtained using a periodic modulation of the SQUID size, similarly to what is done with photonic crystals. Moreover, we provide a new theoretical treatment to describe the nontrivial interplay between nonlinearity and such periodicity. Our approach provides a path to cointegration with other quantum devices such as qubits given the low footprint and easy fabrication of our amplifier.

We experimentally and theoretically investigate the quantum trajectories of jointly monitored transmon qubits embedded in spatially separated microwave cavities. Using nearly quantum-noise-limited superconducting amplifiers and an optimized setup to reduce signal loss between cavities, we can efficiently track measurement-induced entanglement generation as a continuous process for single realizations of the experiment. The quantum trajectories of transmon qubits naturally split into low and high entanglement classes. The distribution of concurrence is found at any given time, and we explore the dynamics of entanglement creation in the state space. The distribution exhibits a sharp cutoff in the high concurrence limit, defining a maximal concurrence boundary. The most-likely paths of the qubits’ trajectories are also investigated, resulting in three probable paths, gradually projecting the system to two even subspaces and an odd subspace, conforming to a “half-parity” measurement. We also investigate the most-likely time for the individual trajectories to reach their most entangled state, and we find that there are two solutions for the local maximum, corresponding to the low and high entanglement routes. The theoretical predictions show excellent agreement with the experimental entangled-qubit trajectory data.

Abstract Patient‐reported outcome measures (PROMs) are used to assess a patient's health status at a particular point in time. They are essential in the development of person‐centred care. This paper reviews studies performed on PROMs for assessing AR and asthma control, in particular VAS scales that are included in the app MASK‐air® (Mobile Airways Sentinel networK) for asthma and rhinitis. VASs were initially developed on paper and pencil and tested for their criterion validity, cut‐offs and responsiveness. Then, a multicentric, multinational, double‐blind, placebo‐controlled, randomised control trial (DB‐PC‐RCT) using an electronic VAS form was carried out. Finally, with the development of MASK‐air® in 2015, previously validated VAS questions were adapted to the digital format and further methodologic evaluations were performed. VAS for asthma, rhinitis, conjunctivitis, work and EQ‐5D are included in the app. Additionally, two control‐medication scores for allergic symptoms of asthma (e‐DASTHMA) were validated for their criterion validity, cut‐offs and responsiveness.

Abstract The problem of missing heritability requires the consideration of genetic interactions among different loci, called epistasis. Current GWAS statistical models require years to assess the entire combinatorial epistatic space for a single phenotype. We propose Next-Gen GWAS (NGG) that evaluates over 60 billion single nucleotide polymorphism combinatorial first-order interactions within hours. We apply NGG to Arabidopsis thaliana providing two-dimensional epistatic maps at gene resolution. We demonstrate on several phenotypes that a large proportion of the missing heritability can be retrieved, that it indeed lies in epistatic interactions, and that it can be used to improve phenotype prediction.

Abstract Rationale It is unclear how each individual asthma symptom is associated with asthma diagnosis or control. Objectives To assess the performance of individual asthma symptoms in the identification of patients with asthma and their association with asthma control. Methods In this cross‐sectional study, we assessed real‐world data using the MASK‐air® app. We compared the frequency of occurrence of five asthma symptoms (dyspnea, wheezing, chest tightness, fatigue and night symptoms, as assessed by the Control of Allergic Rhinitis and Asthma Test [CARAT] questionnaire) in patients with probable, possible or no current asthma. We calculated the sensitivity, specificity and predictive values of each symptom, and assessed the association between each symptom and asthma control (measured using the e‐DASTHMA score). Results were validated in a sample of patients with a physician‐established diagnosis of asthma. Measurement and Main Results We included 951 patients (2153 CARAT assessments), with 468 having probable asthma, 166 possible asthma and 317 no evidence of asthma. Wheezing displayed the highest specificity (90.5%) and positive predictive value (90.8%). In patients with probable asthma, dyspnea and chest tightness were more strongly associated with asthma control than other symptoms. Dyspnea was the symptom with the highest sensitivity (76.1%) and the one consistently associated with the control of asthma as assessed by e‐DASTHMA. Consistent results were observed when assessing patients with a physician‐made diagnosis of asthma. Conclusions Wheezing and chest tightness were the asthma symptoms with the highest specificity for asthma diagnosis, while dyspnea displayed the highest sensitivity and strongest association with asthma control.

Porous-activated carbons (ACs) derived from Moroccan pine cones (PC) were synthesised by a two step-chemical activation/carbonisation method using phosphoric acid (PC-H) and zinc chloride (PC-Z) as activating agents and used for the adsorption of bisphenol A (BPA) from water. Several techniques (TGA/DTA, FT-IR, XRD, SEM and BET) were used to determine the surface area and pore characterisation and variations during the preparation of the adsorbents. The modification significantly increased the surface area of both ACs, resulting in values of 1369.03 m2 g−1 and 1018.86 m2 g−1 for PC-H and PC-Z, respectively. Subsequent adsorption tests were carried out, varying parameters including adsorbent dosage, pH, initial BPA concentration, and contact time. Therefore, the highest adsorption capacity was observed when the BPA molecules were in their neutral form. High pH values were found to be unfavourable for the removal of bisphenol A from water. The results showed that BPA adsorption kinetics and isotherms followed pseudo-second-order and Langmuir models. Thermodynamic studies indicated that the adsorption was spontaneous and endothermic. Besides, the regeneration of spent adsorbents demonstrated their reusability. The adsorption mechanisms can be attributed to physical adsorption, hydrogen bonds, electrostatic forces, hydrophobic interactions, and π-π intermolecular forces.

Background: The quantification of electromyographic activity using surface electrodes is invaluable for understanding gait disorders in patients with central nervous system lesions. We propose to evaluate a commercially available low-cost system compared to a reference system in participants with stroke-related movement disorders in functional situations. Methods: Three hemiparetic participants performed three functional tasks: two treadmill walks at different speeds and a sit-to-stand test. The vastus lateralis and gastrocnemius medialis muscles were equipped with two EMG sensors. The comparison between the two EMG systems was based on 883 identified cycles. Spearman’s correlation coefficients (SCs), linear correlation coefficients (LCCs), and cross-correlation coefficients (CCCs) were calculated. Results: The main results indicate good to very good similarity of the EMG signals collected from the two tested sEMG systems. In the comfortable-walking condition, an SC of 0.894 ± 0.091 and an LCC of 0.909 ± 0.094 were noted. In the fast-walking condition, an SC of 0.918 ± 0.064 and an LCC of 0.935 ± 0.056 were observed. For the 1 min sit-to-stand test, an SC of 0.880 ± 0.058 and an LCC of 0.881 ± 0.065 were noted. Conclusions: This study demonstrates good to very good similarity between the two sEMG systems, enabling the analysis of muscle activity during functional tasks.

A pandemia da COVID-19 afetou as pessoas de diferentes maneiras. Diversas mudanças aconteceram nas atividades de trabalho e de lazer, impactando na saúde física e mental. Este estudo de revisão bibliográfica analisou as adaptações referente às práticas de lazer ativo e social que ocorreram durante a pandemia da COVID-19 e sua influência na saúde mental da população brasileira. Foram selecionados os artigos mais relevantes que foram publicados nos últimos 4 anos (2020- 2023). Os resultados apresentaram que as práticas de lazer durante o período pandêmico foram adaptadas aos pequenos espaços, e que pessoas que já praticavam algum tipo de atividade anteriormente possuem melhor capacidade de adaptação as adversidades. O acesso a internet e as plataformas de entretenimento aumentaram consideravelmente e as práticas de lazer social foram substituídas pelo lazer artístico, virtual, manual e intelectual.

Abstract Introduction Primary spontaneous pneumothorax (PSP) is the presence of air in the pleural space, occurring in the absence of trauma and known lung disease. Standardized expert guidelines on PSP are needed due to the variety of diagnostic methods, therapeutic strategies and medical and surgical disciplines involved in its management. Methods Literature review, analysis of the literature according to the GRADE (Grading of Recommendation, Assessment, Development and Evaluation) methodology; proposals for guidelines rated by experts, patients and organizers to reach a consensus. Only expert opinions with strong agreement were selected. Results A large PSP is defined as presence of a visible rim along the entire axillary line between the lung margin and the chest wall and ≥ 2 cm at the hilum level on frontal chest X-ray. The therapeutic strategy depends on the clinical presentation: emergency needle aspiration for tension PSP; in the absence of signs of severity: conservative management (small PSP), needle aspiration or chest tube drainage (large PSP). Outpatient treatment is possible if a dedicated outpatient care system is previously organized. Indications, surgical procedures and perioperative analgesia are detailed. Associated measures, including smoking cessation, are described. Conclusion These guidelines are a step towards PSP treatment and follow-up strategy optimization in France.

Locomotor and balance disorders are major limitations for subjects with hemiparesis. The Timed Up and Go (TUG) test is a complex navigational task involving oriented walking and obstacle circumvention. We hypothesized that subjects with hemiparesis adopt a cautious gait during complex locomotor tasks. The primary aim was to compare spatio-temporal gait parameters, indicators of cautious gait, between the locomotor subtasks of the TUG (Go, Turn, Return) and a Straight-line walk in people with hemiparesis. Our secondary aim was to analyze the relationships between TUG performance and balance measures, compare spatio-temporal gait parameters between fallers and non-fallers, and identify the biomechanical determinants of TUG performance. Biomechanical parameters during the TUG and Straight-line walk were analyzed using a motion capture system. A repeated measures ANOVA and two stepwise ascending multiple regressions (with performance variables and biomechanical variables) were conducted. Gait speed, step length, and % single support phase (SSP) of the 29 participants were reduced during Turn compared to Go and Return and the Straight-line walk, and step width and % double support phase were increased. TUG performance was related to several balance measures. Turn performance (R2 = 63%) and Turn trajectory deviation followed by % SSP on the paretic side and the vertical center of mass velocity during Go (R2 = 71%) determined TUG performance time. People with hemiparesis adopt a cautious gait during complex navigation at the expense of performance.

Introducción: la ingesta de cuerpos extraños es un problema médico frecuente, especialmente en el servicio de urgencias. Existen algunos estudios pequeños que describen las experiencias al respecto. Materiales y métodos: estudio descriptivo, retrospectivo, en el cual se incluyó a pacientes con sospecha de ingesta de cuerpos extraños, ingresados al servicio de gastroenterología y endoscopia digestiva de La Clínica Universitaria Colombia, entre enero de 2007 y agosto de 2020. Resultados: la edad de ocurrencia del evento se presentó en pacientes desde los 18 hasta los 95 años, y la edad promedio fue de 45 años. Los cuerpos extraños ingeridos y encontrados fueron variables; los más frecuentes fueron la ingesta de espinas de pescado, que representó el 64,11% de los casos, seguido por la ingesta de huesos de pollo y la impactación alimentaria. Un 38% de los pacientes requirieron la extracción de cuerpo extraño y la herramienta usada con mayor frecuencia fue la pinza de cuerpo extraño. La localización principal fue el esófago, en el 12,53% de los casos, seguido por la cricofaringe, en el 11,18%, y la hipofaringe, en el 10%. Conclusiones: la Clínica Universitaria Colombia es un sitio de referencia de una gran cantidad de urgencias en gastroenterología debido a su alto nivel tecnológico y al gran recurso humano que requieren. Este trabajo representa probablemente la cantidad más grande de pacientes con este motivo de consulta, razón por la que se diseñó este estudio descriptivo retrospectivo, que muestra las características demográficas, los tipos de cuerpo extraño, los hallazgos radiológicos y endoscópicos y las complicaciones asociadas, que son de utilidad para tener un conocimiento más real de esta patología.

Aim To compare prednisone and placebo for the treatment of outpatients treated for acute exacerbations of chronic obstructive pulmonary disease (COPD) in a primary care setting. Methods A multicentre, parallel, double-blind, pragmatic randomised controlled trial was performed in France. A total of 66 general practitioners included patients aged ≥40 years with cumulative smoking of ≥10 pack-years and a diagnosis of certain or likely acute exacerbation of COPD. Oral prednisone (40 mg) or placebo were administered daily for 5 days. The main outcome was treatment failure at 8 weeks, defined as a composite criterion based on the occurrence of at least one of the following: unplanned visit to an emergency department or to a practitioner in the ambulatory setting, hospital admission or death. The planned sample size was 202 patients per group. Results 175 patients were included from February 2015 to May 2017 (43% of the planned sample). All-cause 8-week treatment failure rate was 42.0% in the prednisone group and 34.5% in the placebo group (relative risk 1.22, 95% CI 0.87–1.69, p=0.25). Respiratory-related 8-week treatment failure rate was 27.6% in the prednisone group and 13.6% in the placebo group (relative risk 2.00, 95% CI 1.15–3.57, p=0.015). Conclusion Although the planned sample size was not achieved, the study does not suggest that oral corticosteroids are more effective than placebo for the treatment of an acute exacerbation of COPD in a primary care setting.

Abstract Introduction Discriminating asthma from chronic obstructive pulmonary disease (COPD) using medico-administrative databases is challenging but necessary for medico-economic analyses focusing on respiratory diseases. Artificial intelligence (AI) may improve dedicated algorithms. Objectives To assess performance of different AI-based approaches to distinguish asthmatics from COPD patients in medico-administrative databases where the clinical diagnosis is absent. An “Asthma COPD Overlap” category was defined to further test whether AI can detect complexity. Methods This study included 178,962 patients treated by two “R03” treatment prescriptions at least from January 2016 to December 2018 and managed by either a general practitioner and/or a pulmonologist participating in a permanent longitudinal observatory of prescription in ambulatory medicine (LPD). Clinical diagnoses are available in this database and were used as gold standards to develop diagnostic rules. Three types of AI approaches were explored using data restricted to demographics and treatment dispensations: multinomial regression, gradient boosting and recurrent neural networks (RNN). The best performing model (based on metric properties) was then applied to estimate the size of asthma and COPD populations based on a database (LRx) of treatment dispensations between July, 2018 and June, 2019. Results The best models were obtained with the boosting approach and RNN, with an overall accuracy of 68%. Performance metrics were better for asthma than COPD. Based on LRx data, the extrapolated numbers of patients treated for asthma and COPD in France were 3.7 and 1.2 million, respectively. Asthma patients were younger than COPD patients (mean, 49.9 vs. 72.1 years); COPD occurred mostly in men (68%) compared to asthma (33%). Conclusion AI can provide models with acceptable accuracy to distinguish between asthma, ACO and COPD in medico-administrative databases where the clinical diagnosis is absent. Deep learning and machine learning (RNN) had similar performances in this regard.

IntroductionSerious games can be used to provide intensive rehabilitation through attractive exercises as part of post-stroke rehabilitation. However, currently available commercial and serious games systems primarily train shoulder and elbow movements. These games lack the grasping and displacement components that are essential to improve upper limb function. For this reason, we developed a tabletop device that encompassed a serious game with a tangible object to rehabilitate combined reaching and displacement movements: the Ergotact system.ObjectivesThe aim of this pilot study was to assess the feasibility and the short-term effects of a training program using the Ergotact prototype in individuals with chronic stroke.MethodsParticipants were assigned to one of two groups: a serious game training group (Ergotact) or a control training group (Self).ResultsTwenty-eight individuals were included. Upper limb function increased after the Ergotact training program, although not statistically significantly, and the program did not induce pain or fatigue, demonstrating its safety.ConclusionThe Ergotact system for upper limb rehabilitation was well accepted and induced participant satisfaction. It complies with current recommendations for people with stroke to autonomously perform intensive active exercises in a fun context, in addition to conventional rehabilitation sessions with therapists.Clinical trial registrationhttps://clinicaltrials.gov/ct2/show/NCT03166020?term=NCT03166020&draw=2&rank=1, identifier NCT03166020.

Summary: Background: Validated questionnaires are used to assess asthma control over the past 1–4 weeks from reporting. However, they do not adequately capture asthma control in patients with fluctuating symptoms. Using the Mobile Airways Sentinel Network for airway diseases (MASK-air) app, we developed and validated an electronic daily asthma control score (e-DASTHMA). Methods: We used MASK-air data (freely available to users in 27 countries) to develop and assess different daily control scores for asthma. Data-driven control scores were developed based on asthma symptoms reported by a visual analogue scale (VAS) and self-reported asthma medication use. We included the daily monitoring data from all MASK-air users aged 16–90 years (or older than 13 years to 90 years in countries with a lower age of digital consent) who had used the app in at least 3 different calendar months and had reported at least 1 day of asthma medication use. For each score, we assessed construct validity, test–retest reliability, responsiveness, and accuracy. We used VASs on dyspnoea and work disturbance, EQ-5D-VAS, Control of Allergic Rhinitis and Asthma Test (CARAT), CARAT asthma, and Work Productivity and Activity Impairment: Allergy Specific (WPAI:AS) questionnaires as comparators. We performed an internal validation using MASK-air data from Jan 1 to Oct 12, 2022, and an external validation using a cohort of patients with physician-diagnosed asthma (the INSPIRERS cohort) who had had their diagnosis and control (Global Initiative for Asthma [GINA] classification) of asthma ascertained by a physician. Findings: We studied 135 635 days of MASK-air data from 1662 users from May 21, 2015, to Dec 31, 2021. The scores were strongly correlated with VAS dyspnoea (Spearman correlation coefficient range 0·68–0·82) and moderately correlated with work comparators and quality-of-life-related comparators (for WPAI:AS work, we observed Spearman correlation coefficients of 0·59–0·68). They also displayed high test–retest reliability (intraclass correlation coefficients range 0·79–0·95) and moderate-to-high responsiveness (correlation coefficient range 0·69–0·79; effect size measures range 0·57–0·99 in the comparison with VAS dyspnoea). The best-performing score displayed a strong correlation with the effect of asthma on work and school activities in the INSPIRERS cohort (Spearman correlation coefficients 0·70; 95% CI 0·61–0·78) and good accuracy for the identification of patients with uncontrolled or partly controlled asthma according to GINA (area under the receiver operating curve 0·73; 95% CI 0·68–0·78). Interpretation: e-DASTHMA is a good tool for the daily assessment of asthma control. This tool can be used as an endpoint in clinical trials as well as in clinical practice to assess fluctuations in asthma control and guide treatment optimisation. Funding: None.

Background: The aim of this study was to compare energy expenditure (EE) predicted by accelerometery (EEAcc) with indirect calorimetry (EEMETA) in individuals with hemiparesis. Methods: Twenty-four participants (12 with stroke and 12 healthy controls) performed a six-minute walk test (6MWT) during which EEMETA was measured using a portable indirect calorimetry system and EEACC was calculated using Bouten’s equation (1993) with data from a three-axis accelerometer positioned between L3 and L4. Results: The median EEMETA was 9.85 [8.18;11.89] W·kg−1 in the stroke group and 5.0 [4.56;5.46] W·kg−1 in the control group. The median EEACC was 8.57 [7.86;11.24] W·kg−1 in the control group and 8.2 [7.05;9.56] W·kg−1 in the stroke group. The EEACC and EEMETA were not significantly correlated in either the control (p = 0.8) or the stroke groups (p = 0.06). The Bland–Altman method showed a mean difference of 1.77 ± 3.65 W·kg−1 between the EEACC and EEMETA in the stroke group and −2.08 ± 1.59 W·kg−1 in the controls. Conclusions: The accuracy of the predicted EE, based on the accelerometer and the equations proposed by Bouten et al., was low in individuals with hemiparesis and impaired gait. This combination (sensor and Bouten’s equation) is not yet suitable for use as a stand-alone measure in clinical practice for the evaluation of hemiparetic patients.

ObjectivesChatbots, conversational agents that walk medical students (MS) though a clinical case, are serious games that seem to be appreciated by MS. Their impact on MS's performance in exams however was not yet evaluated. Chatprogress is a chatbot-based game developed at Paris Descartes University. It contains 8 pulmonology cases with step-by-step answers delivered with pedagogical comments. The CHATPROGRESS study aimed to evaluate the impact of Chatprogress on students' success rate in their end-term exams.MethodsWe conducted a post-test randomized controlled trial held on all fourth-year MS at Paris Descartes University. All MS were asked to follow the University's regular lectures, and half of them were randomly given access to Chatprogress. At the end of the term, medical students were evaluated on pulmonology, cardiology and critical care medicine.Main outcomes measuresThe primary aim was to evaluate an increase in scores in the pulmonology sub-test for students who had access to Chatprogress, compared to those who didn't. Secondary aims were to evaluate an increase in scores in the overall test (Pulmonology, Cardiology and Critical care medicine test (PCC)) and to evaluate the correlation between access to Chatprogress and overall test score. Finally, students' satisfaction was assessed using a survey.ResultsFrom 10/2018 to 06/2019, 171 students had access to Chatprogress (the Gamers) and among them, 104 ended up using it (the Users). Gamers and Users were compared to 255 Controls with no access to Chatprogress. Differences in scores on the pulmonology sub-test over the academic year were significantly higher among Gamers and Users vs Controls (mean score: 12.7/20 vs 12.0/20, p = 0.0104 and mean score: 12.7/20 vs 12.0/20, p = 0.0365 respectively). This significant difference was present as well in the overall PCC test scores: (mean score: 12.5/20 vs 12.1/20, p = 0.0285 and 12.6/20 vs 12.1/20, p = 0.0355 respectively). Although no significant correlation was found between the pulmonology sub-test's scores and MS's assiduity parameters (number of finished games among the 8 proposed to Users and number of times a User finished a game), there was a trend to a better correlation when users were evaluated on a subject covered by Chatprogress. MS were also found to be fans of this teaching tool, asking for more pedagogical comments even when they got the questions right.ConclusionThis randomised controlled trial is the first to demonstrate a significant improvement in students' results (in both the pulmonology subtest and the overall PCC exam) when they had access to Chatbots, and even more so when they actually used it.

Abstract MASK‐air®, a validated mHealth app (Medical Device regulation Class IIa) has enabled large observational implementation studies in over 58,000 people with allergic rhinitis and/or asthma. It can help to address unmet patient needs in rhinitis and asthma care. MASK‐air® is a Good Practice of DG Santé on digitally‐enabled, patient‐centred care. It is also a candidate Good Practice of OECD (Organisation for Economic Co‐operation and Development). MASK‐air® data has enabled novel phenotype discovery and characterisation, as well as novel insights into the management of allergic rhinitis. MASK‐air® data show that most rhinitis patients (i) are not adherent and do not follow guidelines, (ii) use as‐needed treatment, (iii) do not take medication when they are well, (iv) increase their treatment based on symptoms and (v) do not use the recommended treatment. The data also show that control (symptoms, work productivity, educational performance) is not always improved by medications. A combined symptom‐medication score (ARIA‐EAACI‐CSMS) has been validated for clinical practice and trials. The implications of the novel MASK‐air® results should lead to change management in rhinitis and asthma.

Systemic corticosteroids (SCS) are a highly effective treatment for acute exacerbations and long-term symptom control in asthma. Long-term SCS use is highly prevalent across all asthma severities, occurring in over 20% of patients with severe or uncontrolled disease globally. It is now well known that exposure to both long-term and repeated acute courses of SCS is associated with a high risk of serious adverse effects (AEs), such as osteoporosis, and metabolic and cardiovascular complications, especially when prescribed onto a background of other corticosteroids. The aim of this call-to-action article, endorsed by the World Allergy Organization and the Respiratory Effectiveness Group, is to review the accumulating evidence on the burden of SCS on patients with asthma and provide an overview of potential strategies for implementing SCS Stewardship.Primary prevention of exacerbations and improvement of asthma control is a key first step in achieving SCS Stewardship, by optimizing maintenance asthma medications and addressing modifiable risk factors, such as adherence and inhaler technique. Other key elements of SCS Stewardship include increasing appropriate specialist referrals for multidisciplinary review, assessment of biomarkers, and consideration of oral corticosteroid-sparing add-on therapies (eg, biologics). In cases where SCS use is deemed clinically justified, it should be tapered to the lowest possible dose. In addition, patients receiving long-term SCS or frequent acute courses should be closely monitored for emergence of SCS-related AEs.Because of the extensive data available on the costly and burdensome AEs associated with SCS use, as well as the range of treatment options now available, there is a need for healthcare providers (HCPs) to carefully evaluate whether the benefits of SCS outweigh the potential harms, to adopt SCS-sparing and Stewardship strategies, and to consider alternative therapies where possible. Development of a structured and collaborative SCS Stewardship approach is urgently required to protect patients from the potential harm of SCS use.

Abstract Background Triple therapy with inhaled corticosteroids/long-acting muscarinic antagonists/long-acting β2-agonists (ICS/LAMA/LABA) is recommended for patients with chronic obstructive pulmonary disease (COPD) with continued symptoms or exacerbations, despite treatment with LAMA/LABA or ICS/LABA. The pulmonary, extrathoracic, and regional lung deposition patterns of a radiolabeled ICS/LAMA/LABA triple fixed-dose combination budesonide/glycopyrrolate/formoterol fumarate (BGF 320/18/9.6 μg), delivered via a single Aerosphere metered dose inhaler (MDI) were previously assessed in healthy volunteers and showed good deposition to the central and peripheral airways (whole lung deposition: 37.7%). Here, we report the findings assessing BGF in patients with moderate-to-very severe COPD. Methods This phase I, single-dose, open-label gamma scintigraphy imaging study (NCT03906045) was conducted in patients with moderate-to-very severe COPD. Patients received two actuations of BGF MDI (160/9/4.8 μg per actuation) radiolabeled with technetium‑99‑pertechnetate, not exceeding 5 MBq per actuation. Immediately following each inhalation, patients performed a breath-hold of up to 10 s, then exhaled into an exhalation filter. Gamma scintigraphy imaging of the anterior and posterior views of the lungs and stomach, and a lateral head and neck view, were performed immediately after exhalation. The primary objective of the study was to assess the pulmonary deposition of BGF. Secondary objectives assessed the deposited dose of radiolabeled BGF in the oropharyngeal and stomach regions, on the actuator, and on the exhalation filter in addition to regional airway deposition patterns in the lungs. Results The mean BGF emitted dose deposited in the lungs was 32.1% (standard deviation [SD] 15.6) in patients with moderate-to-very severe COPD, 35.2% (SD 12.8) in patients with moderate COPD, and 28.7% (SD 18.4) in patients with severe/very severe COPD. Overall, the mean normalized outer/inner ratio was 0.55 (SD 0.19), while the standardized central/peripheral ratio was 2.21 (SD 1.64). Conclusions Radiolabeled BGF 320/18/9.6 μg was efficiently delivered and deposited throughout the entire lung, including large and small airways, in patients with moderate-to-very severe COPD, with similar deposition in patients with moderate COPD and patients with severe/very severe COPD. Trial registration: ClinicalTrials.gov, NCT03906045. Registered 8 April 2019, https://clinicaltrials.gov/ct2/show/NCT03906045

Abstract Background The burden of undiagnosed obstructive lung disease (OLD) (mainly asthma and chronic obstructive pulmonary disease) is not fully established, and targets for corrective action are yet to be identified. We assessed the underdiagnosis of OLD and its determinants in France. Methods CONSTANCES is a French population-based cohort of adults aged 18–69 years at inception. We analysed data collected at inclusion in 2013–2014. Undiagnosed OLD was defined as spirometry-confirmed airflow limitation (FEV1/FVC

Abstract Human secretory immunoglobulins (SIg) A1 and SIgA2 guide mucosal responses toward tolerance or inflammation, notably through reverse‐transcytosis, the apical‐to‐basal transport of IgA2 immune complexes via M cells of gut Peyer's patches. As such, the maintenance of a diverse gut microbiota requires broad affinity IgA and glycan–glycan interaction. Here, we asked whether IgA1 and IgA2‐microbiota interactions might be involved in dysbiosis induction during inflammatory bowel diseases. Using stool HPLC‐purified IgA, we show that reverse‐transcytosis is abrogated in ulcerative colitis (UC) while it is extended to IgA1 in Crohn's disease (CD). 16S RNA sequencing of IgA‐bound microbiota in CD and UC showed distinct IgA1‐ and IgA2‐associated microbiota; the IgA1+ fraction of CD microbiota was notably enriched in beneficial commensals. These features were associated with increased IgA anti‐glycan reactivity in CD and an opposite loss of reactivity in UC. Our results highlight previously unknown pathogenic properties of IgA in IBD that could support dysbiosis.

Objective To characterise uncontrolled severe asthma and compare the disease burden with the general and asthmatic populations.Design Retrospective observational study using a national sample of a French healthcare database (Echantillon Généraliste des Bénéficiaires (EGB)).Setting The EGB, an anonymised permanent sample of health insurance databases, representing 1/97th of the French population.Participants Patients (≥12 years) were selected in year 2014 and followed 2 years. A cohort of patients with uncontrolled severe asthma was defined using an algorithm based on peer-reviewed literature and Global Initiative for Asthma recommendations. Index date was the occurrence of the first marker of uncontrolled asthma. This cohort was matched with two control cohorts, general population and asthmatic controls, on baseline characteristics.Main outcomes measures Mortality, healthcare use and associated costs were studied in the 2 years of follow-up.Results Among 467 716 individuals in the EGB, 16 588 patients with asthma were identified, including 739 (4.5%) with uncontrolled severe disease. The survival probability at 2 years for patients with uncontrolled severe asthma (92.0%) was lower than in the general population cohort (96.6%; relative risk of death: 2.35; 95% CI: 1.70 to 3.29; p

Bordetella bronchiseptica (Bb) is a Gram-negative bacterium responsible for canine infectious respiratory disease complex (CIRDC). Several vaccines targeting this pathogen are currently licensed for use in dogs, but their mechanism of action and the correlates of protection are not fully understood. To investigate this, we used a rat model to examine the immune responses induced and the protection conferred by a canine mucosal vaccine after challenge. Wistar rats were vaccinated orally or intranasally on D0 and D21 with a live attenuated Bb vaccine strain. At D35, the rats of all groups were inoculated with 103 CFU of a pathogenic strain of B. bronchiseptica. Animals vaccinated via either the intranasal or the oral route had Bb-specific IgG and IgM in their serum and Bb-specific IgA in nasal lavages. Bacterial load in the trachea, lung, and nasal lavages was lower in vaccinated animals than in non-vaccinated control animals. Interestingly, coughing improved in the group vaccinated intranasally, but not in the orally vaccinated or control group. These results suggest that mucosal vaccination can induce mucosal immune responses and provide protection against a Bb challenge. This study also highlights the advantages of a rat model as a tool for studying candidate vaccines and routes of administration for dogs.

Abstract Background Inhaled corticosteroids (ICS) are indicated for prevention of exacerbations in patients with COPD, but they are frequently overprescribed. ICS withdrawal has been recommended by international guidelines in order to prevent side effects in patients in whom ICS are not indicated. Method Observational comparative effectiveness study aimed to evaluate the effect of ICS withdrawal versus continuation of triple therapy (TT) in COPD patients in primary care. Data were obtained from the Optimum Patient Care Research Database (OPCRD) in the UK. Results A total of 1046 patients who withdrew ICS were matched 1:4 by time on TT to 4184 patients who continued with TT. Up to 76.1% of the total population had 0 or 1 exacerbation the previous year. After controlling for confounders, patients who discontinued ICS did not have an increased risk of moderate or severe exacerbations (adjusted HR: 1.04, 95% confidence interval (CI) 0.94–1.15; p = 0.441). However, rates of exacerbations managed in primary care (incidence rate ratio (IRR) 1.33, 95% CI 1.10–1.60; p = 0.003) or in hospital (IRR 1.72, 95% CI 1.03–2.86; p = 0.036) were higher in the cessation group. Unsuccessful ICS withdrawal was significantly and independently associated with more frequent courses of oral corticosteroids the previous year and with a blood eosinophil count ≥ 300 cells/μL. Conclusions In this primary care population of patients with COPD, composed mostly of infrequent exacerbators, discontinuation of ICS from TT was not associated with an increased risk of exacerbation; however, the subgroup of patients with more frequent courses of oral corticosteroids and high blood eosinophil counts should not be withdrawn from ICS. Trial registration European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (EUPAS30851).

Trafficking of IgA/commensal complex in the gut has been implicated in inflammatory bowel diseases such as Crohn’s disease, but molecular insights are still lacking. Here the authors show, using mouse model or human cells, that NOD2 mutation increases IgA transport, potentially by altering gut microfold cells from the gut, to impact gut inflammation.

Summary: Background: Asthma is an inflammatory heterogeneous disease. Asthma inflammatory phenotypes based on blood eosinophil and neutrophil counts have never been identified and characterized in population-based studies. Methods: Adults with current asthma and available blood eosinophil and neutrophil counts from the French population-based CONSTANCES cohort were included. Current asthma was defined by reports of asthma attacks, symptoms or treatments in the last 12 months. Inflammatory phenotypes were based on low (L) and high (H) blood (B) eosinophil (E) (LBE/HBE:

Abstract Background COPD is a heterogeneous disease and patients may respond differently to therapies depending on baseline symptom burden. Methods This post-hoc analysis from the 52-week FLAME study investigated the impact of baseline symptom burden in terms of health status, dyspnoea, bronchitis status, eosinophil levels and smoking status on the subsequent risk of moderate or severe exacerbations. Health status was measured by St. George’s Respiratory Questionnaire (SGRQ) score (higher ≥46.6 and lower

The rapid growth of anthropogenic activities in recent decades has resulted in the appearance of numerous new chemical compounds in the environment, known as “emerging pollutants” (EPs) or “contaminants of emerging concern” (CECs). Although partially or not yet regulated or monitored, there is growing research interest in these EPs among the scientific community because of their bioaccumulation, persistence, and adverse effects. Among these, endocrine disruptors, pesticides, and pharmaceuticals can have harmful impacts on human health and the ecosystem. Conventional wastewater treatment technologies are not effective in removing these contaminants, allowing them to be released into the receiving environment. In order to improve the understanding of emerging pollutants, this review discusses the source, occurrence, and impacts of bisphenol A, atrazine, amoxicillin, and paracetamol as model molecules of emerging environmental pollutants, an issue that remains underrepresented in Morocco. Then, treatment methods for EPs are reviewed, including adsorption, advanced oxidation processes, biodegradation, and hybrid treatment. It is proposed that adsorption and photocatalysis can be used as simple, effective, and environmentally friendly technologies for their removal. Thus, we summarize some of the adsorbent and photocatalyst materials applied in recent work to control these pollutants. Towards the end of this paper, the development of inexpensive and locally available (Morocco) materials to remove these compounds from wastewater is considered.

Hospitalised patients with coronavirus disease 2019 (COVID-19) have a high mortality rate. There are an increasing number of published randomised controlled trials for anti-inflammatory, anti-viral and other treatments. The European Respiratory Society Living Guidelines for the Management of Hospitalised Adults with COVID-19 were published recently, providing recommendations on appropriate pharmacotherapy. Patient, Intervention, Comparator and Outcomes questions for key interventions were identified by an international panel and systematic reviews were conducted to identify randomised controlled trials meeting the inclusion criteria. The importance of end-points were rated, and mortality was identified as the key “critical” outcome for all interventions. Random-effects meta-analysis was used to pool studies and provide effect estimates for the impact of treatments on mortality. Corticosteroids, hydroxychloroquine, azithromycin, remdesivir, anti-interleukin (IL)-6 monoclonal antibodies, colchicine, lopinavir/ritonavir and interferon-β have been reviewed. Our results found further evidence in support of the use of corticosteroids, particularly dexamethasone, and anti-IL-6 receptor monoclonal antibody therapy. These data support the need to identify additional therapies with beneficial effects on mortality.

Chronic obstructive pulmonary disease (COPD) is a main cause of death due to interplaying factors, including comorbidities that interfere with symptoms and response to therapy. It is now admitted that COPD management should be based on clinical symptoms and health status and should consider the heterogeneity of patients’ phenotypes and treatable traits. This precision medicine approach involves a regular assessment of the patient's status and of the expected benefits and risks of therapy. The cornerstone of COPD pharmacological therapy is inhaled long-acting bronchodilation. In patients with persistent or worsened symptoms, factors likely to interfere with treatment efficacy include the patient's non-adherence to therapy, treatment preference, inhaler misuse and/or comorbidities, which should be systematically investigated before escalation is considered. Several comorbidities are known to impact symptoms, physical and social activity and lung function. The possible long-term side-effects of inhaled corticosteroids contrasting with their over-prescription in COPD patients justify the regular assessment of their benefits and risks, and de-escalation under close monitoring after a sufficient period of stability is to be considered. While commonly used in clinical trials, the relevance of routine blood eosinophil counts to guide therapy adjustment is not fully clear. Patients’ characteristics, which define phenotypes and treatable traits and thus guide therapy, often change during life, forming the basis of the concept of clinical trajectory. The application of individual trajectory-based management of COPD in clinical practice therefore implies that the benefit:risk ratio is regularly reviewed according to the evolution of the patient's traits over time to allow optimised therapy adjustments.

Sjögren’s syndrome (SjS) is a frequent systemic autoimmune disease responsible for a major decrease in patients’ quality of life, potentially leading to life-threatening conditions while facing an unmet therapeutic need. Hence, we assessed the immunogenicity, efficacy, and tolerance of IFN-Kinoid (IFN-K), an anti-IFNα vaccination strategy, in a well-known mouse model of systemic autoimmunity with SjS-like features: MRL/MpJ-Faslpr/lpr (MRL/lpr) mice. Two cohorts (with ISA51 or SWE01 as adjuvants) of 26 female MRL/lpr were divided in parallel groups, “controls” (not treated, PBS and Keyhole Limpet Hemocyanin [KLH] groups) or “IFN-K” and followed up for 122 days. Eight-week-old mice received intra-muscular injections (days 0, 7, 28, 56 and 84) of PBS, KLH or IFN-K, emulsified in the appropriate adjuvant, and blood samples were serially collected. At sacrifice, surviving mice were euthanized and their organs were harvested for histopathological analysis (focus score in salivary/lacrimal glands) and IFN signature evaluation. SjS-like features were monitored. IFN-K induced a disease-modifying polyclonal anti-IFNα antibody response in all treated mice with high IFNα neutralization capacities, type 1 IFN signature’s reduction and disease features’ (ocular and oral sicca syndrome, neuropathy, focus score, glandular production of BAFF) improvement, as reflected by the decrease in Murine Sjögren’s Syndrome Disease Activity Index (MuSSDAI) modelled on EULAR Sjögren’s Syndrome Disease Activity Index (ESSDAI). No adverse effects were observed. We herein report on the strong efficacy of an innovative anti-IFNα vaccination strategy in a mouse model of SjS, paving the way for further clinical development (a phase IIb trial has just been completed in systemic lupus erythematosus with promising results).

Summary: Secretory immunoglobulin A (SIgA) can travel to and from the lumen and transport antigen to subepithelial cells. However, IgM can also multimerize into functional secretory component-bound immunoglobulin. While it is already known that both SIgA and SIgM undergo transcytosis to be secreted at the mucosal surface, only SIgA has been shown to perform retrotranscytosis through microfold cells (M cells) of the Peyer’s patch. Here, we investigate whether SIgM could also be taken up by M cells via retrotranscytosis. This transport involves FcμR binding at the apical membrane of M cells. We then demonstrate that SIgM can be exploited by SIgM-p24 (HIV-capsid protein) complexes during immunization in the nasal- or gut-associated lymphoid tissue (NALT or GALT), conferring efficient immune responses against p24. Our data demonstrate a mucosal function of SIgM, which could play a role in the regulation of mucosal immunity.

(1) Background: Ulcerative colitis (UC) is an inflammatory bowel disease that causes inflammation of the intestines, which participates in human cytomegalovirus (HCMV) reactivation from its latent reservoir. CMV-associated colitis plays a pejorative role in the clinical course of UC. We took advantage of a model of chemically induced enteritis to study the viral reactivation of murine CMV (MCMV) in the context of gut inflammation. (2) Methods: Seven-week-old BALB/c mice were infected by 3 × 103 plaque-forming units (PFU) of MCMV; 2.5% (w/v) DSS was administered in the drinking water from day (D) 30 to D37 post-infection to induce enteritis. (3) Results: MCMV DNA levels in the circulation decreased from D21 after infection until resolution of the acute infection. DSS administration resulted in weight loss, high disease activity index, elevated Nancy index shortening of the colon length and increase in fecal lipocalin. However, chemically induced enteritis had no impact on MCMV reactivation as determined by qPCR and immunohistochemistry of intestinal tissues. (4) Conclusions: Despite the persistence of MCMV in the digestive tissues after the acute phase of infection, the gut inflammation induced by DSS did not induce MCMV reactivation in intestinal tissues, thus failing to recapitulate inflammation-driven HCMV reactivation in human UC.

Background and study aims Endoscopic management of esophagorespiratory fistulas (ERF) is challenging and currently available options (stents, double pigtail, endoscopic vacuum therapy) are not very effective. We report the feasibility and efficacy of endoscopic placement of Amplatzer cardiovascular occluders for this indication. Patients and methods This was a single-center, prospective study (June 2019 to September 2020) of all patients with non-malignant ERF persistent after conventional management with esophageal and/or tracheal stents. The primary outcome was the technical feasibility of Amplatzer placement. Secondary outcomes were clinical success defined by effective ERF occlusion and resolution of respiratory symptoms allowing oral food intake. Results Endoscopic placement of Amplatzer occluders was feasible in 83 % of patients (5/6), with a 50 % (3/6) clinical success rate at 9 months. The mortality rate was 33 % (2/6). Conclusions An Amplatzer cardiac or vascular occluder is a feasible and safe treatment option for refractory ERF, with a 50 % short-term clinical success.

Abstract In this study, a conceptual model to define convective density currents is proposed. Based on theory, observations and modeling studies, we define convective density currents as 3D coherent structures with an anomalously cold core, an adjacent wind gust, and a vertical structure made of two layers: a well‐mixed one near the surface and a stratified one above. With this definition, a methodology is proposed to identify and label individual convective density currents in convection‐permitting simulations. The method is applied to four distinct cloud scenes taken from a convection‐permitting simulation. Our methodology reveals new dynamic, thermodynamic, and geometric features related to the density currents’ imprint on the planetary boundary layer. The method is found to be (i) relevant in distinct convective regimes, (ii) relevant in land and oceanic situations, and (iii) adapted to both Cloud Resolving Models and Large Eddy Simulations. It also provides proxies such as the number, the spatial coverage, the mean radius, and the mean velocity of convective density currents, from which a detailed analysis of their role in the life‐cycle and spatial organization of convection could be performed in the near future.

Abstract Background In all societies, the burden and cost of allergic and chronic respiratory diseases are increasing rapidly. Most economies are struggling to deliver modern health care effectively. There is a need to support the transformation of the health care system into integrated care with organizational health literacy. Main body As an example for chronic disease care, MASK (Mobile Airways Sentinel NetworK), a new project of the ARIA (Allergic Rhinitis and its Impact on Asthma) initiative, and POLLAR (Impact of Air POLLution on Asthma and Rhinitis, EIT Health), in collaboration with professional and patient organizations in the field of allergy and airway diseases, are proposing real-life ICPs centred around the patient with rhinitis, and using mHealth to monitor environmental exposure. Three aspects of care pathways are being developed: (i) Patient participation, health literacy and self-care through technology-assisted “patient activation”, (ii) Implementation of care pathways by pharmacists and (iii) Next-generation guidelines assessing the recommendations of GRADE guidelines in rhinitis and asthma using real-world evidence (RWE) obtained through mobile technology. The EU and global political agendas are of great importance in supporting the digital transformation of health and care, and MASK has been recognized by DG Santé as a Good Practice in the field of digitally-enabled, integrated, person-centred care. Conclusion In 20 years, ARIA has considerably evolved from the first multimorbidity guideline in respiratory diseases to the digital transformation of health and care with a strong political involvement.

Abstract Background Blood eosinophil count (BEC) and fractional exhaled nitric oxide (FeNO) concentration are established biomarkers in asthma, associated particularly with the risk of exacerbations. We evaluated the relationship of BEC and FeNO as complementary and independent biomarkers of severe asthma exacerbations. Methods This observational study included data from the Optimum Patient Care Research Database. Asthma patients (18–80 years) with valid continuous data for 1 year before FeNO reading, ≥ 1 inhaled corticosteroid prescription, and BEC recorded ≤ 5 years before FeNO reading were separated into cohorts. Categorisation 1 was based on the American Thoracic Society criteria for elevated FeNO concentration (high: ≥ 50 ppb; non-high:

Abstract Background Although COPD affects both men and women, its prevalence is increasing more rapidly in women. Disease outcomes appear different among women with more frequent dyspnea and anxiety or depression but whether this translates into a different prognosis remains to be determined. Our aim was to assess whether the greater clinical impact of COPD in women was associated with differences in 3-year mortality rates. Methods In the French Initiatives BPCO real-world cohort, 177 women were matched up to 458 menon age (within 5-year intervals) and FEV1 (within 5% predicted intervals). 3-year mortality rate and survival were analyzed. Univariate and multivariate logistic regression analyses were performed. Results For a given age and level of airflow obstruction, women with COPD had more severe dyspnea, lower BMI, and were more likely to exhibit anxiety. Nevertheless, three-year mortality rate was comparable among men and women, respectively 11.2 and 10.8%. In a multivariate model, the only factors significantly associated with mortality were dyspnea and malnutrition but not gender. Conclusion Although women with COPD experience higher levels of dyspnea and anxiety than men at comparable levels of age and FEV1, these differences do not translate into variations in 3-year mortality rates. Trial registration 04–479.

Abstract Background The number of pharmacological agents and guidelines available for COPD has increased markedly but guidelines remain poorly followed. Understanding underlying clinical reasoning is challenging and could be informed by clinical characteristics associated with treatment prescriptions. Methods To determine whether COPD treatment choices by respiratory physicians correspond to specific patients’ features, this study was performed in 1171 patients who had complete treatment and clinical characterisation data. Multiple statistical models were applied to explain five treatment categories: A: no COPD treatment or short-acting bronchodilator(s) only; B: one long-acting bronchodilator (beta2 agonist, LABA or anticholinergic agent, LAMA); C: LABA+LAMA; D: a LABA or LAMA + inhaled corticosteroid (ICS); E: triple therapy (LABA+LAMA+ICS). Results Mean FEV1 was 60% predicted. Triple therapy was prescribed to 32.9% (treatment category E) of patients and 29.8% received a combination of two treatments (treatment categories C or D); ICS-containing regimen were present for 44% of patients altogether. Single or dual bronchodilation were less frequently used (treatment categories B and C: 19% each). While lung function was associated with all treatment decisions, exacerbation history, scores of clinical impact and gender were associated with the prescription of > 1 maintenance treatment. Statistical models could predict treatment decisions with a

Abstract Background In patients with chronic obstructive pulmonary disease, all efforts should be made to prevent exacerbations because each event modifies the trajectory of the disease. Treatment recommendations are mostly built on results from randomized controlled trials (RCTs) whose methodology ensure internal validity. However, their relevance may be compromised by the lack of generalizability, due to poor representability of study populations compared to real-life patients. In order to delimit to whom the results of studies on current and future treatments apply, we sought to identify and characterize the fraction of COPD population that would be eligible for inclusion into RCTs aiming at decreasing exacerbation risk. Methods We used the Initiatives-BPCO database, a French cohort of 1309 real-life COPD patients monitored in academic centers. We identified industry-sponsored phase III and IV trials that enrolled more than 500 patients, lasted at least one year and used exacerbations related endpoints. Eligibility criteria were extracted from each trial and applied to the patients. Results The eligibility criteria of 16 RCTs were applied to the 1309 patients. The most discriminating eligibility criteria were FEV1, minimum exacerbation rate in the previous year and smoking history, responsible for the exclusion of 39.9, 36.7 and 16.8% of patients, respectively. Altogether, 2.3 to 46.7% of our patients would have satisfied all eligibility criteria. Conclusion These analyses confirm that an important gap exists between real-life patients and clinical trials populations in COPD, which limits the relevance of results and therefore should be considered when grading levels of evidence and designing future studies.

Abstract Allergic mechanisms related to environmental and occupational exposure have been suggested to contribute to the development of chronic obstructive pulmonary disease (COPD). Objectives To investigate the relationships between atopy markers, persistent airflow limitation (PAL) and occupational exposure in dairy farmers. Methods Clinical and biological (total IgE and 21 allergen specific IgE) markers of atopy were assessed in 101 dairy farmers with PAL (DF-PAL), 85 non-farmers with PAL (NF-PAL) (both groups were prospectively included from a screening program performed between 2011 and 2015), and matched controls, i.e. 98 farmers without PAL (DF-controls) and 89 non-farming subjects without PAL (NF-controls). Occupational exposure in farmers was estimated using a validated questionnaire. Results Prevalence of allergy history was significantly higher in DF-PAL and in NF-PAL than in controls. Polysensitization, and sensitization to seasonal and food allergens were more frequent in DF-PAL than in DF-controls, respectively: 13.8% vs 1% (adjusted odds ratio (aOR): 17.5 (2.2–134), 11.9% vs 3.1% (aOR: 4.4 (1.2–7.2) and 16.8% vs 4.1% (aOR: 5.2 (1.7–7.2)). The prevalence of atopy markers was similar between NF-PAL patients and NF-controls. Conclusions PAL in farmers is associated with a high rate of markers of atopy, supporting atopy as a risk indicator. Clinical trial registered with ClinicalTrials.gov (NCT02540408).

Abstract Introduction A Task Force was commissioned jointly by the European Academy of Allergy and Clinical Immunology (EAACI) and the Respiratory Effectiveness Group (REG) to develop a quality assessment tool for real-life observational research to identify high-quality real-life asthma studies that could be considered within future guideline development. Methods The resulting REal Life EVidence AssessmeNt Tool (RELEVANT) was achieved through an extensive analysis of existing initiatives in this area. The first version was piloted among 9 raters across 6 articles; the revised, interim, version underwent extensive testing by 22 reviewers from the EAACI membership and REG collaborator group, leading to further revisions and tool finalisation. RELEVANT was validated through an analysis of real-life effectiveness studies identified via systematic review of Medline and Embase databases and relating to topics for which real-life studies may offer valuable evidence complementary to that from randomised controlled trials. The topics were selected through a vote among Task Force members and related to the influence of adherence, smoking, inhaler device and particle size on asthma treatment effectiveness. Results Although highlighting a general lack of high-quality real-life effectiveness observational research on these clinically important topics, the analysis provided insights into how identified observational studies might inform asthma guidelines developers and clinicians. Overall, RELEVANT appeared reliable and easy to use by expert reviewers. Conclusions Using such quality appraisal tools is mandatory to assess whether specific observational real-life effectiveness studies can be used to inform guideline development and/or decision-making in clinical practice.