5-HT2A and 5-HT2C receptors as hypothalamic targets of developmental programming in male rats.

Although obesity is a global epidemic, the physiological mechanisms involved are not well understood. Recent advances reveal that susceptibility to obesity can be programmed by maternal and neonatal nutrition. Specifically, a maternal low-protein diet during pregnancy causes decreased intrauterine growth, rapid postnatal catch-up growth and an increased risk for diet-induced obesity. Given that the synthesis of the neurotransmitter 5-hydroxytryptamine (5-HT) is nutritionally regulated and 5-HT is a trophic factor, we hypothesised that maternal diet influences fetal 5-HT exposure, which then influences development of the central appetite network and the subsequent efficacy of 5-HT to control energy balance in later life. Consistent with our hypothesis, pregnant rats fed a low-protein diet exhibited elevated serum levels of 5-HT, which was also evident in the placenta and fetal brains at embryonic day 16.5. This increase was associated with reduced levels of 5-HT2CR, the primary 5-HT receptor influencing appetite, in the fetal, neonatal and adult hypothalamus. As expected, a reduction of 5-HT2CR was associated with impaired sensitivity to 5-HT-mediated appetite suppression in adulthood. 5-HT primarily achieves effects on appetite by 5-HT2CR stimulation of pro-opiomelanocortin (POMC) peptides within the arcuate nucleus of the hypothalamus (ARC). We show that 5-HT2ARs are also anatomically positioned to influence the activity of ARC POMC neurons and that mRNA encoding 5-HT2AR is increased in the hypothalamus ofin uterogrowth-restricted offspring that underwent rapid postnatal catch-up growth. Furthermore, these animals at 3 months of age are more sensitive to appetite suppression induced by 5-HT2AR agonists. These findings not only reveal a 5-HT-mediated mechanism underlying the programming of susceptibility to obesity, but also provide a promising means to correct it, by treatment with a 5-HT2AR agonist

Spontaneous Breathing in Early Acute Respiratory Distress Syndrome: Insights From the Large Observational Study to UNderstand the Global Impact of Severe Acute Respiratory FailurE Study

OBJECTIVES: To describe the characteristics and outcomes of patients with acute respiratory distress syndrome with or without spontaneous breathing and to investigate whether the effects of spontaneous breathing on outcome depend on acute respiratory distress syndrome severity. DESIGN: Planned secondary analysis of a prospective, observational, multicentre cohort study. SETTING: International sample of 459 ICUs from 50 countries. PATIENTS: Patients with acute respiratory distress syndrome and at least 2 days of invasive mechanical ventilation and available data for the mode of mechanical ventilation and respiratory rate for the 2 first days. INTERVENTIONS: Analysis of patients with and without spontaneous breathing, defined by the mode of mechanical ventilation and by actual respiratory rate compared with set respiratory rate during the first 48 hours of mechanical ventilation. MEASUREMENTS AND MAIN RESULTS: Spontaneous breathing was present in 67% of patients with mild acute respiratory distress syndrome, 58% of patients with moderate acute respiratory distress syndrome, and 46% of patients with severe acute respiratory distress syndrome. Patients with spontaneous breathing were older and had lower acute respiratory distress syndrome severity, Sequential Organ Failure Assessment scores, ICU and hospital mortality, and were less likely to be diagnosed with acute respiratory distress syndrome by clinicians. In adjusted analysis, spontaneous breathing during the first 2 days was not associated with an effect on ICU or hospital mortality (33% vs 37%; odds ratio, 1.18 [0.92-1.51]; p = 0.19 and 37% vs 41%; odds ratio, 1.18 [0.93-1.50]; p = 0.196, respectively ). Spontaneous breathing was associated with increased ventilator-free days (13 [0-22] vs 8 [0-20]; p = 0.014) and shorter duration of ICU stay (11 [6-20] vs 12 [7-22]; p = 0.04). CONCLUSIONS: Spontaneous breathing is common in patients with acute respiratory distress syndrome during the first 48 hours of mechanical ventilation. Spontaneous breathing is not associated with worse outcomes and may hasten liberation from the ventilator and from ICU. Although these results support the use of spontaneous breathing in patients with acute respiratory distress syndrome independent of acute respiratory distress syndrome severity, the use of controlled ventilation indicates a bias toward use in patients with higher disease severity. In addition, because the lack of reliable data on inspiratory effort in our study, prospective studies incorporating the magnitude of inspiratory effort and adjusting for all potential severity confounders are required

Identifying associations between diabetes and acute respiratory distress syndrome in patients with acute hypoxemic respiratory failure: an analysis of the LUNG SAFE database

Background: Diabetes mellitus is a common co-existing disease in the critically ill. Diabetes mellitus may reduce the risk of acute respiratory distress syndrome (ARDS), but data from previous studies are conflicting. The objective of this study was to evaluate associations between pre-existing diabetes mellitus and ARDS in critically ill patients with acute hypoxemic respiratory failure (AHRF). Methods: An ancillary analysis of a global, multi-centre prospective observational study (LUNG SAFE) was undertaken. LUNG SAFE evaluated all patients admitted to an intensive care unit (ICU) over a 4-week period, that required mechanical ventilation and met AHRF criteria. Patients who had their AHRF fully explained by cardiac failure were excluded. Important clinical characteristics were included in a stepwise selection approach (forward and backward selection combined with a significance level of 0.05) to identify a set of independent variables associated with having ARDS at any time, developing ARDS (defined as ARDS occurring after day 2 from meeting AHRF criteria) and with hospital mortality. Furthermore, propensity score analysis was undertaken to account for the differences in baseline characteristics between patients with and without diabetes mellitus, and the association between diabetes mellitus and outcomes of interest was assessed on matched samples. Results: Of the 4107 patients with AHRF included in this study, 3022 (73.6%) patients fulfilled ARDS criteria at admission or developed ARDS during their ICU stay. Diabetes mellitus was a pre-existing co-morbidity in 913 patients (22.2% of patients with AHRF). In multivariable analysis, there was no association between diabetes mellitus and having ARDS (OR 0.93 (0.78-1.11); p = 0.39), developing ARDS late (OR 0.79 (0.54-1.15); p = 0.22), or hospital mortality in patients with ARDS (1.15 (0.93-1.42); p = 0.19). In a matched sample of patients, there was no association between diabetes mellitus and outcomes of interest. Conclusions: In a large, global observational study of patients with AHRF, no association was found between diabetes mellitus and having ARDS, developing ARDS, or outcomes from ARDS. Trial registration: NCT02010073. Registered on 12 December 2013

Epidemiology and patterns of tracheostomy practice in patients with acute respiratory distress syndrome in ICUs across 50 countries

Background: To better understand the epidemiology and patterns of tracheostomy practice for patients with acute respiratory distress syndrome (ARDS), we investigated the current usage of tracheostomy in patients with ARDS recruited into the Large Observational Study to Understand the Global Impact of Severe Acute Respiratory Failure (LUNG-SAFE) study. Methods: This is a secondary analysis of LUNG-SAFE, an international, multicenter, prospective cohort study of patients receiving invasive or noninvasive ventilation in 50 countries spanning 5 continents. The study was carried out over 4 weeks consecutively in the winter of 2014, and 459 ICUs participated. We evaluated the clinical characteristics, management and outcomes of patients that received tracheostomy, in the cohort of patients that developed ARDS on day 1-2 of acute hypoxemic respiratory failure, and in a subsequent propensity-matched cohort. Results: Of the 2377 patients with ARDS that fulfilled the inclusion criteria, 309 (13.0%) underwent tracheostomy during their ICU stay. Patients from high-income European countries (n = 198/1263) more frequently underwent tracheostomy compared to patients from non-European high-income countries (n = 63/649) or patients from middle-income countries (n = 48/465). Only 86/309 (27.8%) underwent tracheostomy on or before day 7, while the median timing of tracheostomy was 14 (Q1-Q3, 7-21) days after onset of ARDS. In the subsample matched by propensity score, ICU and hospital stay were longer in patients with tracheostomy. While patients with tracheostomy had the highest survival probability, there was no difference in 60-day or 90-day mortality in either the patient subgroup that survived for at least 5 days in ICU, or in the propensity-matched subsample. Conclusions: Most patients that receive tracheostomy do so after the first week of critical illness. Tracheostomy may prolong patient survival but does not reduce 60-day or 90-day mortality. Trial registration: ClinicalTrials.gov, NCT02010073. Registered on 12 December 2013

Hyperoxemia and excess oxygen use in early acute respiratory distress syndrome : Insights from the LUNG SAFE study

Publisher Copyright: © 2020 The Author(s). Copyright: Copyright 2020 Elsevier B.V., All rights reserved.Background: Concerns exist regarding the prevalence and impact of unnecessary oxygen use in patients with acute respiratory distress syndrome (ARDS). We examined this issue in patients with ARDS enrolled in the Large observational study to UNderstand the Global impact of Severe Acute respiratory FailurE (LUNG SAFE) study. Methods: In this secondary analysis of the LUNG SAFE study, we wished to determine the prevalence and the outcomes associated with hyperoxemia on day 1, sustained hyperoxemia, and excessive oxygen use in patients with early ARDS. Patients who fulfilled criteria of ARDS on day 1 and day 2 of acute hypoxemic respiratory failure were categorized based on the presence of hyperoxemia (PaO2 > 100 mmHg) on day 1, sustained (i.e., present on day 1 and day 2) hyperoxemia, or excessive oxygen use (FIO2 ≥ 0.60 during hyperoxemia). Results: Of 2005 patients that met the inclusion criteria, 131 (6.5%) were hypoxemic (PaO2 < 55 mmHg), 607 (30%) had hyperoxemia on day 1, and 250 (12%) had sustained hyperoxemia. Excess FIO2 use occurred in 400 (66%) out of 607 patients with hyperoxemia. Excess FIO2 use decreased from day 1 to day 2 of ARDS, with most hyperoxemic patients on day 2 receiving relatively low FIO2. Multivariate analyses found no independent relationship between day 1 hyperoxemia, sustained hyperoxemia, or excess FIO2 use and adverse clinical outcomes. Mortality was 42% in patients with excess FIO2 use, compared to 39% in a propensity-matched sample of normoxemic (PaO2 55-100 mmHg) patients (P = 0.47). Conclusions: Hyperoxemia and excess oxygen use are both prevalent in early ARDS but are most often non-sustained. No relationship was found between hyperoxemia or excessive oxygen use and patient outcome in this cohort. Trial registration: LUNG-SAFE is registered with ClinicalTrials.gov, NCT02010073publishersversionPeer reviewe

Geoeconomic variations in epidemiology, ventilation management, and outcomes in invasively ventilated intensive care unit patients without acute respiratory distress syndrome: a pooled analysis of four observational studies

Background: Geoeconomic variations in epidemiology, the practice of ventilation, and outcome in invasively ventilated intensive care unit (ICU) patients without acute respiratory distress syndrome (ARDS) remain unexplored. In this analysis we aim to address these gaps using individual patient data of four large observational studies. Methods: In this pooled analysis we harmonised individual patient data from the ERICC, LUNG SAFE, PRoVENT, and PRoVENT-iMiC prospective observational studies, which were conducted from June, 2011, to December, 2018, in 534 ICUs in 54 countries. We used the 2016 World Bank classification to define two geoeconomic regions: middle-income countries (MICs) and high-income countries (HICs). ARDS was defined according to the Berlin criteria. Descriptive statistics were used to compare patients in MICs versus HICs. The primary outcome was the use of low tidal volume ventilation (LTVV) for the first 3 days of mechanical ventilation. Secondary outcomes were key ventilation parameters (tidal volume size, positive end-expiratory pressure, fraction of inspired oxygen, peak pressure, plateau pressure, driving pressure, and respiratory rate), patient characteristics, the risk for and actual development of acute respiratory distress syndrome after the first day of ventilation, duration of ventilation, ICU length of stay, and ICU mortality. Findings: Of the 7608 patients included in the original studies, this analysis included 3852 patients without ARDS, of whom 2345 were from MICs and 1507 were from HICs. Patients in MICs were younger, shorter and with a slightly lower body-mass index, more often had diabetes and active cancer, but less often chronic obstructive pulmonary disease and heart failure than patients from HICs. Sequential organ failure assessment scores were similar in MICs and HICs. Use of LTVV in MICs and HICs was comparable (42\ub74% vs 44\ub72%; absolute difference \u20131\ub769 [\u20139\ub758 to 6\ub711] p=0\ub767; data available in 3174 [82%] of 3852 patients). The median applied positive end expiratory pressure was lower in MICs than in HICs (5 [IQR 5\u20138] vs 6 [5\u20138] cm H2O; p=0\ub70011). ICU mortality was higher in MICs than in HICs (30\ub75% vs 19\ub79%; p=0\ub70004; adjusted effect 16\ub741% [95% CI 9\ub752\u201323\ub752]; p&lt;0\ub70001) and was inversely associated with gross domestic product (adjusted odds ratio for a US$10 000 increase per capita 0\ub780 [95% CI 0\ub775\u20130\ub786]; p&lt;0\ub70001). Interpretation: Despite similar disease severity and ventilation management, ICU mortality in patients without ARDS is higher in MICs than in HICs, with a strong association with country-level economic status. Funding: No funding

Étude expérimentale de l’atmosphère et des aérosols de Pluton

On July 14th, 2015, NASA’s New Horizons spacecraft flew by Pluto, revealing a complex atmosphere and surface seen nowhere else in the Solar System. Pluto’s surface ices are composed of molecular nitrogen N2, methane CH4, and carbon monoxide CO. During Pluto’s elliptical orbit, these ices undergo a sublimation/condensation cycle resulting in a tenuous atmosphere (~11 µbar at the surface). This atmosphere is mostly composed of N2 and CH4, with ~500 ppm of CO. Subjected to extreme ultraviolet radiation and Lyman-α photons, it is the place of photochemical aerosol production, aerosols being solid particles in suspension in the atmosphere. The exact processes of formation of these aerosols are however not well constrained yet. These solid particles, whose chemical composition and optical properties are unknown, are observed up to more than 350 km of altitude in the atmosphere of Pluto. Numerical models have shown that the presence of these aerosols in the atmosphere could have an impact on the atmospheric chemistry and climate of Pluto. Moreover, it has been suggested that these aerosols sediment and constitute a source of organic matter on the surface of Pluto.During my Ph.D., I used an experimental approach to study the aerosols of Pluto, from their formation in the upper atmosphere to their evolution on the surface, through their interactions with the atmosphere. The formation of Pluto’s aerosols by photochemistry and their chemical composition are the subjects of the first and second part of this Ph.D. thesis (Chapter III and Chapter IV). The interaction of Pluto’s aerosols with solar radiation and the contribution of photochemical aerosols as a coloring agent on the surface of Pluto are the subjects of the third and fourth part of this Ph.D. thesis (Chapter V and Chapter VI).The experimental setup PAMPRE (Production of Aerosols in Microgravity by REactive Plasma), located at LATMOS, has been used to simulate the atmospheric chemistry of Pluto and to synthesize analogues of photochemical aerosols, usually called "tholins". Experiments have also been performed at GANIL, using the IGLIAS (Irradiation of astrophysical ices) experimental setup. By irradiating tholins with heavy ions, the objective was to simulate the ageing of organic matter on the surface of Pluto due to the charged particles constituting the galactic cosmic rays.Thanks to the physicochemical analyses carried out to characterize the chemical composition of Pluto-simulated atmosphere as well as that of the synthesized aerosol analogues, I was able to conclude to the importance of N2 and CO reactivity in the atmospheric chemistry of Pluto. The nitrogen constituting the molecules produced in the gas phase and ultimately incorporated in the solid particles is included not only in the form of terminal functional groups (amine, nitrile, isocyanide), but also in the form of nitrogen heterocycles (triazine, pyrazole, pyrazine, pyrrole). Regarding oxygen, only terminal oxygenated chemical functions (alcohol, carboxylic acid, carbonyl) were detected. These nitrogenous and/or oxygenated organic molecules are responsible for a strong absorption in the ultraviolet spectral range by Pluto aerosol analogues and a more moderate absorption in the visible and near-infrared. These results are consistent with spectral observations of Pluto’s surface and atmosphere by instruments onboard New Horizons. Finally, thanks to the experiments of irradiation of Pluto aerosol analogues by heavy ions, I was able to conclude that the surface of Pluto is processed by galactic cosmic ray irradiation, probably explaining the characteristic featureless spectra of the Cthulhu region.Le 14 Juillet 2015, la sonde New Horizons de la NASA a survolé Pluton, révélant une atmosphère et une surface complexes observées nulle part ailleurs dans le Système Solaire. La surface de Pluton est composée de glaces de diazote N2, de méthane CH4, et de monoxyde de carbone CO. Au cours de l’orbite elliptique de Pluton, ces glaces subissent un cycle de sublimation/condensation à l’origine d’une atmosphère ténue (~11 µbar à la surface). Cette atmosphère est majoritairement composée de N2 et CH4, avec ~500 ppm de CO. Soumise au rayonnement ultraviolet extrême et aux photons Lyman-α, elle est le siège de la production d’aérosols photochimiques, des particules solides en suspension dans l’atmosphère. Les processus exacts de formation de ces aérosols ne sont toutefois pas encore bien définis. Ces particules solides, dont la composition chimique et les propriétés optiques sont inconnues, sont observées jusqu’à plus de 350 km d’altitude dans l’atmosphère de Pluton. Des modèles numériques ont montré que la présence de ces aérosols dans l’atmosphère pouvait avoir un impact sur la chimie atmosphérique et le climat de Pluton. De plus, il a été suggéré que ces aérosols sédimentent et constituent une source de matière organique à la surface de Pluton.Dans le cadre de ma thèse, j’ai utilisé une approche expérimentale afin d’étudier les aérosols de Pluton, de leur formation dans la haute atmosphère à leur devenir en surface, en passant par leurs interactions avec l’atmosphère. La formation des aérosols de Pluton par photochimie et leur composition chimique sont les sujets de la première et de la deuxième partie de cette thèse de Doctorat (Chapitre III et Chapitre IV). L’interaction des aérosols de Pluton avec le rayonnement solaire et la contribution des aérosols photochimiques en tant qu’agent colorant à la surface de Pluton sont les sujets de la troisième et de la quatrième partie de cette thèse de Doctorat (Chapitre V et Chapitre VI).Le dispositif expérimental PAMPRE (Production d’Aérosols en Microgravité par Plasma REactif), situé au LATMOS, a été utilisé afin de simuler la chimie atmosphérique de Pluton et synthétiser des analogues d’aérosols photochimiques, communément appelés "tholins". Des expériences ont également été réalisées au GANIL, en utilisant le dispositif expérimental IGLIAS (Irradiation de GLaces d’Intérêt Astrophysique). En irradiant les tholins avec des ions lourds, l’objectif était de simuler le vieillissement de la matière organique à la surface de Pluton dû aux particules chargées constituant le rayonnement cosmique galactique.Grâce aux analyses physico-chimiques effectuées, tant pour caractériser la composition chimique de l’atmosphère simulée de Pluton que celle des analogues d’aérosols synthétisés, j’ai pu conclure à l’importance de la réactivité de N2 et CO dans la chimie atmosphérique de Pluton. L’azote constituant les molécules produites en phase gazeuse et incorporées ultimement dans les particules solides est inclus non seulement sous la forme de fonctions chimiques terminales (amine, nitrile, isonitrile), mais aussi sous la forme d’hétérocycles azotés (triazine, pyrazole, pyrazine, pyrrole). Quant à l’oxygène, seules des fonctions chimiques oxygénées terminales (alcool, acide carboxylique, carbonyle) ont été détectées. Ces molécules organiques azotées et/ou oxygénées sont responsables d’une forte absorption dans le domaine spectral ultraviolet par les analogues d’aérosols de Pluton et une absorption plus modérée dans le visible et l’infrarouge proche. Ces résultats sont cohérents avec les observations spectrales faites de la surface et de l’atmosphère de Pluton par les instruments à bord de la sonde New Horizons. Enfin, grâce aux expériences d’irradiation des analogues d’aérosols de Pluton par des ions lourds, j’ai pu conclure au vieillissement de la surface de Pluton par irradiation par le rayonnement cosmique galactique, expliquant probablement les spectres caractéristiques de la région Cthulhu

Cation Chemistry in Titan’s Upper Atmosphere and its Influence on Tholin Formation

International audienceTitan is Saturn’s largest satellite. This object is unique in the solar system as it hosts a dense atmosphere mainly made of molecular nitrogen N and methane CH4, with a surface pressure of 1.5 bar. The nitrogen rich atmosphere and the presence of liquid areas on the surface make it one of the most interesting nearby objects to understand the evolution of the primitive Earth before the emergence of life and to look for habitable environments in the solar system. The Cassini-Huygens Mission has been probing Titan since 2004. It has revealed an intense atmospheric photochemistry initiated by the photo-dissociation and ionization of N2 and CH4. Photochemistry on Titan leads to the formation of solid organic aerosols responsible for asmog permanently surrounding the moon. In the upper atmosphere, Cassini detected signatures compatible with the presence of heavily charged molecules which are precursors for the solid core of the aerosols. These observations indicate that ion chemistry has an important role for organic growth. However, the processes coupling ion chemistry and aerosol production are mostly still unknown. In this study, we investigate the cation chemistry, responsible for the organic growth that we observe in Titan’s upper atmosphere, simulated using the PAMPRE plasma reactor. Positive ions are investigated by in situ ion mass spectrometry in a dusty cold plasma, alongside neutral products additionally studied through infrared absorption spectroscopy and mass spectrometry

Laboratory simulation of Pluto's atmospheric chemistry

International audienceThe detection of thin haze layers in Pluto's atmosphere highlighted the complex photochemistry occurring in it. In order to understand the processes leading to the formation of Pluto's aerosols, we produced in laboratory a plasma mimicking Pluto's atmospheric chemistry and we analyzed this plasma by in situ mass spectrometry

Positive Ion Chemistry in an N₂-CH₄ Plasma Discharge: Key Precursors to the Growth of Titan Tholins

International audienceTitan is unique in the solar system as it hosts a dense atmosphere mainly made of molecular nitrogen N2 and methane CH4. The Cassini-Huygens Mission revealed the presence of an intense atmospheric photochemistry initiated by the photo-dissociation and ionization of N2 and CH4. In the upper atmosphere, Cassini detected signatures compatible with the presence of heavily charged molecules which are precursors for the solid core of the aerosols. These observations have indicated that ion chemistry has an important role for organic growth. However, the processes coupling ion chemistry and aerosol formation and growth are still mostly unknown. In this study, we investigated the cation chemistry responsible for an efficient organic growth that we observe in Titan's upper atmosphere, simulated using the PAMPRE plasma reactor. Positive ion precursors were measured by in situ ion mass spectrometry in a cold plasma and compared with INMS observations taken during the T40 flyby. A series of positive ion measurements were performed in three CH4 mixing ratios (1%, 5% and 10%) showing a variability in ion population. Low methane concentrations result in an abundance of amine cations such as NH4+ whereas aliphatic compounds dominate at higher methane concentrations. In conditions of favored tholin production, the presence of C2 compounds such as HCNH+ and C2H5+ is found to be consistent with copolymeric growth structures seen in tholin material. The observed abundance of these two ions particularly in conditions with lower CH4 amounts is consistent with modeling work simulating aerosol growth in Titan's ionosphere, which includes mass exchange primarily between HCNH+ and C2H5+ and negatively charged particles. These results also confirm the prevalent role of C2 cations as precursors to molecular growth and subsequent mass transfer to the charged aerosol particles as the CH4 abundance decreases towards lower altitudes