A Planetary Microlensing Event with an Unusually Red Source Star: MOA-2011-BLG-291

We present the analysis of planetary microlensing event MOA-2011-BLG-291, which has a mass ratio of $q=(3.8\pm0.7)\times10^{-4}$ and a source star that is redder (or brighter) than the bulge main sequence. This event is located at a low Galactic latitude in the survey area that is currently planned for NASA's WFIRST exoplanet microlensing survey. This unusual color for a microlensed source star implies that we cannot assume that the source star is in the Galactic bulge. The favored interpretation is that the source star is a lower main sequence star at a distance of $D_S=4.9\pm1.3\,$kpc in the Galactic disk. However, the source could also be a turn-off star on the far side of the bulge or a sub-giant in the far side of the Galactic disk if it experiences significantly more reddening than the bulge red clump stars. However, these possibilities have only a small effect on our mass estimates for the host star and planet. We find host star and planet masses of $M_{\rm host} =0.15^{+0.27}_{-0.10}M_\odot$ and $m_p=18^{+34}_{-12}M_\oplus$ from a Bayesian analysis with a standard Galactic model under the assumption that the planet hosting probability does not depend on the host mass or distance. However, if we attempt to measure the host and planet masses with host star brightness measurements from high angular resolution follow-up imaging, the implied masses will be sensitive to the host star distance. The WFIRST exoplanet microlensing survey is expected to use this method to determine the masses for many of the planetary systems that it discovers, so this issue has important design implications for the WFIRST exoplanet microlensing survey

A chemical survey of exoplanets with ARIEL

Thousands of exoplanets have now been discovered with a huge range of masses, sizes and orbits: from rocky Earth-like planets to large gas giants grazing the surface of their host star. However, the essential nature of these exoplanets remains largely mysterious: there is no known, discernible pattern linking the presence, size, or orbital parameters of a planet to the nature of its parent star. We have little idea whether the chemistry of a planet is linked to its formation environment, or whether the type of host star drives the physics and chemistry of the planet’s birth, and evolution. ARIEL was conceived to observe a large number (~1000) of transiting planets for statistical understanding, including gas giants, Neptunes, super-Earths and Earth-size planets around a range of host star types using transit spectroscopy in the 1.25–7.8 μm spectral range and multiple narrow-band photometry in the optical. ARIEL will focus on warm and hot planets to take advantage of their well-mixed atmospheres which should show minimal condensation and sequestration of high-Z materials compared to their colder Solar System siblings. Said warm and hot atmospheres are expected to be more representative of the planetary bulk composition. Observations of these warm/hot exoplanets, and in particular of their elemental composition (especially C, O, N, S, Si), will allow the understanding of the early stages of planetary and atmospheric formation during the nebular phase and the following few million years. ARIEL will thus provide a representative picture of the chemical nature of the exoplanets and relate this directly to the type and chemical environment of the host star. ARIEL is designed as a dedicated survey mission for combined-light spectroscopy, capable of observing a large and well-defined planet sample within its 4-year mission lifetime. Transit, eclipse and phase-curve spectroscopy methods, whereby the signal from the star and planet are differentiated using knowledge of the planetary ephemerides, allow us to measure atmospheric signals from the planet at levels of 10–100 part per million (ppm) relative to the star and, given the bright nature of targets, also allows more sophisticated techniques, such as eclipse mapping, to give a deeper insight into the nature of the atmosphere. These types of observations require a stable payload and satellite platform with broad, instantaneous wavelength coverage to detect many molecular species, probe the thermal structure, identify clouds and monitor the stellar activity. The wavelength range proposed covers all the expected major atmospheric gases from e.g. H2O, CO2, CH4 NH3, HCN, H2S through to the more exotic metallic compounds, such as TiO, VO, and condensed species. Simulations of ARIEL performance in conducting exoplanet surveys have been performed – using conservative estimates of mission performance and a full model of all significant noise sources in the measurement – using a list of potential ARIEL targets that incorporates the latest available exoplanet statistics. The conclusion at the end of the Phase A study, is that ARIEL – in line with the stated mission objectives – will be able to observe about 1000 exoplanets depending on the details of the adopted survey strategy, thus confirming the feasibility of the main science objectives.Peer reviewedFinal Published versio

The vitamin D, ionised calcium and parathyroid hormone axis of cerebral capillary function: Therapeutic considerations for vascular-based neurodegenerative disorders

Blood-brain barrier dysfunction characterised by brain parenchymal extravasation of plasma proteins may contribute to risk of neurodegenerative disorders, however the mechanisms for increased capillary permeability are not understood. Increasing evidence suggests vitamin D confers central nervous system benefits and there is increasing demand for vitamin D supplementation. Vitamin D may influence the CNS via modulation of capillary function, however such effects may be indirect as it has a central role in maintaining calcium homeostasis, in concert with calcium regulatory hormones. This study utilised an integrated approach and investigated the effects of vitamin D supplementation, parathyroid tissue ablation (PTX), or exogenous infusion of parathyroid hormone (PTH) on cerebral capillary integrity. Parenchymal extravasation of immunoglobulin G (IgG) was used as a marker of cerebral capillary permeability. In C57BL/6J mice and Sprague Dawley rats, dietary vitamin D was associated with exaggerated abundance of IgG within cerebral cortex (CTX) and hippocampal formation (HPF). Vitamin D was also associated with increased plasma ionised calcium (iCa) and decreased PTH. A response to dose was suggested and parenchymal effects persisted for up to 24 weeks. Ablation of parathyroid glands increased CTX- and HPF-IgG abundance concomitant with a reduction in plasma iCa. With the provision of PTH, iCa levels increased, however the PTH treated animals did not show increased cerebral permeability. Vitamin D supplemented groups and rats with PTH-tissue ablation showed modestly increased parenchymal abundance of glial-fibrillary acidic protein (GFAP), a marker of astroglial activation. PTH infusion attenuated GFAP abundance. The findings suggest that vitamin D can compromise capillary integrity via a mechanism that is independent of calcium homeostasis. The effects of exogenous vitamin D supplementation on capillary function and in the context of prevention of vascular neurodegenerative conditions should be considered in the context of synergistic effects with calcium modulating hormones

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

DÉTECTION DE PLANÈTES EXTRASOLAIRES PAR LA MÉTHODE DES MICROLENTILLES GRAVITATIONNELLES ET ATMOSPHÈRES PLANÉTAIRES

In the last 15 years, more than 500 exoplanets have been discovered, revealing systems very different from our solar system. These discoveries have modified our understanding of planetary systems formation and evolution. Nowadays, the two principal challenges are the estimation of planet abundance and the characterization of exoplanets. This thesis examines two different aspects of the exoplanets research : the first and main aspect in this thesis is the detection of exoplanets via the microlensing and it is illustrated by the analysis of 3 events. The second one is the detection of molecules in the atmospheres of exoplanets, with the analysis of a hot Jupiter's atmosphere. Microlensing has led to the detection of 20 exoplanets (published and in preparation), including two super Earth-like planets of 3.2 and 5.5 $M_\oplus$. Even if this number is modest, this technique allows the exploration of regions of parameter space regions that are not accessible to any other methods. We first detail the analysis of a high magnification event and its sensitivity to the presence of a planet. With a star at 5.5 kpc from us, an Earth-like companion orbiting at several AU from its star could have been detected. This detection efficiency analysis has contributed to a larger study that gives an estimate of the abundance of giants in our Galaxy. We then present a planetary event that implies a massive planet orbiting an M dwarf and discuss the low probability of such a system according to the planetary formation theory. Taking into account some higher-order effects, such as orbital motion and parallax, combined with a Bayesian analysis, permits to constrain the dynamics of the system. Moreover, additional adaptive-optics data have been taken and give more constraints on the host star mass. Finally, a cold-Neptune detection in which I participated is presented. On the theme of planetary atmospheres, we present in part 2 the analysis of a hot Jupiter-like planet, HD209458b, and in particular the detection of water in its atmosphere, based on primary transit measurements by Spitzer. I developed an MCMC algorithm adapted to transit light curves to estimate the orbital and physical planet characteristics. These characteristics are then considered as inputs in the atmosphere models. The transmission spectrum of HD209458b is dominated by water absorption.Au cours des 15 dernières années, plus de 500 exoplanètes ont été détectées, révélant l'existence de systèmes souvent très différents du nôtre. Ces découvertes ont profondément affecté notre compréhension des mécanismes de formation des systèmes planétaires et de leur évolution dynamique. Aujourd'hui, les deux défis principaux sont d'estimer l'abondance des planètes jusqu'aux masses telluriques et d'effectuer la transition de la détection vers la caractérisation des exoplanètes. Cette thèse apporte une contribution sur les deux aspects, détection d'exoplanètes par microlentilles gravitationnelles et de molécules dans les atmosphères. Les microlentilles gravitationnelles ont permis de détecter 20 exoplanètes (publiées ou en cours de publication), incluant deux super-Terres de 3.2 et 5.5 $M_\oplus$. Bien que ce nombre soit modeste, cette technique permet l'exploration de systèmes inaccessibles via d'autres methodes, ayant son maximum de sensibilité au-delà de la limite des glaces. Nous détaillons tout d'abord l'analyse d'un évènement de haute amplification et sa sensibilité à la présence potentielle d'une planète. Avec une étoile à 5.5 kpc du système solaire, un compagnon de type terrestre orbitant à quelques UA aurait pu être détecté. Cette analyse d'efficacité de détection a contribué à une étude plus large visant à estimer l'abondance de planètes au sein de la Galaxie, montrant que les Saturne glacées sont abondantes. Nous traitons ensuite d'un évènement impliquant une planète massive orbitant une étoile naine et discutons de la faible probabilité d'existence d'un tel système selon les théories de formation planétaire du modèle d'accrétion de coeur. La prise en compte d'effets du second ordre dans la modélisation de cet évènement, doublée d'une analyse bayesienne à partir des distributions de vitesse et de luminosité des étoiles de la Galaxie, a permis de contraindre la dynamique du système. Enfin, la découverte d'une planète de type Neptune dont j'ai participé à la détection est présentée. Sur le thème des atmosphères planétaires, nous présentons l'analyse du Jupiter chaud HD209458b basée sur des mesures de transits primaires par Spitzer dans l'infrarouge. J'ai développé un algorithme de type MCMC adapté aux courbes de transits afin d'estimer les paramètres physiques et orbitaux de la planète. Ces paramètres constituent alors des données d'entrée pour les modèles d'atmosphère planétaire. Le spectre en transmission de HD209458b est dominé par l'absorption de vapeur d'eau

Détection de planètes extrasolaires par la méthode des microlentilles gravitationnelles et atmosphères planétaires

A ce jour, presque 500 exoplanètes ont été détectées. Ces découvertes ont profondément affecté notre compréhension de la formation des systèmes planétaires. Aujourd'hui, les défis principaux sont de caractériser les exoplanètes et d'estimer leur abondance. Cette thèse apporte une contribution sur les deux aspects, détection d'exoplanètes par microlentilles gravitationnelles et de molécules dans les atmosphères. Les microlentilles ont permis de détecter 20 exoplanètes. Bien que ce nombre soit modeste, cette technique permet l'exploration de systèmes inaccessibles via d'autres methodes. Nous détaillons l'analyse d'un évènement de haute amplification et sa sensibilité à la présence potentielle d'une planète. Cette analyse d'efficacité de détection a contribué à une étude plus large visant à estimer l'abondance de planètes au sein de la Galaxie, montrant que les Saturne glacées sont abondantes. Nous traitons ensuite d'un évènement impliquant une planète massive orbitant une étoile naine. La prise en compte d'effets du second ordre dans la modélisation de cet évènement, doublée d'une analyse bayesienne, a permis de contraindre la dynamique du système. Enfin, la découverte d'une planète de type Neptune dont j'ai participé à la détection est présentée. Sur le thème des atmosphères planétaires, nous présentons l'analyse du Jupiter chaud HD209458b basée sur des mesures de transits primaires par Spitzer. J'ai développé un algorithme afin d'estimer les paramètres physiques et orbitaux de la planète. Ces paramètres consistuent alors des données d'entrée pour les modèles d'atmosphère planétaire. Le spectre de HD209458b est dominé par l'absorption de vapeur d'eauPARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF

TRANSIT SPECTROSCOPY : ON THE INFLUENCE OF STELLAR MOLECULARLINES IN THE RETRIEVAL OF EXOPLANETS ATMOSPHERIC ABSORPTION

International audienc

How to START? Four pillars to optimally begin your orphan drug development

Abstract Drug development is a complex, resource intensive and long process in any disease area, and developing medicines to treat rare diseases presents even more challenges due to the small patient populations, often limited disease knowledge, heterogeneous clinical manifestations, and disease progression. However, common to all drug development programs is the need to gather as much information as possible on both the disease and the patients’ needs ahead of the development path definition. Here, we propose a checklist named START, a tool that provides an overview of the key pillars to be considered when starting an orphan drug development: STakeholder mapping, Available information on the disease, Resources, and Target patient value profile. This tool helps to build solid foundations of a successful patient-centered medicines development program and guides different types of developers through a set of questions to ask for guidance through the starting phase of a rare disease therapeutic pathway