Diagnosis, treatment, and follow-up of a case of Wolman disease with hemophagocytic lymphohistiocytosis

: Wolman Disease (WD) is a severe multi-system metabolic disease due to lysosomal acid lipase (LAL) deficiency. We report on a WD infant who developed an unusual hemophagocytic lymphohistiocytosis (HLH) phenotype related to WD treated with sebelipase alfa. A male baby came to our attention at six months of life for respiratory insufficiency and sepsis, abdominal distension, severe hepatosplenomegaly, diarrhea, and severe growth retardation. HLH was diagnosed and treated with intravenous immunoglobulin, steroids, cyclosporine, broad-spectrum antimicrobial therapy, and finally with the anti-IL-6 drug tocilizumab. WD was suspected for the presence of adrenal calcifications and it was confirmed by LAL enzyme activity and by molecular analysis of LIPA. Plasma oxysterols cholestan-3β,5α,6β-triol (C-triol), and 7-ketocholesterol (7-KC) were markedly increased. Sebelipase alfa was started with progressive amelioration of biochemical and clinical features. The child died from sepsis, 2 months after sebelipase discontinuation requested by parents. Our case shows the importance of an early diagnosis of WD and confirms the difficulty to reach a diagnosis in the HLH phenotype. Sebelipase alpha is an effective treatment for LAL deficiency, also in children affected by WD. Further data are necessary to confirm the utility of measuring plasma c-triol as a biochemical marker of the disease

Enabling planetary science across light-years. Ariel Definition Study Report

Ariel, the Atmospheric Remote-sensing Infrared Exoplanet Large-survey, was adopted as the fourth medium-class mission in ESA's Cosmic Vision programme to be launched in 2029. During its 4-year mission, Ariel will study what exoplanets are made of, how they formed and how they evolve, by surveying a diverse sample of about 1000 extrasolar planets, simultaneously in visible and infrared wavelengths. It is the first mission dedicated to measuring the chemical composition and thermal structures of hundreds of transiting exoplanets, enabling planetary science far beyond the boundaries of the Solar System. The payload consists of an off-axis Cassegrain telescope (primary mirror 1100 mm x 730 mm ellipse) and two separate instruments (FGS and AIRS) covering simultaneously 0.5-7.8 micron spectral range. The satellite is best placed into an L2 orbit to maximise the thermal stability and the field of regard. The payload module is passively cooled via a series of V-Groove radiators; the detectors for the AIRS are the only items that require active cooling via an active Ne JT cooler. The Ariel payload is developed by a consortium of more than 50 institutes from 16 ESA countries, which include the UK, France, Italy, Belgium, Poland, Spain, Austria, Denmark, Ireland, Portugal, Czech Republic, Hungary, the Netherlands, Sweden, Norway, Estonia, and a NASA contribution

Accuracy of ALMA estimates of young disk radii and masses: Predicted observations from numerical simulations

International audienceContext. Protoplanetary disks, which are the natural consequence of the gravitational collapse of the dense molecular cloud cores, host the formation of the known planetary systems in our universe. Substantial efforts have been dedicated to investigating the properties of these disks in the more mature Class II stage, either via numerical simulations of disk evolution from a limited range of initial conditions or observations of their dust continuum and line emission from specific molecular tracers. The results coming from these two standpoints have been used to draw comparisons. However, few studies have investigated the main limitations at work when measuring the embedded Class 0/I disk properties from observations, especially in a statistical fashion.Aims. In this study, we provide a first attempt to compare the accuracy of some critical disk parameters in Class 0/I systems, as derived on real ALMA observational data, with the corresponding physical parameters that can be directly defined by theoreticians and modellers in numerical simulations. The approach we follow here is to provide full post-processing of the numerical simulations and apply it to the synthetic observations the same techniques used by observers to derive the physical parameters.Methods. We performed 3D Monte Carlo radiative transfer and mock interferometric observations of the disk populations formed in a magnetohydrodynamic (MHD) simulation model of disk formation through the collapse of massive clumps with the tools RADMC-3D and CASA, respectively, to obtain their synthetic observations. With these observations, we re-employed the techniques commonly used in disk modelling from their continuum emissions to infer the properties that would most likely be obtained with real interferometers. We then demonstrated how these properties may vary with respect to the gas kinematics analyses and dust continuum modelling.Results. Our modelling procedure, based on a two-component model for the disk and the envelope, shows that the disk sizes can be properly recovered from observations with sufficient angular resolutions, with an uncertainty of a factor ≈1.6–2.2, whereas their masses cannot be accurately measured. Overall, the masses are predominantly underestimated for larger, more massive disks by a median factor of ≈2.5, and even up to 10 in extreme cases, with the conversion from flux to dust mass under the optically thin assumption. We also find that the single Gaussian fittings are not a reliable modelling technique for young, embedded disks characterised by a strong presence of the envelopes. Thus, such an approach is to be used with caution.Conclusions. The radiative transfer post-processing and synthetic observations of MHD simulations offer genuine help in linking important observable properties of young planet-forming disks to their intrinsic values in simulations. Further extended investigations that tackle the caveats of this study, such as the lack of variation in the dust composition and distribution, dust-to-gas ratio, and other shortcomings in the numerical models, would be essential for setting constraints on our understanding of disk and planet formations

Impact of the COVID-19 pandemic on patients with paediatric cancer in low-income, middle-income and high-income countries: a multicentre, international, observational cohort study

OBJECTIVES: Paediatric cancer is a leading cause of death for children. Children in low-income and middle-income countries (LMICs) were four times more likely to die than children in high-income countries (HICs). This study aimed to test the hypothesis that the COVID-19 pandemic had affected the delivery of healthcare services worldwide, and exacerbated the disparity in paediatric cancer outcomes between LMICs and HICs. DESIGN: A multicentre, international, collaborative cohort study. SETTING: 91 hospitals and cancer centres in 39 countries providing cancer treatment to paediatric patients between March and December 2020. PARTICIPANTS: Patients were included if they were under the age of 18 years, and newly diagnosed with or undergoing active cancer treatment for Acute lymphoblastic leukaemia, non-Hodgkin's lymphoma, Hodgkin lymphoma, Wilms' tumour, sarcoma, retinoblastoma, gliomas, medulloblastomas or neuroblastomas, in keeping with the WHO Global Initiative for Childhood Cancer. MAIN OUTCOME MEASURE: All-cause mortality at 30 days and 90 days. RESULTS: 1660 patients were recruited. 219 children had changes to their treatment due to the pandemic. Patients in LMICs were primarily affected (n=182/219, 83.1%). Relative to patients with paediatric cancer in HICs, patients with paediatric cancer in LMICs had 12.1 (95% CI 2.93 to 50.3) and 7.9 (95% CI 3.2 to 19.7) times the odds of death at 30 days and 90 days, respectively, after presentation during the COVID-19 pandemic (p<0.001). After adjusting for confounders, patients with paediatric cancer in LMICs had 15.6 (95% CI 3.7 to 65.8) times the odds of death at 30 days (p<0.001). CONCLUSIONS: The COVID-19 pandemic has affected paediatric oncology service provision. It has disproportionately affected patients in LMICs, highlighting and compounding existing disparities in healthcare systems globally that need addressing urgently. However, many patients with paediatric cancer continued to receive their normal standard of care. This speaks to the adaptability and resilience of healthcare systems and healthcare workers globally

ICAM-1-based rabies virus vaccine shows increased infection and activation of primary murine B cells in vitro and enhanced antibody titers in-vivo.

We have previously shown that live-attenuated rabies virus (RABV)-based vaccines infect and directly activate murine and human primary B cells in-vitro, which we propose can be exploited to help develop a single-dose RABV-based vaccine. Here we report on a novel approach to utilize the binding of Intracellular Adhesion Molecule-1 (ICAM-1) to its binding partner, Lymphocyte Function-associated Antigen-1 (LFA-1), on B cells to enhance B cell activation and RABV-specific antibody responses. We used a reverse genetics approach to clone, recover, and characterize a live-attenuated recombinant RABV-based vaccine expressing the murine Icam1 gene (rRABV-mICAM-1). We show that the murine ICAM-1 gene product is incorporated into virus particles, potentially exposing ICAM-1 to extracellular binding partners. While rRABV-mICAM-1 showed 10-100-fold decrease in viral titers on baby hamster kidney cells compared to the parental virus (rRABV), rRABV-mICAM-1 infected and activated primary murine B cells in-vitro more efficiently than rRABV, as indicated by significant upregulation of CD69, CD40, and MHCII on the surface of infected B cells. ICAM-1 expression on the virus surface was responsible for enhanced B cell infection since pre-treating rRABV-mICAM-1 with a neutralizing anti-ICAM-1 antibody reduced B cell infection to levels observed with rRABV alone. Furthermore, 100-fold less rRABV-mICAM-1 was needed to induce antibody titers in immunized mice equivalent to antibody titers observed in rRABV-immunized mice. Of note, only 10(3) focus forming units (ffu)/mouse of rRABV-mICAM-1 was needed to induce significant anti-RABV antibody titers as early as five days post-immunization. As both speed and potency of antibody responses are important in controlling human RABV infection in a post-exposure setting, these data show that expression of Icam1 from the RABV genome, which is then incorporated into the virus particle, is a promising strategy for the development of a single-dose RABV vaccine that requires only a minimum of virus

Ariel: Enabling planetary science across light-years

Ariel, the Atmospheric Remote-sensing Infrared Exoplanet Large-survey, was adopted as the fourth medium-class mission in ESA's Cosmic Vision programme to be launched in 2029. During its 4-year mission, Ariel will study what exoplanets are made of, how they formed and how they evolve, by surveying a diverse sample of about 1000 extrasolar planets, simultaneously in visible and infrared wavelengths. It is the first mission dedicated to measuring the chemical composition and thermal structures of hundreds of transiting exoplanets, enabling planetary science far beyond the boundaries of the Solar System. The payload consists of an off-axis Cassegrain telescope (primary mirror 1100 mm x 730 mm ellipse) and two separate instruments (FGS and AIRS) covering simultaneously 0.5-7.8 micron spectral range. The satellite is best placed into an L2 orbit to maximise the thermal stability and the field of regard. The payload module is passively cooled via a series of V-Groove radiators; the detectors for the AIRS are the only items that require active cooling via an active Ne JT cooler. The Ariel payload is developed by a consortium of more than 50 institutes from 16 ESA countries, which include the UK, France, Italy, Belgium, Poland, Spain, Austria, Denmark, Ireland, Portugal, Czech Republic, Hungary, the Netherlands, Sweden, Norway, Estonia, and a NASA contribution

Ariel: Enabling planetary science across light-years

The concept of a mission devoted to atmospheric characterization of exoplanets through transit spectroscopy was first considered in Europe in 2007, shortly after the DARWIN proposal submitted to ESA for the first Cosmic Vision call for L-class missions was rejected because of the need for further scientific and technical developments. Following the decision, both ESA (EP-RAT panel report, October 2010) and the Exoplanetary Community (Blue Dot Team – Barcelona conference, September 2009) started a discussion to define a roadmap for exoplanetary research. Both groups concluded that an intermediate step was needed, both scientifically and technically, before the characterisation of Earth-like planets could be tackled, and recommended a transit spectroscopy mission as a first step to atmospheric characterisation. A short study was undertaken at ESTEC in the context of the ExoPlanet Roadmap Advisory Team mandate under the name ESM (Exoplanet Spectroscopy Mission). Following this study the Exoplanet Characterisation Observatory (EChO) was proposed and accepted for assessment phase study in the context of the ESA Cosmic Vision 2015-2025 programme M3 medium class mission opportunity. Although eventually not selected, the EChO study1 allowed further development of the technical building blocks and the science case for an eventual transit spectroscopy mission. In response to the call for the next medium class opportunity, Cosmic Vision M4, a proposal was submitted in January 2015: the Atmospheric Remote-sensing InfraRed Large-survey (ARIEL). The mission was one of the three selected in June 2015 for study in a Phase 0/A, a competitive assessment phase2. ARIEL was eventually selected as M4 in March 2018, and went into Phase B1, the definition study phase. The name of the mission has been changed to Ariel after selection. During Phase B1, the science case was studied in depth and consolidated under auspices of the Science Advisory Team, the bulk of the work being performed in a large number of science working groups in the Ariel Mission Consortium (AMC). The ESA Study Team and AMC reviewed the mission requirements, the technical design and analysis of the complete payload module (including telescope, instruments, guidance system and supporting infrastructure). The AMC developed an end-to-end performance simulator of the complete system. Two industrial contractors (Airbus Defence and Space, France and ThalesAlenia Space, France) reviewed the mission requirements, the technical design and analysis of the s/c and performed a programmatic analysis of the mission. Dedicated iterations were done in conjunction with both industrial and payload studies to harmonise the interfaces between the s/c and the payload, and to consolidate the payload accommodation. Recently the ESA Mission Adoption Review has successfully been concluded. This definition study report presents a summary of the very large body of work that has been undertaken on the Ariel mission over the 30-month period of the Ariel definition phase. As such, it represents the contributions of a large number of parties (ESA, industry, institutes and universities from 17 ESA member states, NASA CASE team), encompassing a very large number of people. The successful public Ariel: Science, Mission &amp; Community 2020 workshop was held in ESTEC, Noordwijk, on 14-16 January 2020 (https://www.cosmos.esa.int/web/ariel/conference-2020). Over 200 participants from 19 countries attended the conference which had the objectives to present the mission and its science asproposed for mission adoption, and involve the planetary and astrophysical community at large in the mission. Presentations and discussions addressed how Ariel can work in conjunction with other ground-based and space-based observatories to best further our knowledge of exoplanetary science.In the six years since Ariel was first conceived in 2014, the number of confirmed exoplanets has increased from ~1000 to over 4300, providing an ever more tantalising prospect of looking beyond our solar system and enabling planetary science across light years