Sustained Reduction in Third-generation Cephalosporin Usage in Adult Inpatients Following Introduction of an Antimicrobial Stewardship Program in a Large, Urban Hospital in Malawi

Background Third-generation cephalosporins (3GC) remain the first-choice empiric antibiotic for severe infection in many sub-Saharan African hospitals. In Malawi, limited availability of alternatives, mean that strategies to prevent spread of 3GC-resistance (3GC-R) are imperative, however suitable approaches to antimicrobial stewardship (AMS) in low-income settings are not well studied. Methods We introduced an AMS intervention to Queen Elizabeth Central Hospital (QECH) in Blantyre. The intervention consisted of a smartphone prescribing application and regular point-prevalence surveys (PPS) with prescriber feedback. We evaluate the effects of the intervention on 3GC usage and on cost of providing antibiotics. Using thematic analysis of semi-structured interviews and participant observations, we additionally evaluate the acceptability of the stewardship program. Results The proportion of antibiotic prescriptions for a 3GC reduced from 193/241 (80.1%) to 177/330 (53.6%) (percentage decrease 26.5% [95%CI; 18.7 to 34.1]) with no change in case-fatality rate. Cost analysis estimated annual savings of US$15,000. Qualitative research revealed trust in the guideline and found its accessibility through smartphones helpful to guide clinical decisions. Operational health-system barriers and hierarchal clinical relationships lead to continued reliance on 3GC. Conclusions We report the successful introduction of an antimicrobial stewardship approach in Malawi. By focusing on pragmatic interventions and simple aims, we demonstrate the feasibility, acceptability and cost-saving of a stewardship program where resources are limited. In doing so, we provide a suitable starting point for expansion of AMS interventions in this and other low-income settings

Earth Observation Technologies: Low-End-Market Disruptive Innovation

After decades of traditional space businesses, the space paradigm is changing. New approaches to more efficient missions in terms of costs, design, and manufacturing processes are fostered. For instance, placing big constellations of micro- and nano-satellites in Low Earth Orbit and Very Low Earth Orbit (LEO and VLEO) enables the space community to obtain a huge amount of data in near real-time with an unprecedented temporal resolution. Beyond technology innovations, other drivers promote innovation in the space sector like the increasing demand for Earth Observation (EO) data by the commercial sector. Perez et al. stated that the EO industry is the second market in terms of operative satellites (661 units), micro- and nano-satellites being the higher share of them (61%). Technological and market drivers encourage the emergence of new start-ups in the space environment like Skybox, OneWeb, Telesat, Planet, and OpenCosmos, among others, with novel business models that change the accessibility, affordability, ownership, and commercialization of space products and services. This chapter shows some results of the H2020 DISCOVERER (DISruptive teChnOlogies for VERy low Earth oRbit platforms) Project and focuses on understanding how micro- and nano-satellites have been disrupting the EO market in front of traditional platforms

The Long-Baseline Neutrino Experiment: Exploring Fundamental Symmetries of the Universe

The preponderance of matter over antimatter in the early Universe, the dynamics of the supernova bursts that produced the heavy elements necessary for life and whether protons eventually decay --- these mysteries at the forefront of particle physics and astrophysics are key to understanding the early evolution of our Universe, its current state and its eventual fate. The Long-Baseline Neutrino Experiment (LBNE) represents an extensively developed plan for a world-class experiment dedicated to addressing these questions. LBNE is conceived around three central components: (1) a new, high-intensity neutrino source generated from a megawatt-class proton accelerator at Fermi National Accelerator Laboratory, (2) a near neutrino detector just downstream of the source, and (3) a massive liquid argon time-projection chamber deployed as a far detector deep underground at the Sanford Underground Research Facility. This facility, located at the site of the former Homestake Mine in Lead, South Dakota, is approximately 1,300 km from the neutrino source at Fermilab -- a distance (baseline) that delivers optimal sensitivity to neutrino charge-parity symmetry violation and mass ordering effects. This ambitious yet cost-effective design incorporates scalability and flexibility and can accommodate a variety of upgrades and contributions. With its exceptional combination of experimental configuration, technical capabilities, and potential for transformative discoveries, LBNE promises to be a vital facility for the field of particle physics worldwide, providing physicists from around the globe with opportunities to collaborate in a twenty to thirty year program of exciting science. In this document we provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess.Comment: Major update of previous version. This is the reference document for LBNE science program and current status. Chapters 1, 3, and 9 provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess. 288 pages, 116 figure

Should rehabilitated hedgehogs be released in winter? A comparison of survival, nest use and weight change in wild and rescued animals

The rehabilitation of sick or injured wildlife and their subsequent release back into the wild is considered important, not only for the welfare of the individual animal but also for the conservation and management of endangered and threatened wildlife. The European hedgehog Erinaceus europaeus has declined by 25% in Britain over the last decade and is the most common mammal admitted to wildlife rehabilitation centres in Britain, with a large proportion of individuals admitted to gain body weight overwinter prior to release in the spring. Consequently, many thousands of hedgehogs are housed overwinter which incurs significant costs for rehabilitation centres, and has potentially animal welfare issues, such as, stress in captivity, reintroduction stress, increased mortality risk and impaired or altered behaviour. To determine if releasing rehabilitated hedgehogs during autumn and winter had an effect on their survival, body weight or nesting behaviour, we compared these factors between 34 rehabilitated hedgehogs with 23 wild hedgehogs across five sites in England over four different winters. Overwinter survival was high for both wild and rehabilitated hedgehogs, with a significant decrease in survival across both groups when hedgehogs became active post hibernation in spring. We found no differences in the survival rates up to 150 days post release, in weight change, or nest use between wild- and winter-released rehabilitated hedgehogs. Our results suggest that under the correct conditions, rehabilitated hedgehogs can be released successfully during winter, therefore avoiding or reducing time in captivity

Chapter Earth Observation Technologies: Low-End-Market Disruptive Innovation

After decades of traditional space businesses, the space paradigm is changing. New approaches to more efficient missions in terms of costs, design, and manufacturing processes are fostered. For instance, placing big constellations of micro- and nano-satellites in Low Earth Orbit and Very Low Earth Orbit (LEO and VLEO) enables the space community to obtain a huge amount of data in near real-time with an unprecedented temporal resolution. Beyond technology innovations, other drivers promote innovation in the space sector like the increasing demand for Earth Observation (EO) data by the commercial sector. Perez et al. stated that the EO industry is the second market in terms of operative satellites (661 units), micro- and nano-satellites being the higher share of them (61%). Technological and market drivers encourage the emergence of new start-ups in the space environment like Skybox, OneWeb, Telesat, Planet, and OpenCosmos, among others, with novel business models that change the accessibility, affordability, ownership, and commercialization of space products and services. This chapter shows some results of the H2020 DISCOVERER (DISruptive teChnOlogies for VERy low Earth oRbit platforms) Project and focuses on understanding how micro- and nano-satellites have been disrupting the EO market in front of traditional platforms

Testing novel strategies for patients hospitalised with HIV-associated disseminated tuberculosis (NewStrat-TB): protocol for a randomised controlled trial

Background: HIV-associated tuberculosis (TB) contributes disproportionately to global tuberculosis mortality. Patients hospitalised at the time of the diagnosis of HIV-associated disseminated TB are typically severely ill and have a high mortality risk despite initiation of tuberculosis treatment. The objective of the study is to assess the safety and efficacy of both intensified TB treatment (high dose rifampicin plus levofloxacin) and immunomodulation with corticosteroids as interventions to reduce early mortality in hospitalised patients with HIV-associated disseminated TB. Methods: This is a phase III randomised controlled superiority trial, evaluating two interventions in a 2 × 2 factorial design: (1) high dose rifampicin (35 mg/kg/day) plus levofloxacin added to standard TB treatment for the first 14 days versus standard tuberculosis treatment and (2) adjunctive corticosteroids (prednisone 1.5 mg/kg/day) versus identical placebo for the first 14 days of TB treatment. The study population is HIV-positive patients diagnosed with disseminated TB (defined as being positive by at least one of the following assays: urine Alere LAM, urine Xpert MTB/RIF Ultra or blood Xpert MTB/RIF Ultra) during a hospital admission. The primary endpoint is all-cause mortality at 12 weeks comparing, first, patients receiving intensified TB treatment to standard of care and, second, patients receiving corticosteroids to those receiving placebo. Analysis of the primary endpoint will be by intention to treat. Secondary endpoints include all-cause mortality at 2 and 24 weeks. Safety and tolerability endpoints include hepatoxicity evaluations and corticosteroid-related adverse events. Discussion: Disseminated TB is characterised by a high mycobacterial load and patients are often critically ill at presentation, with features of sepsis, which carries a high mortality risk. Interventions that reduce this high mycobacterial load or modulate associated immune activation could potentially reduce mortality. If found to be safe and effective, the interventions being evaluated in this trial could be easily implemented in clinical practice. Trial registration: ClinicalTrials.gov NCT04951986. Registered on 7 July 2021 https://clinicaltrials.gov/study/NCT04951986

The EChO science case

The discovery of almost two thousand exoplanets has revealed an unexpectedly diverse planet population. We see gas giants in few-day orbits, whole multi-planet systems within the orbit of Mercury, and new populations of planets with masses between that of the Earth and Neptune—all unknown in the Solar System. Observations to date have shown that our Solar System is certainly not representative of the general population of planets in our Milky Way. The key science questions that urgently need addressing are therefore: What are exoplanets made of? Why are planets as they are? How do planetary systems work and what causes the exceptional diversity observed as compared to the Solar System? The EChO (Exoplanet Characterisation Observatory) space mission was conceived to take up the challenge to explain this diversity in terms of formation, evolution, internal structure and planet and atmospheric composition. This requires in-depth spectroscopic knowledge of the atmospheres of a large and well-defined planet sample for which precise physical, chemical and dynamical information can be obtained. In order to fulfil this ambitious scientific program, EChO was designed as a dedicated survey mission for transit and eclipse spectroscopy capable of observing a large, diverse and well-defined planet sample within its 4-year mission lifetime. The transit and eclipse spectroscopy method, whereby the signal from the star and planet are differentiated using knowledge of the planetary ephemerides, allows us to measure atmospheric signals from the planet at levels of at least 10[Superscript: −4] relative to the star. This can only be achieved in conjunction with a carefully designed stable payload and satellite platform. It is also necessary to provide broad instantaneous wavelength coverage to detect as many molecular species as possible, to probe the thermal structure of the planetary atmospheres and to correct for the contaminating effects of the stellar photosphere. This requires wavelength coverage of at least 0.55 to 11 μm with a goal of covering from 0.4 to 16 μm. Only modest spectral resolving power is needed, with R ~ 300 for wavelengths less than 5 μm and R ~ 30 for wavelengths greater than this. The transit spectroscopy technique means that no spatial resolution is required. A telescope collecting area of about 1 m[Superscript: 2] is sufficiently large to achieve the necessary spectro-photometric precision: for the Phase A study a 1.13 m2 telescope, diffraction limited at 3 μm has been adopted. Placing the satellite at L2 provides a cold and stable thermal environment as well as a large field of regard to allow efficient time-critical observation of targets randomly distributed over the sky. EChO has been conceived to achieve a single goal: exoplanet spectroscopy. The spectral coverage and signal-to-noise to be achieved by EChO, thanks to its high stability and dedicated design, would be a game changer by allowing atmospheric composition to be measured with unparalleled exactness: at least a factor 10 more precise and a factor 10 to 1000 more accurate than current observations. This would enable the detection of molecular abundances three orders of magnitude lower than currently possible and a fourfold increase from the handful of molecules detected to date. Combining these data with estimates of planetary bulk compositions from accurate measurements of their radii and masses would allow degeneracies associated with planetary interior modelling to be broken, giving unique insight into the interior structure and elemental abundances of these alien worlds. EChO would allow scientists to study exoplanets both as a population and as individuals. The mission can target super-Earths, Neptune-like, and Jupiter-like planets, in the very hot to temperate zones (planet temperatures of 300–3000 K) of F to M-type host stars. The EChO core science would be delivered by a three-tier survey. The EChO Chemical Census: This is a broad survey of a few-hundred exoplanets, which allows us to explore the spectroscopic and chemical diversity of the exoplanet population as a whole. The EChO Origin: This is a deep survey of a subsample of tens of exoplanets for which significantly higher signal to noise and spectral resolution spectra can be obtained to explain the origin of the exoplanet diversity (such as formation mechanisms, chemical processes, atmospheric escape). The EChO Rosetta Stones: This is an ultra-high accuracy survey targeting a subsample of select exoplanets. These will be the bright “benchmark” cases for which a large number of measurements would be taken to explore temporal variations, and to obtain two and three dimensional spatial information on the atmospheric conditions through eclipse-mapping techniques. If EChO were launched today, the exoplanets currently observed are sufficient to provide a large and diverse sample. The Chemical Census survey would consist of > 160 exoplanets with a range of planetary sizes, temperatures, orbital parameters and stellar host properties. Additionally, over the next 10 years, several new ground- and space-based transit photometric surveys and missions will come on-line (e.g. NGTS, CHEOPS, TESS, PLATO), which will specifically focus on finding bright, nearby systems. The current rapid rate of discovery would allow the target list to be further optimised in the years prior to EChO’s launch and enable the atmospheric characterisation of hundreds of planets

Deep Underground Neutrino Experiment (DUNE), Far Detector Technical Design Report, Volume II: DUNE Physics

The preponderance of matter over antimatter in the early universe, the dynamics of the supernovae that produced the heavy elements necessary for life, and whether protons eventually decay -- these mysteries at the forefront of particle physics and astrophysics are key to understanding the early evolution of our universe, its current state, and its eventual fate. DUNE is an international world-class experiment dedicated to addressing these questions as it searches for leptonic charge-parity symmetry violation, stands ready to capture supernova neutrino bursts, and seeks to observe nucleon decay as a signature of a grand unified theory underlying the standard model. The DUNE far detector technical design report (TDR) describes the DUNE physics program and the technical designs of the single- and dual-phase DUNE liquid argon TPC far detector modules. Volume II of this TDR, DUNE Physics, describes the array of identified scientific opportunities and key goals. Crucially, we also report our best current understanding of the capability of DUNE to realize these goals, along with the detailed arguments and investigations on which this understanding is based. This TDR volume documents the scientific basis underlying the conception and design of the LBNF/DUNE experimental configurations. As a result, the description of DUNE's experimental capabilities constitutes the bulk of the document. Key linkages between requirements for successful execution of the physics program and primary specifications of the experimental configurations are drawn and summarized. This document also serves a wider purpose as a statement on the scientific potential of DUNE as a central component within a global program of frontier theoretical and experimental particle physics research. Thus, the presentation also aims to serve as a resource for the particle physics community at large