Disease modifying therapy for multiple system atrophy – Parkinsonian Type

BACKGROUND: Multiple System Atrophy –Parkinsonian Type (MSA-P) is a rare, rapidly progressive neurodegenerative disease without any current treatment. Recent research has increased the understanding of brain iron accumulation and its association with neurodegenerative synucleinopathies, like MSA-P. Because of this improved understanding of the disease process, there is potential for new therapies that could benefit patients with MSA-P. Unfortunately, many attempts at finding a new and effective treatments for MSA-P have been unsuccessful. Two drugs that have shown potential in neurodegenerative synucleinopathies associated with brain iron accumulation are iron chelators (Deferiprone) and tyrosine kinase inhibitors (Nilotinib.) METHODS: The proposed study is a multicenter, double blind, randomized control study of Nilotinib and Deferiprone for the treatment of MSA-P. There will be two treatment arms; Nilotinib and a placebo group vs. Nilotinib and Deferiprone. There will be a 24 week treatment phase, followed by a 24 week wash-out phase. All patients will have a baseline evaluation including: a full neurological exam with rating scales (UMSARS, UPDRS, SCOPA, and MOCA) to assess motor and non-motor symptoms of MSA-P. Lab and imaging data will include CBC, CMP, serum iron panel, CSF iron panel and brain SWI-MR scans. Neurological exams and rating scales will be assessed every four weeks while imaging and laboratory data will be assessed at baseline (week 0) at the end of the intervention phase (week 24) and at the end of the follow-up phase (week 48). CONCLUSIONS: Deferiprone and Nilotinib when used together will have a synergistic impact on the symptoms of MSA-P and will be more effective when used together versus when they are used individually. SIGNIFICANCE: Patients with MSA-P have shortened life expectancy as well as severely diminished quality of life due to rapidly progressive neurodegeneration. This trial aims to implementing evidence based treatment for MSA-P that could potentially improve life expectancy as well as quality of life in this patient population

Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study

Background: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p\textless0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p\textless0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research

Search for gravitational-lensing signatures in the full third observing run of the LIGO-Virgo network

Gravitational lensing by massive objects along the line of sight to the source causes distortions of gravitational wave-signals; such distortions may reveal information about fundamental physics, cosmology and astrophysics. In this work, we have extended the search for lensing signatures to all binary black hole events from the third observing run of the LIGO--Virgo network. We search for repeated signals from strong lensing by 1) performing targeted searches for subthreshold signals, 2) calculating the degree of overlap amongst the intrinsic parameters and sky location of pairs of signals, 3) comparing the similarities of the spectrograms amongst pairs of signals, and 4) performing dual-signal Bayesian analysis that takes into account selection effects and astrophysical knowledge. We also search for distortions to the gravitational waveform caused by 1) frequency-independent phase shifts in strongly lensed images, and 2) frequency-dependent modulation of the amplitude and phase due to point masses. None of these searches yields significant evidence for lensing. Finally, we use the non-detection of gravitational-wave lensing to constrain the lensing rate based on the latest merger-rate estimates and the fraction of dark matter composed of compact objects

Search for eccentric black hole coalescences during the third observing run of LIGO and Virgo

Despite the growing number of confident binary black hole coalescences observed through gravitational waves so far, the astrophysical origin of these binaries remains uncertain. Orbital eccentricity is one of the clearest tracers of binary formation channels. Identifying binary eccentricity, however, remains challenging due to the limited availability of gravitational waveforms that include effects of eccentricity. Here, we present observational results for a waveform-independent search sensitive to eccentric black hole coalescences, covering the third observing run (O3) of the LIGO and Virgo detectors. We identified no new high-significance candidates beyond those that were already identified with searches focusing on quasi-circular binaries. We determine the sensitivity of our search to high-mass (total mass M>70 M⊙) binaries covering eccentricities up to 0.3 at 15 Hz orbital frequency, and use this to compare model predictions to search results. Assuming all detections are indeed quasi-circular, for our fiducial population model, we place an upper limit for the merger rate density of high-mass binaries with eccentricities 0<e≤0.3 at 0.33 Gpc−3 yr−1 at 90\% confidence level

Prioritising the protection of habitat utilised by southern cassowaries 'Casuarius casuarius johnsonii'

The southern cassowary 'Casuarius casuarius johnsonii' L. is an endangered flightless bird from northern Australia. The cassowaries' rainforest habitat has been extensively cleared, and the population primarily exists within discrete protected areas. They do, however, venture outside the reserves into modified landscapes, and it is here they are exposed to threatening processes. We used GPS-based telemetry and the adaptive local convex hull (a-LoCoH) non-parametric kernel method to define the relationship between cassowary home range (HR) and a protection-area network. The study showed that: (1) females had a larger HR than males; (2) overlapping HR occurred between but not within the sexes; (3) HRs of the same sex partitioned along defined boundaries; and (4) the current protected areas only encompassed core HR for the inhabiting cassowaries. This information was incorporated within a spatial-conservation-prioritisation analysis to define the relative cost:benefit relationship for protecting the currently non-protected land utilised by the cassowaries. The results showed that the current reserve system may accommodate up to 24 adult cassowaries, only offering HR protection at the 40 to 60% a-LoCoH. This could be raised, relatively cheaply (1.2-fold the current costs), to 70% a-LoCoH for all birds by protecting adjacent forested areas on private land. Protection beyond the 70% a-LoCoH, however, required protection of large expanses of agricultural land, resulting in an exponential increase in monetary cost (5.1-fold). We argue that total HR protection for the cassowaries was an unfeasible conservation option, but protection of core habitat was achieved relatively cheaply. Combining core HS protection with target incentives to landowners of adjacent cleared land may be the most cost-effective conservation strategy for 'C.c. johnsonii'

Prioritising the protection of habitat utilised by southern cassowaries Casuarius casuarius johnsonii

The southern cassowary Casuarius casuarius johnsonii L. is an endangered flightless bird from northern Australia. The cassowaries' rainforest habitat has been extensively cleared, and the population primarily exists within discrete protected areas. They do, however, venture outside the reserves into modified landscapes, and it is here they are exposed to threatening processes. We used GPS-based telemetry and the adaptive local convex hull (a-LoCoH) non-parametric kernel method to define the relationship between cassowary home range (HR) and a protection- area network. The study showed that: (1) females had a larger HR than males; (2) overlapping HR occurred between but not within the sexes; (3) HRs of the same sex partitioned along defined boundaries; and (4) the current protected areas only encompassed core HR for the inhabiting cassowaries. This information was incorporated within a spatial-conservation-prioritisation analysis to define the relative cost:benefit relationship for protecting the currently non-protected land utilised by the cassowaries. The results showed that the current reserve system may accommodate up to 24 adult cassowaries, only offering HR protection at the 40 to 60% a-LoCoH. This could be raised, relatively cheaply (1.2-fold the current costs), to 70% a-LoCoH for all birds by protecting adjacent forested areas on private land. Protection beyond the 70% a-LoCoH, however, required protection of large expanses of agricultural land, resulting in an exponential increase in monetary cost (5.1-fold). We argue that total HR protection for the cassowaries was an unfeasible conservation option, but protection of core habitat was achieved relatively cheaply. Combining core HS protection with target incentives to landowners of adjacent cleared land may be the most costeffective conservation strategy for C.c. johnsonii

Deep Underground Neutrino Experiment (DUNE) Near Detector Conceptual Design Report

International audienceThe Deep Underground Neutrino Experiment (DUNE) is an international, world-class experiment aimed at exploring fundamental questions about the universe that are at the forefront of astrophysics and particle physics research. DUNE will study questions pertaining to the preponderance of matter over antimatter in the early universe, the dynamics of supernovae, the subtleties of neutrino interaction physics, and a number of beyond the Standard Model topics accessible in a powerful neutrino beam. A critical component of the DUNE physics program involves the study of changes in a powerful beam of neutrinos, i.e., neutrino oscillations, as the neutrinos propagate a long distance. The experiment consists of a near detector, sited close to the source of the beam, and a far detector, sited along the beam at a large distance. This document, the DUNE Near Detector Conceptual Design Report (CDR), describes the design of the DUNE near detector and the science program that drives the design and technology choices. The goals and requirements underlying the design, along with projected performance are given. It serves as a starting point for a more detailed design that will be described in future documents

Reconstruction of interactions in the ProtoDUNE-SP detector with Pandora

International audienceThe Pandora Software Development Kit and algorithm libraries provide pattern-recognition logic essential to the reconstruction of particle interactions in liquid argon time projection chamber detectors. Pandora is the primary event reconstruction software used at ProtoDUNE-SP, a prototype for the Deep Underground Neutrino Experiment far detector. ProtoDUNE-SP, located at CERN, is exposed to a charged-particle test beam. This paper gives an overview of the Pandora reconstruction algorithms and how they have been tailored for use at ProtoDUNE-SP. In complex events with numerous cosmic-ray and beam background particles, the simulated reconstruction and identification efficiency for triggered test-beam particles is above 80% for the majority of particle type and beam momentum combinations. Specifically, simulated 1 GeV/$c$ charged pions and protons are correctly reconstructed and identified with efficiencies of 86.1$\pm0.6$% and 84.1$\pm0.6$%, respectively. The efficiencies measured for test-beam data are shown to be within 5% of those predicted by the simulation

Reconstruction of interactions in the ProtoDUNE-SP detector with Pandora

International audienceThe Pandora Software Development Kit and algorithm libraries provide pattern-recognition logic essential to the reconstruction of particle interactions in liquid argon time projection chamber detectors. Pandora is the primary event reconstruction software used at ProtoDUNE-SP, a prototype for the Deep Underground Neutrino Experiment far detector. ProtoDUNE-SP, located at CERN, is exposed to a charged-particle test beam. This paper gives an overview of the Pandora reconstruction algorithms and how they have been tailored for use at ProtoDUNE-SP. In complex events with numerous cosmic-ray and beam background particles, the simulated reconstruction and identification efficiency for triggered test-beam particles is above 80% for the majority of particle type and beam momentum combinations. Specifically, simulated 1 GeV/$c$ charged pions and protons are correctly reconstructed and identified with efficiencies of 86.1$\pm0.6$% and 84.1$\pm0.6$%, respectively. The efficiencies measured for test-beam data are shown to be within 5% of those predicted by the simulation