Symptom-driven inhaled corticosteroid/long-acting beta-agonist therapy for adult patients with asthma who are non-adherent to daily maintenance inhalers: A study protocol for a pragmatic randomized controlled trial

BACKGROUND: While inhaled corticosteroids (ICS) are considered the essential foundation of most asthma therapy, ICS inhaler nonadherence is a notoriously common problem and a significant cause of asthma-related morbidity. Partially acknowledging the problem of nonadherence, international organizations recently made paradigm-shifting recommendations that all patients with mild-to-moderate persistent asthma be considered for symptom-driven ICS-containing inhalers rather than relying on adherence to traditional maintenance ICS inhalers and symptom-driven short-acting beta-agonists (SABA). With this new approach, asthma patients are at least exposed to the important anti-inflammatory effects of ICS-containing inhalers when their symptom reliever inhaler is deployed due to acute symptoms. METHODS: This study will (Part 1) complete a pragmatic randomized controlled trial to evaluate if an inhaler strategy that utilizes symptom-driven ICS inhalers is particularly beneficial in maintenance ICS inhaler non-adherent asthma patients, and (Part 2) use a dissemination and implementation (D&I) science conceptual framework to better understand patients\u27 and providers\u27 views of inhaler nonadherence. This study, which will have an option of taking place entirely remotely, will use a Food and Drug Administration (FDA)-approved electronic sensor (Hailie® sensor) to monitor inhaler adherence and includes semi-structured interviews guided by the Consolidated Framework for Implementation Research (CFIR). DISCUSSION: This study is assessing the problem of nonadherence using a D&I implementation science research lens while testing a new inhaler approach to potentially ameliorate the detrimental consequences of maintenance inhaler nonadherence. We hypothesize that the use of a symptom-driven ICS/LABA management strategy, as compared to traditional maintenance ICS treatment and symptom-driven SABA, will lead to improved adherence to an asthma treatment strategy, decreased asthma-related morbidity, less cumulative ICS exposure, and greater patient satisfaction with an inhaler approach. TRIAL REGISTRATION: ClinicalTrials.gov NCT05111262. Registered on November 8, 2021

A novel satellite mission concept for upper air water vapour, aerosol and cloud observations using integrated path differential absorption LiDAR limb sounding

We propose a new satellite mission to deliver high quality measurements of upper air water vapour. The concept centres around a LiDAR in limb sounding by occultation geometry, designed to operate as a very long path system for differential absorption measurements. We present a preliminary performance analysis with a system sized to send 75 mJ pulses at 25 Hz at four wavelengths close to 935 nm, to up to 5 microsatellites in a counter-rotating orbit, carrying retroreflectors characterized by a reflected beam divergence of roughly twice the emitted laser beam divergence of 15 µrad. This provides water vapour profiles with a vertical sampling of 110 m; preliminary calculations suggest that the system could detect concentrations of less than 5 ppm. A secondary payload of a fairly conventional medium resolution multispectral radiometer allows wide-swath cloud and aerosol imaging. The total weight and power of the system are estimated at 3 tons and 2,700 W respectively. This novel concept presents significant challenges, including the performance of the lasers in space, the tracking between the main spacecraft and the retroreflectors, the refractive effects of turbulence, and the design of the telescopes to achieve a high signal-to-noise ratio for the high precision measurements. The mission concept was conceived at the Alpbach Summer School 2010

Timeless Links Replication Termination to Mitotic Kinase Activation

The mechanisms that coordinate the termination of DNA replication with progression through mitosis are not completely understood. The human Timeless protein (Tim) associates with S phase replication checkpoint proteins Claspin and Tipin, and plays an important role in maintaining replication fork stability at physical barriers, like centromeres, telomeres and ribosomal DNA repeats, as well as at termination sites. We show here that human Tim can be isolated in a complex with mitotic entry kinases CDK1, Auroras A and B, and Polo-like kinase (Plk1). Plk1 bound Tim directly and colocalized with Tim at a subset of mitotic structures in M phase. Tim depletion caused multiple mitotic defects, including the loss of sister-chromatid cohesion, loss of mitotic spindle architecture, and a failure to exit mitosis. Tim depletion caused a delay in mitotic kinase activity in vivo and in vitro, as well as a reduction in global histone H3 S10 phosphorylation during G2/M phase. Tim was also required for the recruitment of Plk1 to centromeric DNA and formation of catenated DNA structures at human centromere alpha satellite repeats. Taken together, these findings suggest that Tim coordinates mitotic kinase activation with termination of DNA replication

ANTARES and IceCube Combined Search for Neutrino Point-like and Extended Sources in the Southern Sky

[EN] A search for point-like and extended sources of cosmic neutrinos using data collected by the ANTARES and IceCube neutrino telescopes is presented. The data set consists of all the track-like and shower-like events pointing in the direction of the Southern Sky included in the nine-year ANTARES point-source analysis, combined with the throughgoing track-like events used in the seven-year IceCube point-source search. The advantageous ¿eld of view of ANTARES and the large size of IceCube are exploited to improve the sensitivity in the Southern Sky by a factor of ~2 compared to both individual analyses. In this work, the Southern Sky is scanned for possible excesses of spatial clustering, and the positions of preselected candidate sources are investigated. In addition, special focus is given to the region around the Galactic Center, whereby a dedicated search at the location of SgrA* is performed, and to the location of the supernova remnant RXJ 1713.7-3946. No signi¿cant evidence for cosmic neutrino sources is found, and upper limits on the ¿ux from the various searches are presented.The authors of the IceCube Collaboration acknowledge the support from the following agencies and institutions: USA-U.S. National Science Foundation-Office of Polar Programs, U.S. National Science Foundation-Physics Division, Wisconsin Alumni Research Foundation, Center for High Throughput Computing (CHTC) at the University of Wisconsin-Madison, Open Science Grid (OSG), Extreme Science and Engineering Discovery Environment (XSEDE), U.S. Department of Energy-National Energy Research Scientific Computing Center, Particle astrophysics research computing center at the University of Maryland, Institute for Cyber-Enabled Research at Michigan State University, and Astroparticle physics computational facility at Marquette University; Belgium-Funds for Scientific Research (FRS-FNRS and FWO), FWO Odysseus and Big Science programmes, and Belgian Federal Science Policy Office (Belspo); Germany-Bundesministerium fur Bildung und Forschung (BMBF), Deutsche Forschungsgemeinschaft (DFG), Helmholtz Alliance for Astroparticle Physics (HAP), Initiative and Networking Fund of the Helmholtz Association, Deutsches Elektronen Synchrotron (DESY), and High Performance Computing Cluster of the RWTH Aachen; Sweden-Swedish Research Council, Swedish Polar Research Secretariat, Swedish National Infrastructure for Computing (SNIC), and Knut and Alice Wallenberg Foundation; Australia - Australian Research Council; Canada-Natural Sciences and Engineering Research Council of Canada, Calcul Quebec, Compute Ontario, Canada Foundation for Innovation, WestGrid, and Compute Canada; Denmark-Villum Fonden, Danish National Research Foundation (DNRF), Carlsberg Foundation; New Zealand-Marsden Fund; Japan-Japan Society for Promotion of Science (JSPS) and Institute for Global Prominent Research (IGPR) of Chiba University; Korea-National Research Foundation of Korea (NRF); Switzerland-Swiss National Science Foundation (SNSF); United Kingdom-Department of Physics, University of Oxford.Albert, A.; Andre, M.; Anghinolfi, M.; Anton, G.; Ardid Ramírez, M.; Aubert, J.; Aublin, J.... (2020). ANTARES and IceCube Combined Search for Neutrino Point-like and Extended Sources in the Southern Sky. The Astrophysical Journal. 892(2):1-12. https://doi.org/10.3847/1538-4357/ab7afbS112892

Joint Constraints on Galactic Diffuse Neutrino Emission from the ANTARES and IceCube Neutrino Telescopes

[EN] The existence of diffuse Galactic neutrino production is expected from cosmic-ray interactions with Galactic gas and radiation ¿elds. Thus, neutrinos are a unique messenger offering the opportunity to test the products of Galactic cosmic-ray interactions up to energies of hundreds of TeV. Here we present a search for this production using ten years of Astronomy with a Neutrino Telescope and Abyss environmental RESearch (ANTARES) track and shower data, as well as seven years of IceCube track data. The data are combined into a joint likelihood test for neutrino emission according to the KRAg model assuming a 5 PeV per nucleon Galactic cosmic-ray cutoff. No signi¿cant excess is found. As a consequence, the limits presented in this Letter start constraining the model parameter space for Galactic cosmic-ray production and transport.Albert, A.; Andre, M.; Anghinolfi, M.; Ardid Ramírez, M.; Aubert, J-.; Aublin, J.; Avgitas, T.... (2018). Joint Constraints on Galactic Diffuse Neutrino Emission from the ANTARES and IceCube Neutrino Telescopes. The Astrophysical Journal. 868(2):1-7. https://doi.org/10.3847/2041-8213/aaeecfS178682Aartsen, M. G., Ackermann, M., Adams, J., Aguilar, J. A., Ahlers, M., Ahrens, M., … Anderson, T. (2017). Search for Astrophysical Sources of Neutrinos Using Cascade Events in IceCube. The Astrophysical Journal, 846(2), 136. doi:10.3847/1538-4357/aa8508Aartsen, M. G., Abraham, K., Ackermann, M., Adams, J., Aguilar, J. A., Ahlers, M., … Archinger, M. (2015). A COMBINED MAXIMUM-LIKELIHOOD ANALYSIS OF THE HIGH-ENERGY ASTROPHYSICAL NEUTRINO FLUX MEASURED WITH ICECUBE. The Astrophysical Journal, 809(1), 98. doi:10.1088/0004-637x/809/1/98Aartsen, M. G., Abraham, K., Ackermann, M., Adams, J., Aguilar, J. A., Ahlers, M., … Anderson, T. (2017). All-sky Search for Time-integrated Neutrino Emission from Astrophysical Sources with 7 yr of IceCube Data. The Astrophysical Journal, 835(2), 151. doi:10.3847/1538-4357/835/2/151Aartsen, M. G., Ackermann, M., Adams, J., Aguilar, J. A., Ahlers, M., Ahrens, M., … Anderson, T. (2017). Constraints on Galactic Neutrino Emission with Seven Years of IceCube Data. The Astrophysical Journal, 849(1), 67. doi:10.3847/1538-4357/aa8dfbAartsen, M. G., Ackermann, M., Adams, J., Aguilar, J. A., Ahlers, M., Ahrens, M., … Ansseau, I. (2017). The IceCube Neutrino Observatory: instrumentation and online systems. Journal of Instrumentation, 12(03), P03012-P03012. doi:10.1088/1748-0221/12/03/p03012Ackermann, M., Ajello, M., Atwood, W. B., Baldini, L., Ballet, J., Barbiellini, G., … Berenji, B. (2012). FERMI-LAT OBSERVATIONS OF THE DIFFUSE γ-RAY EMISSION: IMPLICATIONS FOR COSMIC RAYS AND THE INTERSTELLAR MEDIUM. The Astrophysical Journal, 750(1), 3. doi:10.1088/0004-637x/750/1/3Adrián-Martínez, S., Ageron, M., Aguilar, J. A., Samarai, I. A., Albert, A., André, M., … Ardid, M. (2012). The positioning system of the ANTARES Neutrino Telescope. Journal of Instrumentation, 7(08), T08002-T08002. doi:10.1088/1748-0221/7/08/t08002Ageron, M., Aguilar, J. A., Al Samarai, I., Albert, A., Ameli, F., André, M., … Ardid, M. (2011). ANTARES: The first undersea neutrino telescope. Nuclear Instruments and Methods in Physics Research Section A: Accelerators, Spectrometers, Detectors and Associated Equipment, 656(1), 11-38. doi:10.1016/j.nima.2011.06.103Ahn, H. S., Allison, P., Bagliesi, M. G., Beatty, J. J., Bigongiari, G., Childers, J. T., … Zinn, S. Y. (2010). DISCREPANT HARDENING OBSERVED IN COSMIC-RAY ELEMENTAL SPECTRA. The Astrophysical Journal, 714(1), L89-L93. doi:10.1088/2041-8205/714/1/l89Albert, A., André, M., Anghinolfi, M., Anton, G., Ardid, M., Aubert, J.-J., … Basa, S. (2017). New constraints on all flavor Galactic diffuse neutrino emission with the ANTARES telescope. Physical Review D, 96(6). doi:10.1103/physrevd.96.062001Antoni, T., Apel, W. D., Badea, A. F., Bekk, K., Bercuci, A., Blümer, J., … Zabierowski, J. (2005). KASCADE measurements of energy spectra for elemental groups of cosmic rays: Results and open problems. Astroparticle Physics, 24(1-2), 1-25. doi:10.1016/j.astropartphys.2005.04.001Apel, W. D., Arteaga-Velázquez, J. C., Bekk, K., Bertaina, M., Blümer, J., Bozdog, H., … Cossavella, F. (2013). KASCADE-Grande measurements of energy spectra for elemental groups of cosmic rays. Astroparticle Physics, 47, 54-66. doi:10.1016/j.astropartphys.2013.06.004Gaggero, D., Grasso, D., Marinelli, A., Taoso, M., & Urbano, A. (2017). Diffuse Cosmic Rays Shining in the Galactic Center: A Novel Interpretation of H.E.S.S. and Fermi-LAT γ -Ray Data. Physical Review Letters, 119(3). doi:10.1103/physrevlett.119.031101Gaggero, D., Grasso, D., Marinelli, A., Urbano, A., & Valli, M. (2015). THE GAMMA-RAY AND NEUTRINO SKY: A CONSISTENT PICTURE OF FERMI -LAT, MILAGRO, AND ICECUBE RESULTS. The Astrophysical Journal, 815(2), L25. doi:10.1088/2041-8205/815/2/l25Gaggero, D., Urbano, A., Valli, M., & Ullio, P. (2015). Gamma-ray sky points to radial gradients in cosmic-ray transport. Physical Review D, 91(8). doi:10.1103/physrevd.91.083012Vladimirov, A. E., Digel, S. W., Jóhannesson, G., Michelson, P. F., Moskalenko, I. V., Nolan, P. L., … Strong, A. W. (2011). GALPROP WebRun: An internet-based service for calculating galactic cosmic ray propagation and associated photon emissions. Computer Physics Communications, 182(5), 1156-1161. doi:10.1016/j.cpc.2011.01.01

Combined search for neutrinos from dark matter self-annihilation in the Galactic Center with ANTARES and IceCube

[EN] We present the results of the first combined dark matter search targeting the Galactic Center using the ANTARES and IceCube neutrino telescopes. For dark matter particles with masses from 50 to 1000 GeV, the sensitivities on the self-annihilation cross section set by ANTARES and IceCube are comparable, making this mass range particularly interesting for a joint analysis. Dark matter self-annihilation through the ¿+¿¿, ¿+¿¿, b¯b, and W+W¿ channels is considered for both the Navarro-Frenk-White and Burkert halo profiles. In the combination of 2101.6 days of ANTARES data and 1007 days of IceCube data, no excess over the expected background is observed. Limits on the thermally averaged dark matter annihilation cross section h¿A¿i are set. These limits present an improvement of up to a factor of 2 in the studied dark matter mass range with respect to the individual limits published by both collaborations. When considering dark matter particles with a mass of 200 GeV annihilating through the ¿þ¿¿ channel, the value obtained for the limit is 7.44 × 10¿24 cm3 s¿1 for the Navarro-Frenk-White halo profile. For the purpose of this joint analysis, the model parameters and the likelihood are unified, providing a benchmark for forthcoming dark matter searches performed by neutrino telescopes.The authors from the ANTARES Collaboration acknowledge the financial support of the following funding agencies: Centre National de la Recherche Scientifique (CNRS), Commissariat a l'energie atomique et auxenergies alternatives (CEA), Commission Europeenne (FEDER fund and Marie Curie Program), Institut Universitaire de France (IUF), IdEx program and UnivEarthS Labex program at Sorbonne Paris Cite (ANR-10-LABX-0023 and ANR-11IDEX-0005-02), Labex OCEVU (ANR-11-LABX-0060) and the A*MIDEX project (ANR-11-IDEX-0001-02), Region Ile-de-France (DIM-ACAV), Region Alsace (contrat CPER), Region Provence-Alpes-Cote d'Azur, Departement du Var and Ville de La Seyne-sur-Mer, France; Bundesministerium fur Bildung und Forschung (BMBF), Germany; Istituto Nazionale di Fisica Nucleare (INFN), Italy; Nederlandse organisatie voor Wetenschappelijk Onderzoek (NWO), the Netherlands; Council of the President of the Russian Federation for young scientists and leading scientific schools supporting grants, Russia; Executive Unit for Financing Higher Education, Research, Development and Innovation (UEFISCDI), Romania; Ministerio de Ciencia, Innovacion, Investigacion y Universidades (MCIU): Programa Estatal de Generacion de Conocimiento (refs. PGC2018-096663-B-C41, -A-C42, -B-C43, -B-C44) (MCIU/FEDER), Severo Ochoa Centre of Excellence and MultiDark Consolider (MCIU), Junta de Andalucia (ref. SOMM17/6104/UGR), Generalitat Valenciana: Grisolia (ref. GRISOLIA/2018/119), Spain; Ministry of Higher Education, Scientific Research and Professional Training, Morocco. We also acknowledge the technical support of Ifremer, AIM and Foselev Marine for the sea operation and CC-IN2P3 for the computing facilities. The authors from the IceCube Collaboration gratefully acknowledge the support from the following agencies and institutions: USA-U.S. National Science Foundation-Office of Polar Programs, U.S. National Science Foundation-Physics Division, Wisconsin Alumni Research Foundation, Center for High Throughput Computing (CHTC) at the University of Wisconsin-Madison, Open Science Grid (OSG), Extreme Science and Engineering Discovery Environment (XSEDE), U.S. Department of Energy-National Energy Research Scientific Computing Center, Particle astrophysics research computing center at the University of Maryland, Institute for Cyber-Enabled Research at Michigan State University, and Astroparticle physics computational facility at Marquette University; Belgium-Funds for Scientific Research (FRS-FNRS and FWO), FWO Odysseus and Big Science programmes, and Belgian Federal Science Policy Office (Belspo); Germany-Bundesministerium fur Bildung und Forschung (BMBF), Deutsche Forschungsgemeinschaft (DFG), Helmholtz Alliance for Astroparticle Physics (HAP), Initiative and Networking Fund of the Helmholtz Association, Germany-Deutsches Elektronen Synchrotron (DESY), and High Performance Computing cluster of the RWTH Aachen; Sweden-Swedish Research Council, Swedish Polar Research Secretariat, Swedish National Infrastructure for Computing (SNIC), and Knut and Alice Wallenberg Foundation; Australia-Australian Research Council; Canada-Natural Sciences and Engineering Research Council of Canada, Calcul Quebec, Compute Ontario, Canada Foundation for Innovation, WestGrid, and Compute Canada; Denmark-Villum Fonden, Danish National Research Foundation (DNRF), Carlsberg Foundation; New Zealand-Marsden Fund; Japan-Japan Society for Promotion of Science (JSPS) and Institute for Global Prominent Research (IGPR) of Chiba University; Korea-National Research Foundation of Korea (NRF); Switzerland-Swiss National Science Foundation (SNSF); United Kingdom-Department of Physics, University of Oxford. The IceCube collaboration acknowledges the significant contributions to this manuscript from Sebastian Baur, Nadege Iovine and Sara Rebecca Gozzini.Albert, A.; Andre, M.; Anghinolfi, M.; Ardid Ramírez, M.; Aubert, J.; Aublin, J.; Baret, B.... (2020). Combined search for neutrinos from dark matter self-annihilation in the Galactic Center with ANTARES and IceCube. Physical Review D: covering particles, fields, gravitation, and cosmology. 102(8):1-13. https://doi.org/10.1103/PhysRevD.102.082002S113102

Multimessenger Search for Sources of Gravitational Waves and High-Energy Neutrinos: Results for Initial LIGO-Virgo and IceCube

We report the results of a multimessenger search for coincident signals from the LIGO and Virgo gravitational-wave observatories and the partially completed IceCube high-energy neutrino detector, including periods of joint operation between 2007-2010. These include parts of the 2005-2007 run and the 2009-2010 run for LIGO-Virgo, and IceCube's observation periods with 22, 59 and 79 strings. We find no significant coincident events, and use the search results to derive upper limits on the rate of joint sources for a range of source emission parameters. For the optimistic assumption of gravitational-wave emission energy of $10^{-2}$\,M$_\odot$c$^2$ at $\sim 150$\,Hz with $\sim 60$\,ms duration, and high-energy neutrino emission of $10^{51}$\,erg comparable to the isotropic gamma-ray energy of gamma-ray bursts, we limit the source rate below $1.6 \times 10^{-2}$\,Mpc$^{-3}$yr$^{-1}$. We also examine how combining information from gravitational waves and neutrinos will aid discovery in the advanced gravitational-wave detector era

Multi-messenger observations of a binary neutron star merger

On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ~1.7 s with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of 40+8-8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 Mo. An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ~40 Mpc) less than 11 hours after the merger by the One- Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ~10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ~9 and ~16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta