Virtual Machine Language 2.1

VML (Virtual Machine Language) is an advanced computing environment that allows spacecraft to operate using mechanisms ranging from simple, time-oriented sequencing to advanced, multicomponent reactive systems. VML has developed in four evolutionary stages. VML 0 is a core execution capability providing multi-threaded command execution, integer data types, and rudimentary branching. VML 1 added named parameterized procedures, extensive polymorphism, data typing, branching, looping issuance of commands using run-time parameters, and named global variables. VML 2 added for loops, data verification, telemetry reaction, and an open flight adaptation architecture. VML 2.1 contains major advances in control flow capabilities for executable state machines. On the resource requirements front, VML 2.1 features a reduced memory footprint in order to fit more capability into modestly sized flight processors, and endian-neutral data access for compatibility with Intel little-endian processors. Sequence packaging has been improved with object-oriented programming constructs and the use of implicit (rather than explicit) time tags on statements. Sequence event detection has been significantly enhanced with multi-variable waiting, which allows a sequence to detect and react to conditions defined by complex expressions with multiple global variables. This multi-variable waiting serves as the basis for implementing parallel rule checking, which in turn, makes possible executable state machines. The new state machine feature in VML 2.1 allows the creation of sophisticated autonomous reactive systems without the need to develop expensive flight software. Users specify named states and transitions, along with the truth conditions required, before taking transitions. Transitions with the same signal name allow separate state machines to coordinate actions: the conditions distributed across all state machines necessary to arm a particular signal are evaluated, and once found true, that signal is raised. The selected signal then causes all identically named transitions in all present state machines to be taken simultaneously. VML 2.1 has relevance to all potential space missions, both manned and unmanned. It was under consideration for use on Orion

Autonomous GN and C for Spacecraft Exploration of Comets and Asteroids

A spacecraft guidance, navigation, and control (GN&C) system is needed to enable a spacecraft to descend to a surface, take a sample using a touch-and-go (TAG) sampling approach, and then safely ascend. At the time of this reporting, a flyable GN&C system that can accomplish these goals is beyond state of the art. This article describes AutoGNC, which is a GN&C system capable of addressing these goals, which has recently been developed and demonstrated to a maturity TRL-5-plus. The AutoGNC solution matures and integrates two previously existing JPL capabilities into a single unified GN&C system. The two capabilities are AutoNAV and GREX. AutoNAV is JPL s current flight navigation system, and is fairly mature with respect to flybys and rendezvous with small bodies, but is lacking capability for close surface proximity operations, sampling, and contact. G-REX is a suite of low-TRL algorithms and capabilities that enables spacecraft operations in close surface proximity and for performing sampling/contact. The development and integration of AutoNAV and G-REX components into AutoGNC provides a single, unified GN&C capability for addressing the autonomy, close-proximity, and sampling/contact aspects of small-body sample return missions. AutoGNC is an integrated capability comprising elements that were developed separately. The main algorithms and component capabilities that have been matured and integrated are autonomy for near-surface operations, terrain-relative navigation (TRN), real-time image-based feedback guidance and control, and six degrees of freedom (6DOF) control of the TAG sampling event. Autonomy is achieved based on an AutoGNC Executive written in Virtual Machine Language (VML) incorporating high-level control, data management, and fault protection. In descending to the surface, the AutoGNC system uses camera images to determine its position and velocity relative to the terrain. This capability for TRN leverages native capabilities of the original AutoNAV system, but required advancements that integrate the separate capabilities for shape modeling, state estimation, image rendering, defining a database of onboard maps, and performing real-time landmark recognition against the stored maps. The ability to use images to guide the spacecraft requires the capability for image-based feedback control. In Auto- GNC, navigation estimates are fed into an onboard guidance and control system that keeps the spacecraft guided along a desired path, as it descends towards its targeted landing or sampling site. Once near the site, AutoGNC achieves a prescribed guidance condition for TAG sampling (position/orientation, velocity), and a prescribed force profile on the sampling end-effector. A dedicated 6DOF TAG control then implements the ascent burn while recovering from sampling disturbances and induced attitude rates. The control also minimizes structural interactions with flexible solar panels and disallows any part of the spacecraft from making contact with the ground (other than the intended end-effector)

Current perspectives on bone metastases in castrate-resistant prostate cancer

Prostate cancer is the most frequent noncutaneous cancer occurring in men. On average, men with localized prostate cancer have a high 10-year survival rate, and many can be cured. However, men with metastatic castrate-resistant prostate cancer have incurable disease with poor survival despite intensive therapy. This unmet need has led to recent advances in therapy aimed at treating bone metastases resulting from prostate cancer. The bone microenvironment lends itself to metastases in castrate-resistant prostate cancer, as a result of complex interactions between the microenvironment and tumor cells. The development of 223radium dichloride (Ra-223) to treat symptomatic bone metastases has improved survival in men with metastatic castrate-resistant prostate cancer. Moreover, Ra-223 may have effects on the tumor microenvironment that enhance its activity. Ra-223 treatment has been shown to prolong survival, and its effects on the immune system are under investigation. Because prostate cancer affects a sizable portion of the adult male population, understanding how it metastasizes to bone is an important step in advancing therapy. Clinical trials that are underway should yield new information on whether Ra-223 synergizes effectively with immunotherapy agents and whether Ra-223 has enhancing effects on the immune system in patients with prostate cancer

First-line ovulation induction for polycystic ovary syndrome : an individual participant data meta-analysis

Acknowledgements We would like to thank Mr M. Draper from Barr Smith Library, University of Adelaide, for his assistance in developing the search strategies and Dr M. H. Zafarmand from University of Amsterdam for assisting with the translation. We would like to acknowledge all the investigators and participants of the primary trials. The investigators of individual trials are listed in Supplementary Table SIV. We would like to acknowledge the assistance of NICHD, the Reproductive Medicine Network (RMN) and the Protocol Subcommittee, in making the database for PPCOS I and II available. +The authors of the Reproductive Medicine Network are R.S.L., R.G. Brzyski, M.P. Diamond, C. Coutifaris, W.D. Schlaff, P. Casson, G.M. Christman, H. Huang, Q. Yan, R. Alvero, D.J. Haisenleder, K.T. Barnhart, G.W. Bates, R. Usadi, S. Lucidi, V. Baker, J.C. Trussell, S.A. Krawetz, P. Snyder, D. Ohl, N. Santoro, H.X. Barnhart, B.R. Carr, S.A. Carson, M.P. Steinkampf, P.G. McGovern, N.A. Cataldo, G.G. Gosman, J.E. Nestler, L.C. Giudice, P.C. Leppert, E.R. Myers, E. Eisenberg and H. Zhang. The details of their affiliations and NIH Grants are listed in Supplementary Table SV. Funding An Australian government research training programme scholarship (to R.W.); Australian National Health and Medical Research Council-funded Centre for Research Excellence in Polycystic Ovary Syndrome (APP1078444). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.Peer reviewedPostprin

DNA Repair in Prostate Cancer: Biology and Clinical Implications

CONTEXT: For more precise, personalized care in prostate cancer (PC), a new classification based on molecular features relevant for prognostication and treatment stratification is needed. Genomic aberrations in the DNA damage repair pathway are common in PC, particularly in late-stage disease, and may be relevant for treatment stratification. OBJECTIVE: To review current knowledge on the prevalence and clinical significance of aberrations in DNA repair genes in PC, particularly in metastatic disease. EVIDENCE ACQUISITION: A literature search up to July 2016 was conducted, including clinical trials and preclinical basic research studies. Keywords included DNA repair, BRCA, ATM, CRPC, prostate cancer, PARP, platinum, predictive biomarkers, and hereditary cancer. EVIDENCE SYNTHESIS: We review how the DNA repair pathway is relevant to prostate carcinogenesis and progression. Data on how this may be relevant to hereditary cancer and genetic counseling are included, as well as data from clinical trials of PARP inhibitors and platinum therapeutics in PC. CONCLUSIONS: Relevant studies have identified genomic defects in DNA repair in PCs in 20-30% of advanced castration-resistant PC cases, a proportion of which are germline aberrations and heritable. Phase 1/2 clinical trial data, and other supporting clinical data, support the development of PARP inhibitors and DNA-damaging agents in this molecularly defined subgroup of PC following success in other cancer types. These studies may be an opportunity to improve patient care with personalized therapeutic strategies. PATIENT SUMMARY: Key literature on how genomic defects in the DNA damage repair pathway are relevant for prostate cancer biology and clinical management is reviewed. Potential implications for future changes in patient care are discussed

Regional and experiential differences in surgeon preference for the treatment of cervical facet injuries: a case study survey with the AO Spine Cervical Classification Validation Group

PURPOSE: The management of cervical facet dislocation injuries remains controversial. The main purpose of this investigation was to identify whether a surgeon\u27s geographic location or years in practice influences their preferred management of traumatic cervical facet dislocation injuries. METHODS: A survey was sent to 272 AO Spine members across all geographic regions and with a variety of practice experience. The survey included clinical case scenarios of cervical facet dislocation injuries and asked responders to select preferences among various diagnostic and management options. RESULTS: A total of 189 complete responses were received. Over 50% of responding surgeons in each region elected to initiate management of cervical facet dislocation injuries with an MRI, with 6 case exceptions. Overall, there was considerable agreement between American and European responders regarding management of these injuries, with only 3 cases exhibiting a significant difference. Additionally, results also exhibited considerable management agreement between those with ≤ 10 and \u3e 10 years of practice experience, with only 2 case exceptions noted. CONCLUSION: More than half of responders, regardless of geographical location or practice experience, identified MRI as a screening imaging modality when managing cervical facet dislocation injuries, regardless of the status of the spinal cord and prior to any additional intervention. Additionally, a majority of surgeons would elect an anterior approach for the surgical management of these injuries. The study found overall agreement in management preferences of cervical facet dislocation injuries around the globe

Sequencing of prostate cancers identifies new cancer genes, routes of progression and drug targets

Prostate cancer represents a substantial clinical challenge because it is difficult to predict outcome and advanced disease is often fatal. We sequenced the whole genomes of 112 primary and metastatic prostate cancer samples. From joint analysis of these cancers with those from previous studies (930 cancers in total), we found evidence for 22 previously unidentified putative driver genes harboring coding mutations, as well as evidence for NEAT1 and FOXA1 acting as drivers through noncoding mutations. Through the temporal dissection of aberrations, we identified driver mutations specifically associated with steps in the progression of prostate cancer, establishing, for example, loss of CHD1 and BRCA2 as early events in cancer development of ETS fusion-negative cancers. Computational chemogenomic (canSAR) analysis of prostate cancer mutations identified 11 targets of approved drugs, 7 targets of investigational drugs, and 62 targets of compounds that may be active and should be considered candidates for future clinical trials

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

A922 Sequential measurement of 1 hour creatinine clearance (1-CRCL) in critically ill patients at risk of acute kidney injury (AKI)

Meeting abstrac

Cold atoms in space: community workshop summary and proposed road-map

We summarise the discussions at a virtual Community Workshop on Cold Atoms in Space concerning the status of cold atom technologies, the prospective scientific and societal opportunities offered by their deployment in space, and the developments needed before cold atoms could be operated in space. The cold atom technologies discussed include atomic clocks, quantum gravimeters and accelerometers, and atom interferometers. Prospective applications include metrology, geodesy and measurement of terrestrial mass change due to, e.g., climate change, and fundamental science experiments such as tests of the equivalence principle, searches for dark matter, measurements of gravitational waves and tests of quantum mechanics. We review the current status of cold atom technologies and outline the requirements for their space qualification, including the development paths and the corresponding technical milestones, and identifying possible pathfinder missions to pave the way for missions to exploit the full potential of cold atoms in space. Finally, we present a first draft of a possible road-map for achieving these goals, that we propose for discussion by the interested cold atom, Earth Observation, fundamental physics and other prospective scientific user communities, together with the European Space Agency (ESA) and national space and research funding agencies