The Locations of Gamma-Ray Bursts Measured by COMPTEL

The COMPTEL instrument on the Compton Gamma Ray Observatory is used to measure the locations of gamma-ray bursts through direct imaging of MeV photons. In a comprehensive search, we have detected and localized 29 bursts observed between 1991 April 19 and 1995 May 31. The average location accuracy of these events is 1.25\arcdeg (1$\sigma$), including a systematic error of \sim0.5\arcdeg, which is verified through comparison with Interplanetary Network (IPN) timing annuli. The combination of COMPTEL and IPN measurements results in locations for 26 of the bursts with an average ``error box'' area of only $\sim$0.3 deg$^2$ (1$\sigma$). We find that the angular distribution of COMPTEL burst locations is consistent with large-scale isotropy and that there is no statistically significant evidence of small-angle auto-correlations. We conclude that there is no compelling evidence for burst repetition since no more than two of the events (or $\sim$7% of the 29 bursts) could possibly have come from the same source. We also find that there is no significant correlation between the burst locations and either Abell clusters of galaxies or radio-quiet quasars. Agreement between individual COMPTEL locations and IPN annuli places a lower limit of $\sim$100~AU (95% confidence) on the distance to the stronger bursts.Comment: Accepted for publication in the Astrophysical Journal, 1998 Jan. 1, Vol. 492. 33 pages, 9 figures, 5 table

Single-mode instability in standing-wave lasers: The quantum cascade laser as a self-pumped parametric oscillator

We report the observation of a clear single-mode instability threshold in continuous-wave Fabry-Perot quantum cascade lasers (QCLs). The instability is characterized by the appearance of sidebands separated by tens of free spectral ranges (FSR) from the first lasing mode, at a pump current not much higher than the lasing threshold. As the current is increased, higher-order sidebands appear that preserve the initial spacing, and the spectra are suggestive of harmonically phase-locked waveforms. We present a theory of the instability that applies to all homogeneously broadened standing-wave lasers. The low instability threshold and the large sideband spacing can be explained by the combination of an unclamped, incoherent Lorentzian gain due to the population grating, and a coherent parametric gain caused by temporal population pulsations that changes the spectral gain line shape. The parametric term suppresses the gain of sidebands whose separation is much smaller than the reciprocal gain recovery time, while enhancing the gain of more distant sidebands. The large gain recovery frequency of the QCL compared to the FSR is essential to observe this parametric effect, which is responsible for the multiple-FSR sideband separation. We predict that by tuning the strength of the incoherent gain contribution, for example by engineering the modal overlap factors and the carrier diffusion, both amplitude-modulated (AM) or frequency-modulated emission can be achieved from QCLs. We provide initial evidence of an AM waveform emitted by a QCL with highly asymmetric facet reflectivities, thereby opening a promising route to ultrashort pulse generation in the mid-infrared. Together, the experiments and theory clarify a deep connection between parametric oscillation in optically pumped microresonators and the single-mode instability of lasers, tying together literature from the last 60 years.United States. Defense Advanced Research Projects Agency. Spectral Combs from UV to THz Program (Grant W31P4Q-16-1-0002)National Science Foundation (U.S.) (Awards ECCS-1230477, ECCS-1614631 and ECCS- 1614531)United States. Dept. of Defense. Assistant Secretary of Defense for Research & Engineering (Air Force Contracts FA8721-05-C- 0002 and No. FA8702-15-D-0001

Genome-Wide Discovery of Somatic Regulatory Variants in Diffuse Large B-Cell Lymphoma

Diffuse large B-cell lymphoma (DLBCL) is an aggressive cancer originating from mature B-cells. Prognosis is strongly associated with molecular subgroup, although the driver mutations that distinguish the two main subgroups remain poorly defined. Through an integrative analysis of whole genomes, exomes, and transcriptomes, we have uncovered genes and non-coding loci that are commonly mutated in DLBCL. Our analysis has identified novel cis-regulatory sites, and implicates recurrent mutations in the 3′ UTR of NFKBIZ as a novel mechanism of oncogene deregulation and NF-κB pathway activation in the activated B-cell (ABC) subgroup. Small amplifications associated with over-expression of FCGR2B (the Fcγ receptor protein IIB), primarily in the germinal centre B-cell (GCB) subgroup, correlate with poor patient outcomes suggestive of a novel oncogene. These results expand the list of subgroup driver mutations that may facilitate implementation of improved diagnostic assays and could offer new avenues for the development of targeted therapeutics.&nbsp

The Simons Observatory microwave SQUID multiplexing detector module design

Advances in cosmic microwave background (CMB) science depend on increasing the number of sensitive detectors observing the sky. New instruments deploy large arrays of superconducting transition-edge sensor (TES) bolometers tiled densely into ever larger focal planes. High multiplexing factors reduce the thermal loading on the cryogenic receivers and simplify their design. We present the design of focal-plane modules with an order of magnitude higher multiplexing factor than has previously been achieved with TES bolometers. We focus on the novel cold readout component, which employs microwave SQUID multiplexing ($\mu$mux). Simons Observatory will use 49 modules containing 60,000 bolometers to make exquisitely sensitive measurements of the CMB. We validate the focal-plane module design, presenting measurements of the readout component with and without a prototype detector array of 1728 polarization-sensitive bolometers coupled to feedhorns. The readout component achieves a $95\%$ yield and a 910 multiplexing factor. The median white noise of each readout channel is 65 $\mathrm{pA/\sqrt{Hz}}$. This impacts the projected SO mapping speed by $< 8\%$, which is less than is assumed in the sensitivity projections. The results validate the full functionality of the module. We discuss the measured performance in the context of SO science requirements, which are exceeded.Comment: Accepted to The Astrophysical Journa

Study protocol: national research partnership to improve primary health care performance and outcomes for Indigenous peoples

Background Strengthening primary health care is critical to reducing health inequity between Indigenous and non-Indigenous Australians. The Audit and Best practice for Chronic Disease Extension (ABCDE) project has facilitated the implementation of modern Continuous Quality Improvement (CQI) approaches in Indigenous community health care centres across Australia. The project demonstrated improvements in health centre systems, delivery of primary care services and in patient intermediate outcomes. It has also highlighted substantial variation in quality of care. Through a partnership between academic researchers, service providers and policy makers, we are now implementing a study which aims to 1) explore the factors associated with variation in clinical performance; 2) examine specific strategies that have been effective in improving primary care clinical performance; and 3) work with health service staff, management and policy makers to enhance the effective implementation of successful strategies. Methods/Design The study will be conducted in Indigenous community health centres from at least six States/Territories (Northern Territory, Western Australia, New South Wales, South Australia, Queensland and Victoria) over a five year period. A research hub will be established in each region to support collection and reporting of quantitative and qualitative clinical and health centre system performance data, to investigate factors affecting variation in quality of care and to facilitate effective translation of research evidence into policy and practice. The project is supported by a web-based information system, providing automated analysis and reporting of clinical care performance to health centre staff and management. Discussion By linking researchers directly to users of research (service providers, managers and policy makers), the partnership is well placed to generate new knowledge on effective strategies for improving the quality of primary health care and fostering effective and efficient exchange and use of data and information among service providers and policy makers to achieve evidence-based resource allocation, service planning, system development, and improvements of service delivery and Indigenous health outcomes.Ross Bailie, Damin Si, Cindy Shannon, James Semmens, Kevin Rowley, David J Scrimgeour, Tricia Nage, Ian Anderson, Christine Connors, Tarun Weeramanthri, Sandra Thompson, Robyn McDermott, Hugh Burke, Elizabeth Moore, Dallas Leon, Richard Weston, Haylene Grogan, Andrew Stanley and Karen Gardne

The Changing Landscape for Stroke\ua0Prevention in AF: Findings From the GLORIA-AF Registry Phase 2

Background GLORIA-AF (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation) is a prospective, global registry program describing antithrombotic treatment patterns in patients with newly diagnosed nonvalvular atrial fibrillation at risk of stroke. Phase 2 began when dabigatran, the first non\u2013vitamin K antagonist oral anticoagulant (NOAC), became available. Objectives This study sought to describe phase 2 baseline data and compare these with the pre-NOAC era collected during phase&nbsp;1. Methods During phase 2, 15,641 consenting patients were enrolled (November 2011 to December 2014); 15,092 were eligible. This pre-specified cross-sectional analysis describes eligible patients\u2019 baseline characteristics. Atrial fibrillation&nbsp;disease characteristics, medical outcomes, and concomitant diseases and medications were collected. Data were analyzed using descriptive statistics. Results Of the total patients, 45.5% were female; median age was 71 (interquartile range: 64, 78) years. Patients were from Europe (47.1%), North America (22.5%), Asia (20.3%), Latin America (6.0%), and the Middle East/Africa (4.0%). Most had high stroke risk (CHA2DS2-VASc [Congestive heart failure, Hypertension, Age&nbsp; 6575 years, Diabetes mellitus, previous Stroke, Vascular disease, Age 65 to 74 years, Sex category] score&nbsp; 652; 86.1%); 13.9% had moderate risk (CHA2DS2-VASc&nbsp;= 1). Overall, 79.9% received oral anticoagulants, of whom 47.6% received NOAC and 32.3% vitamin K antagonists (VKA); 12.1% received antiplatelet agents; 7.8% received no antithrombotic treatment. For comparison, the proportion of phase 1 patients (of N&nbsp;= 1,063 all eligible) prescribed VKA was 32.8%, acetylsalicylic acid 41.7%, and no therapy 20.2%. In Europe in phase 2, treatment with NOAC was more common than VKA (52.3% and 37.8%, respectively); 6.0% of patients received antiplatelet treatment; and 3.8% received no antithrombotic treatment. In North America, 52.1%, 26.2%, and 14.0% of patients received NOAC, VKA, and antiplatelet drugs, respectively; 7.5% received no antithrombotic treatment. NOAC use was less common in Asia (27.7%), where 27.5% of patients received VKA, 25.0% antiplatelet drugs, and 19.8% no antithrombotic treatment. Conclusions The baseline data from GLORIA-AF phase 2 demonstrate that in newly diagnosed nonvalvular atrial fibrillation patients, NOAC have been highly adopted into practice, becoming more frequently prescribed than VKA in&nbsp;Europe and North America. Worldwide, however, a large proportion of patients remain undertreated, particularly in&nbsp;Asia&nbsp;and North America. (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients With Atrial Fibrillation [GLORIA-AF]; NCT01468701

Genetics and Pathogenesis of Diffuse Large B-Cell Lymphoma.

BACKGROUND: Diffuse large B-cell lymphomas (DLBCLs) are phenotypically and genetically heterogeneous. Gene-expression profiling has identified subgroups of DLBCL (activated B-cell-like [ABC], germinal-center B-cell-like [GCB], and unclassified) according to cell of origin that are associated with a differential response to chemotherapy and targeted agents. We sought to extend these findings by identifying genetic subtypes of DLBCL based on shared genomic abnormalities and to uncover therapeutic vulnerabilities based on tumor genetics. METHODS: We studied 574 DLBCL biopsy samples using exome and transcriptome sequencing, array-based DNA copy-number analysis, and targeted amplicon resequencing of 372 genes to identify genes with recurrent aberrations. We developed and implemented an algorithm to discover genetic subtypes based on the co-occurrence of genetic alterations. RESULTS: We identified four prominent genetic subtypes in DLBCL, termed MCD (based on the co-occurrence of MYD88L265P and CD79B mutations), BN2 (based on BCL6 fusions and NOTCH2 mutations), N1 (based on NOTCH1 mutations), and EZB (based on EZH2 mutations and BCL2 translocations). Genetic aberrations in multiple genes distinguished each genetic subtype from other DLBCLs. These subtypes differed phenotypically, as judged by differences in gene-expression signatures and responses to immunochemotherapy, with favorable survival in the BN2 and EZB subtypes and inferior outcomes in the MCD and N1 subtypes. Analysis of genetic pathways suggested that MCD and BN2 DLBCLs rely on "chronic active" B-cell receptor signaling that is amenable to therapeutic inhibition. CONCLUSIONS: We uncovered genetic subtypes of DLBCL with distinct genotypic, epigenetic, and clinical characteristics, providing a potential nosology for precision-medicine strategies in DLBCL. (Funded by the Intramural Research Program of the National Institutes of Health and others.).This research was supported by the Intramural Research Program of the NIH, Center for Cancer Research, National Cancer Institute and by a National Cancer Institute Strategic Partnering to Evaluate Cancer Signatures (SPECS II) grant (5U01CA157581-05). R.S. was supported by the Dr Mildred Scheel Stiftung für Krebsforschung (Deutsche Krebshilfe). D.J.H. was a Kay Kendall Leukaemia Fund Intermediate research fellow. M.K. was supported by the National Institutes of Health Oxford-Cambridge Scholars Program and the Washington University in St. Louis Medical Scientist Training Progra

Sensor fusion for intelligent process control.

An integrated system for the fusion of product and process sensors and controls for production of flat glass was envisioned, having as its objective the maximization of throughput and product quality subject to emission limits, furnace refractory wear, and other constraints. Although the project was prematurely terminated, stopping the work short of its goal, the tasks that were completed show the value of the approach and objectives. Though the demonstration was to have been done on a flat glass production line, the approach is applicable to control of production in the other sectors of the glass industry. Furthermore, the system architecture is also applicable in other industries utilizing processes in which product uniformity is determined by ability to control feed composition, mixing, heating and cooling, chemical reactions, and physical processes such as distillation, crystallization, drying, etc. The first phase of the project, with Visteon Automotive Systems as industrial partner, was focused on simulation and control of the glass annealing lehr. That work produced the analysis and computer code that provide the foundation for model-based control of annealing lehrs during steady state operation and through color and thickness changes. In the second phase of the work, with PPG Industries as the industrial partner, the emphasis was on control of temperature and combustion stoichiometry in the melting furnace, to provide a wider operating window, improve product yield, and increase energy efficiency. A program of experiments with the furnace, CFD modeling and simulation, flow measurements, and sensor fusion was undertaken to provide the experimental and theoretical basis for an integrated, model-based control system utilizing the new infrastructure installed at the demonstration site for the purpose. In spite of the fact that the project was terminated during the first year of the second phase of the work, the results of these first steps toward implementation of model-based control were sufficient to demonstrate the value of the approach to improving the productivity of glass manufacture