Outcome-driven Service Provider Performance under Conditions of Complexity and Uncertainty

Proceedings Paper (for Acquisition Research Program)This paper describes applying ROI analysis principles for SOA performance management, creating Service-level Agreements (SLAs) to articulate agreements between the Government and external service providers, and managing SLAs through a governance framework (Hanf & Buck, 2009, March). This white paper highlights key findings of research undertaken by The MITRE Corporation (MITRE) and the resulting recommendations for (1) applying Return-on-Investment (ROI) analysis principles as the foundation for more effective performance management of Government Service-oriented Architecture (SOA), (2) creating comprehensive Service-level Agreements (SLAs) to articulate agreements between the Government and external service providers, and (3) managing SLAs through a governance framework (Oakley-Bogdewic & Buck, 2009; Hanf & Buck, 2009, March 25). As illustrated in Figure 1, MITRE''s recommendations address the additional managerial complexity and uncertainty that SOA objectives and proposed solutions often create.Naval Postgraduate School Acquisition Research ProgramApproved for public release; distribution is unlimited

Low voltage to high voltage level shifter and related methods

A shifter circuit comprises a high and low voltage buffer stages and an output buffer stage. The high voltage buffer stage comprises multiple transistors arranged in a transistor stack having a plurality of intermediate nodes connecting individual transistors along the stack. The transistor stack is connected between a voltage level being shifted to and an input voltage. An inverter of this stage comprises multiple inputs and an output. Inverter inputs are connected to a respective intermediate node of the transistor stack. The low voltage buffer stage has an input connected to the input voltage and an output, and is operably connected to the high voltage buffer stage. The low voltage buffer stage is connected between a voltage level being shifted away from and a lower voltage. The output buffer stage is driven by the outputs of the high voltage buffer stage inverter and the low voltage buffer stage

The Development of a Human Well-Being Index for the United States

The US Environmental Protection Agency (EPA) has developed a human well-being index (HWBI) that assesses the over-all well-being of its population at the county level. The HWBI contains eight domains representing social, economic and environmental well-being. These domains include 25 indicators comprised of 80 metrics and 22 social, economic and environmental services. The application of the HWBI has been made for the nation as a whole at the county level and two alternative applications have been made to represent key populations within the overall US population—Native Americans and children. A number of advances have been made to estimate the values of metrics for counties where no data is available and one such estimator—MERLIN—is discussed. Finally, efforts to make the index into an interactive web site are described

Regionalizing Resilience to Acute Meteorological Events: Comparison of Regions in the U.S.

Using a Climate Resilience Screening Index (CRSI) that was developed to represent resilience to acute weather events at multiple scales for the United States, nine regions of the United States are compared for resilience for these types of natural hazards. The comparison examines the domains, indicators, and metrics of CRSI addressing environmental, economic, and societal aspects of resilience to acute climate events at county scales. The index was applied at the county scale and aggregated to represent select regions of the United States. Comparisons showed higher levels of resilience in the Northeast and West, including Alaska, (>4.0) while counties in the South Atlantic and South-Central regions exhibited lower resilience (<2.0) to acute climate events. Northeast, West and Mountain regions of the US are characterized by relatively low levels of risk (<0.26), higher levels of governance (>0.60), and above national median scores for society, built environment and natural environment domains which enhances their resilience scores. South Atlantic and South-Central regions of the US are characterized by higher risk scores (>0.31) accompanied by lower levels of governance (<0.48) and below national median scores for society and built environment domains reducing the region's overall resilience

Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial

Background: Rucaparib, a poly(ADP-ribose) polymerase inhibitor, has anticancer activity in recurrent ovarian carcinoma harbouring a BRCA mutation or high percentage of genome-wide loss of heterozygosity. In this trial we assessed rucaparib versus placebo after response to second-line or later platinum-based chemotherapy in patients with high-grade, recurrent, platinum-sensitive ovarian carcinoma. Methods: In this randomised, double-blind, placebo-controlled, phase 3 trial, we recruited patients from 87 hospitals and cancer centres across 11 countries. Eligible patients were aged 18 years or older, had a platinum-sensitive, high-grade serous or endometrioid ovarian, primary peritoneal, or fallopian tube carcinoma, had received at least two previous platinum-based chemotherapy regimens, had achieved complete or partial response to their last platinum-based regimen, had a cancer antigen 125 concentration of less than the upper limit of normal, had a performance status of 0–1, and had adequate organ function. Patients were ineligible if they had symptomatic or untreated central nervous system metastases, had received anticancer therapy 14 days or fewer before starting the study, or had received previous treatment with a poly(ADP-ribose) polymerase inhibitor. We randomly allocated patients 2:1 to receive oral rucaparib 600 mg twice daily or placebo in 28 day cycles using a computer-generated sequence (block size of six, stratified by homologous recombination repair gene mutation status, progression-free interval after the penultimate platinum-based regimen, and best response to the most recent platinum-based regimen). Patients, investigators, site staff, assessors, and the funder were masked to assignments. The primary outcome was investigator-assessed progression-free survival evaluated with use of an ordered step-down procedure for three nested cohorts: patients with BRCA mutations (carcinoma associated with deleterious germline or somatic BRCA mutations), patients with homologous recombination deficiencies (BRCA mutant or BRCA wild-type and high loss of heterozygosity), and the intention-to-treat population, assessed at screening and every 12 weeks thereafter. This trial is registered with ClinicalTrials.gov, number NCT01968213; enrolment is complete. Findings: Between April 7, 2014, and July 19, 2016, we randomly allocated 564 patients: 375 (66%) to rucaparib and 189 (34%) to placebo. Median progression-free survival in patients with a BRCA-mutant carcinoma was 16·6 months (95% CI 13·4–22·9; 130 [35%] patients) in the rucaparib group versus 5·4 months (3·4–6·7; 66 [35%] patients) in the placebo group (hazard ratio 0·23 [95% CI 0·16–0·34]; p<0·0001). In patients with a homologous recombination deficient carcinoma (236 [63%] vs 118 [62%]), it was 13·6 months (10·9–16·2) versus 5·4 months (5·1–5·6; 0·32 [0·24–0·42]; p<0·0001). In the intention-to-treat population, it was 10·8 months (8·3–11·4) versus 5·4 months (5·3–5·5; 0·36 [0·30–0·45]; p<0·0001). Treatment-emergent adverse events of grade 3 or higher in the safety population (372 [99%] patients in the rucaparib group vs 189 [100%] in the placebo group) were reported in 209 (56%) patients in the rucaparib group versus 28 (15%) in the placebo group, the most common of which were anaemia or decreased haemoglobin concentration (70 [19%] vs one [1%]) and increased alanine or aspartate aminotransferase concentration (39 [10%] vs none). Interpretation: Across all primary analysis groups, rucaparib significantly improved progression-free survival in patients with platinum-sensitive ovarian cancer who had achieved a response to platinum-based chemotherapy. ARIEL3 provides further evidence that use of a poly(ADP-ribose) polymerase inhibitor in the maintenance treatment setting versus placebo could be considered a new standard of care for women with platinum-sensitive ovarian cancer following a complete or partial response to second-line or later platinum-based chemotherapy. Funding: Clovis Oncology

Digital Signal Processing Research Program

Contains table of contents for Section 2, an introduction and reports on seventeen research projects.U.S. Navy - Office of Naval Research Grant N00014-91-J-1628Vertical Arrays for the Heard Island Experiment Award No. SC 48548Charles S. Draper Laboratories, Inc. Contract DL-H-418472Defense Advanced Research Projects Agency/U.S. Navy - Office of Naval Research Grant N00014-89-J-1489Rockwell Corporation Doctoral FellowshipMIT - Woods Hole Oceanographic Institution Joint ProgramDefense Advanced Research Projects Agency/U.S. Navy - Office of Naval Research Grant N00014-90-J-1109Lockheed Sanders, Inc./U.S. Navy - Office of Naval Research Contract N00014-91-C-0125U.S. Air Force - Office of Scientific Research Grant AFOSR-91-0034AT&T Laboratories Doctoral ProgramU.S. Navy - Office of Naval Research Grant N00014-91-J-1628General Electric Foundation Graduate Fellowship in Electrical EngineeringNational Science Foundation Grant MIP 87-14969National Science Foundation Graduate FellowshipCanada Natural Sciences and Engineering Research CouncilLockheed Sanders, Inc

Serum neurofilament dynamics predicts neurodegeneration and clinical progression in presymptomatic Alzheimer's disease

Neurofilament light chain (NfL) is a promising fluid biomarker of disease progression for various cerebral proteopathies. Here we leverage the unique characteristics of the Dominantly Inherited Alzheimer Network and ultrasensitive immunoassay technology to demonstrate that NfL levels in the cerebrospinal fluid (n = 187) and serum (n = 405) are correlated with one another and are elevated at the presymptomatic stages of familial Alzheimer's disease. Longitudinal, within-person analysis of serum NfL dynamics (n = 196) confirmed this elevation and further revealed that the rate of change of serum NfL could discriminate mutation carriers from non-mutation carriers almost a decade earlier than cross-sectional absolute NfL levels (that is, 16.2 versus 6.8 years before the estimated symptom onset). Serum NfL rate of change peaked in participants converting from the presymptomatic to the symptomatic stage and was associated with cortical thinning assessed by magnetic resonance imaging, but less so with amyloid-β deposition or glucose metabolism (assessed by positron emission tomography). Serum NfL was predictive for both the rate of cortical thinning and cognitive changes assessed by the Mini-Mental State Examination and Logical Memory test. Thus, NfL dynamics in serum predict disease progression and brain neurodegeneration at the early presymptomatic stages of familial Alzheimer's disease, which supports its potential utility as a clinically useful biomarker

Highly parallel oligonucleotide purification and functionalization using reversible chemistry

We have developed a cost-effective, highly parallel method for purification and functionalization of 5′-labeled oligonucleotides. The approach is based on 5′-hexa-His phase tag purification, followed by exchange of the hexa-His tag for a functional group using reversible reaction chemistry. These methods are suitable for large-scale (micromole to millimole) production of oligonucleotides and are amenable to highly parallel processing of many oligonucleotides individually or in high complexity pools. Examples of the preparation of 5′-biotin, 95-mer, oligonucleotide pools of >40K complexity at micromole scale are shown. These pools are prepared in up to ~16% yield and 90–99% purity. Approaches for using this method in other applications are also discussed

Digital Signal Processing Research Program

Contains table of contents for Section 2, an introduction and reports on fourteen research projects.U.S. Navy - Office of Naval Research Grant N00014-91-J-1628Defense Advanced Research Projects Agency/U.S. Navy - Office of Naval Research Grant N00014-89-J-1489MIT - Woods Hole Oceanographic Institution Joint ProgramLockheed Sanders, Inc./U.S. Navy Office of Naval Research Contract N00014-91-C-0125U.S. Air Force - Office of Scientific Research Grant AFOSR-91-0034U.S. Navy - Office of Naval Research Grant N00014-91-J-1628AT&T Laboratories Doctoral Support ProgramNational Science Foundation Fellowshi