United States Air Force fighter jet maintenance Models : effectiveness of index policies

Thesis (S.M.)--Massachusetts Institute of Technology, Sloan School of Management, Operations Research Center, 2013.Cataloged from PDF version of thesis. "June 2013."Includes bibliographical references (pages 107-109).As some of the most technically complex systems in the world, United States fighter aircraft require a complex logistics system to sustain their reliable operation and ensure that the day-to-day Air Force missions can be satisfied. While there has been a lot of attention among academics and practitioners regarding the study of this complex logistics system, most of the focus has been on availability of spare parts that are indeed essential for the smooth operations of the fighter aircraft. However, in recent years there has been an increasing awareness that maintenance resources are an equally important enabler and should be considered together with inventory issues. The maintenance resources required to repair the fighter aircraft are expensive and therefore limited. Moreover, there are various types of maintenance that compete for the same resources. It .is therefore imperative that the allocation of maintenance resources is done as efficiently as possible. In this thesis, we study two areas of fighter aircraft maintenance that could significantly benefit from improved resource allocation and scheduling strategies. We use quantitative and qualitative data from Air Force data-bases and logistics personnel to develop an innovative modeling framework to capture these challenging maintenance problems. This modeling framework is based on a generalization of the of the well-known multi-armed bandit superprocess problem. Using these models, we develop index policies which provide intuitive, easily implemented, and effective rules for scheduling maintenance activities and allocating maintenance resources. These policies seem to improve on existing best practices within the Air Force, and perform well in extensive data-driven simulated computational experiments. The first area is focused on the challenges of scheduling maintenance for the low observable (stealth) capabilities of the F-22 Raptor, specifically, maintenance of the outer coating of the aircraft that is essential to maintain its radar invisibility. In particular, we generate index policies that efficiently schedule which aircraft should enter low observable maintenance, how long they should be worked on, and which aircraft should fly in order to maximize the stealth capability of the fleet. Secondly, we model the maintenance process of the F100-229 engine, which is the primary propulsion method used in the F-16C/D and F-15E aircraft. In particular, we generate index policies to decide which engines should take priority over others, and whether or not certain components of the engines should be repaired or replaced. The policies address both elective (planned) and unplanned maintenance tasks.by John M. Kessler.S.M

Rationale and design for the development of a novel nitroxyl donor in patients with acute heart failure

Hospitalisation for acute heart failure remains a major public health problem with high prevalence, morbidity, mortality, and cost. Prior attempts to develop new therapies for this condition have not been successful. Nitroxyl (HNO) plays a unique role in cardiovascular physiology by direct post‐translational modification of thiol residues on target proteins, specifically SERCA2a, phospholamban, the ryanodine receptor and myofilament proteins in cardiomyocytes. In animal models, these biological effects lead to vasodilatation, increased inotropy and lusitropy, but without tachyphylaxis, pro‐arrhythmia or evidence of increased myocardial oxygen demand. BMS‐986231 is an HNO donor being developed as a therapy for heart failure, and initial studies in patients with heart failure support the potential clinical value of these physiological effects. In this manuscript, we describe the ongoing phase II development programme for BMS‐986231, which consists of three related randomised placebo‐controlled clinical trials, StandUP‐AHF, StandUP‐Imaging and StandUP‐Kidney, which are designed to provide evidence of tolerability and efficacy as well as confirm the anticipated physiological effects in patients with heart failure with reduced ejection fraction. These studies will set the stage for the further study of BMS‐986231 in future phase III clinical trials

Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program

The Trans-Omics for Precision Medicine (TOPMed) programme seeks to elucidate the genetic architecture and biology of heart, lung, blood and sleep disorders, with the ultimate goal of improving diagnosis, treatment and prevention of these diseases. The initial phases of the programme focused on whole-genome sequencing of individuals with rich phenotypic data and diverse backgrounds. Here we describe the TOPMed goals and design as well as the available resources and early insights obtained from the sequence data. The resources include a variant browser, a genotype imputation server, and genomic and phenotypic data that are available through dbGaP (Database of Genotypes and Phenotypes)1. In the first 53,831 TOPMed samples, we detected more than 400 million single-nucleotide and insertion or deletion variants after alignment with the reference genome. Additional previously undescribed variants were detected through assembly of unmapped reads and customized analysis in highly variable loci. Among the more than 400 million detected variants, 97% have frequencies of less than 1% and 46% are singletons that are present in only one individual (53% among unrelated individuals). These rare variants provide insights into mutational processes and recent human evolutionary history. The extensive catalogue of genetic variation in TOPMed studies provides unique opportunities for exploring the contributions of rare and noncoding sequence variants to phenotypic variation. Furthermore, combining TOPMed haplotypes with modern imputation methods improves the power and reach of genome-wide association studies to include variants down to a frequency of approximately 0.01%

Recombinant tissue-type plasminogen activator versus a novel dosing regimen of urokinase in acute pulmonary embolism: a randomized controlled multicenter trial

AbstractThrombolysis of acute pulmonary embolism can be accomplished more rapidly and safely with 100 mg of recombinant human tissue-type plasminogen activator (rt-PA) (Activase) than with a conventional dose of urokinase (Abbokinase) given as a 4,400-U/kg bolus dose, followed by 4,400 U/kg per h for 24 h. To determine the effects of a more concentrated urokinase dose administered over a shorter time course, this trial enrolled 90 patients with baseline perfusion lung scans and angiographically documented pulmonary embolism. They were randomized to receive either 100 mg/2 h of rt-PA or a novel dosing regimen of urokinase: 3 million U/2 h with the initial 1 million U given as a bolus injection over 10 min. Both drugs were delivered through a peripheral vein.To assess efficacy after initiation of therapy, repeat pulmonary angiograms at 2 h were performed in 87 patients and then graded in a blinded manner by a panel of six investigators. Of the 42 patients allocated to rt-PA therapy, 79% showed angiographic improvement at 2 h, compared with 67% of the 45 patients randomized to urokinase therapy (95% confidence interval for the difference in these proportions [rt-PA minus urokinase] is −6.6% to 30.4%; p = 0.11). The mean change in perfusion lung scans between baseline and 24 h was similar for both treatments. Three patients (two treated with rt-PA and one with urokinase) had an intracranial hemorrhage, which was fatal in one.The results indicate that a 2-h regimen of rt-PA and a new dosing regimen of urokinase exhibit similar efficacy and safety for treatment of acute pulmonary embolism

Neural Tube Defects and Folate Pathway Genes: Family-Based Association Tests of Gene–Gene and Gene–Environment Interactions

BACKGROUND: Folate metabolism pathway genes have been examined for association with neural tube defects (NTDs) because folic acid supplementation reduces the risk of this debilitating birth defect. Most studies addressed these genes individually, often with different populations providing conflicting results. OBJECTIVES: Our study evaluates several folate pathway genes for association with human NTDs, incorporating an environmental cofactor: maternal folate supplementation. METHODS: In 304 Caucasian American NTD families with myelomeningocele or anencephaly, we examined 28 polymorphisms in 11 genes: folate receptor 1, folate receptor 2, solute carrier family 19 member 1, transcobalamin II, methylenetetrahydrofolate dehydrogenase 1, serine hydroxymethyl-transferase 1, 5,10-methylenetetrahydrofolate reductase (MTHFR), 5-methyltetrahydrofolate-homo-cysteine methyltransferase, 5-methyltetrahydrofolate-homocysteine methyltransferase reductase, betaine-homocysteine methyltransferase (BHMT), and cystathionine-beta-synthase. RESULTS: Only single nucleotide polymorphisms (SNPs) in BHMT were significantly associated in the overall data set; this significance was strongest when mothers took folate-containing nutritional supplements before conception. The BHMT SNP rs3733890 was more significant when the data were stratified by preferential transmission of the MTHFR rs1801133 thermolabile T allele from parent to offspring. Other SNPs in folate pathway genes were marginally significant in some analyses when stratified by maternal supplementation, MTHFR, or BHMT allele transmission. CONCLUSIONS: BHMT rs3733890 is significantly associated in our data set, whereas MTHFR rs1801133 is not a major risk factor. Further investigation of folate and methionine cycle genes will require extensive SNP genotyping and/or resequencing to identify novel variants, inclusion of environmental factors, and investigation of gene–gene interactions in large data sets

Effects of a Novel Nitroxyl Donor in Acute Heart Failure The STAND-UP AHF Study

Objectives: The primary objective was to identify well-tolerated doses of cimlanod in patients with acute heart failure (AHF). Secondary objectives were to identify signals of efficacy, including biomarkers, symptoms, and clinical events. Background: Nitroxyl (HNO) donors have vasodilator, inotropic and lusitropic effects. Bristol-Myers Squibb-986231 (cimlanod) is an HNO donor being developed for acute heart failure (AHF). Methods: This was a phase IIb, double-blind, randomized, placebo-controlled trial of 48-h treatment with cimlanod compared with placebo in patients with left ventricular ejection fraction ≤40% hospitalized for AHF. In part I, patients were randomized in a 1:1 ratio to escalating doses of cimlanod or matching placebo. In part II, patients were randomized in a 1:1:1 ratio to either of the 2 highest tolerated doses of cimlanod from part I or placebo. The primary endpoint was the rate of clinically relevant hypotension (systolic blood pressure <90 mm Hg or patients became symptomatic). Results: In part I (n = 100), clinically relevant hypotension was more common with cimlanod than placebo (20% vs. 8%; relative risk [RR]: 2.45; 95% confidence interval [CI]: 0.83 to 14.53). In part II (n = 222), the incidence of clinically relevant hypotension was 18% for placebo, 21% for cimlanod 6 μg/kg/min (RR: 1.15; 95% CI: 0.58 to 2.43), and 35% for cimlanod 12 μg/kg/min (RR: 1.9; 95% CI: 1.04 to 3.59). N-terminal pro–B-type natriuretic peptide and bilirubin decreased during infusion of cimlanod treatment compared with placebo, but these differences did not persist after treatment discontinuation. Conclusions: Cimlanod at a dose of 6 μg/kg/min was reasonably well-tolerated compared with placebo. Cimlanod reduced markers of congestion, but this did not persist beyond the treatment period. (Evaluate the Safety and Efficacy of 48-Hour Infusions of HNO (Nitroxyl) Donor in Hospitalized Patients With Heart Failure [STANDUP AHF]; NCT03016325

The Sloan Digital Sky Survey-II Supernova Survey: Search Algorithm and Follow-up Observations

The Sloan Digital Sky Survey-II Supernova Survey has identified a large number of new transient sources in a 300 sq. deg. region along the celestial equator during its first two seasons of a three-season campaign. Multi-band (ugriz) light curves were measured for most of the sources, which include solar system objects, Galactic variable stars, active galactic nuclei, supernovae (SNe), and other astronomical transients. The imaging survey is augmented by an extensive spectroscopic follow-up program to identify SNe, measure their redshifts, and study the physical conditions of the explosions and their environment through spectroscopic diagnostics. During the survey, light curves are rapidly evaluated to provide an initial photometric type of the SNe, and a selected sample of sources are targeted for spectroscopic observations. In the first two seasons, 476 sources were selected for spectroscopic observations, of which 403 were identified as SNe. For the Type Ia SNe, the main driver for the Survey, our photometric typing and targeting efficiency is 90%. Only 6% of the photometric SN Ia candidates were spectroscopically classified as non-SN Ia instead, and the remaining 4% resulted in low signal-to-noise, unclassified spectra. This paper describes the search algorithm and the software, and the real-time processing of the SDSS imaging data. We also present the details of the supernova candidate selection procedures and strategies for follow-up spectroscopic and imaging observations of the discovered sources.Comment: Accepted for publication in The Astronomical Journal (66 pages, 13 figures); typos correcte

First-Year Spectroscopy for the SDSS-II Supernova Survey

This paper presents spectroscopy of supernovae discovered in the first season of the Sloan Digital Sky Survey-II Supernova Survey. This program searches for and measures multi-band light curves of supernovae in the redshift range z = 0.05 - 0.4, complementing existing surveys at lower and higher redshifts. Our goal is to better characterize the supernova population, with a particular focus on SNe Ia, improving their utility as cosmological distance indicators and as probes of dark energy. Our supernova spectroscopy program features rapid-response observations using telescopes of a range of apertures, and provides confirmation of the supernova and host-galaxy types as well as precise redshifts. We describe here the target identification and prioritization, data reduction, redshift measurement, and classification of 129 SNe Ia, 16 spectroscopically probable SNe Ia, 7 SNe Ib/c, and 11 SNe II from the first season. We also describe our efforts to measure and remove the substantial host galaxy contamination existing in the majority of our SN spectra.Comment: Accepted for publication in The Astronomical Journal(47pages, 9 figures