Estimating the cost-effectiveness of fluticasone propionate for treating chronic obstructive pulmonary disease in the presence of missing data

Objectives: To explore the cost-effectiveness of fluticasone propionate (FP) for the treatment of chronic obstructive pulmonary disease (COPD), we estimated costs and qualityadjusted life-years (QALYs) over 3 years, based on an economic appraisal of a previously reported clinical trial (Inhaled Steroids in Obstructive Lung Disease in Europe [ISOLDE]). Methods: Seven hundred forty-two patients enrolled in the ISOLDE trial who received either FP or placebo had data available on health-care costs and quality of life over the period of the study. The SF-36-based utility scores for quality of life were used to calculate QALYs. A combined imputation and bootstrapping procedure was employed to handle missing data and to estimate statistical uncertainty in the estimated cumulative costs and QALYs over the study period. The imputation approach was based on propensity scoring and nesting this approach within the bootstrap ensured that multiple imputations were performed such that statistical estimates included imputation uncertainty. Results: Complete data were available on mortality within the follow-up period of the study and a nonsignificant trend toward improved survival of 0.06 (95% confidence interval [CI] –0.01 to 0.15) life-years was observed. In an analysis based on a propensity scoring approach to missing data we estimated the incremental costs of FP versus placebo to be £1021 (95% CI £619–1338) with an additional effect of 0.11 QALYs (CI 0.04–0.20). Cost-effectiveness estimates for the within-trial period of £17,700 per life-year gained (£6900 to ∞) and £9500 per QALY gained (CI £4300–26,500) were generated that include uncertainty due to the imputation process. An alternative imputation approach did not materially affect these estimates. Conclusions: Previous analyses of the ISOLDE study showed significant improvement on disease-specific health status measures and a trend toward a survival advantage for treatment with FP. This analysis shows that joint considerations of quality of life and survival result in a substantial increase in QALYs favoring treatment with FP. Based on these data, the inhaled corticosteroid FP appears costeffective for the treatment of COPD. Confirmation or refutation of this result may be achieved once the Towards a Revolution in COPD Health (TORCH) study reports, a large randomized controlled trial powered to detect mortality changes associated with the use of FP alone, or in combination with salmeterol, which is also collecting resource use and utility data suitable for estimating cost-effectiveness

Increased Adenine Nucleotide Degradation in Skeletal Muscle Atrophy

Adenine nucleotides (AdNs: ATP, ADP, AMP) are essential biological compounds that facilitate many necessary cellular processes by providing chemical energy, mediating intracellular signaling, and regulating protein metabolism and solubilization. A dramatic reduction in total AdNs is observed in atrophic skeletal muscle across numerous disease states and conditions, such as cancer, diabetes, chronic kidney disease, heart failure, COPD, sepsis, muscular dystrophy, denervation, disuse, and sarcopenia. The reduced AdNs in atrophic skeletal muscle are accompanied by increased expression/activities of AdN degrading enzymes and the accumulation of degradation products (IMP, hypoxanthine, xanthine, uric acid), suggesting that the lower AdN content is largely the result of increased nucleotide degradation. Furthermore, this characteristic decrease of AdNs suggests that increased nucleotide degradation contributes to the general pathophysiology of skeletal muscle atrophy. In view of the numerous energetic, and non-energetic, roles of AdNs in skeletal muscle, investigations into the physiological consequences of AdN degradation may provide valuable insight into the mechanisms of muscle atrophy

Recent ν\nus from IceCube

IceCube is a 1 km$^3$ neutrino detector now being built at the South Pole. Its 4800 optical modules will detect Cherenkov radiation from charged particles produced in neutrino interactions. IceCube will search for neutrinos of astrophysical origin, with energies from 100 GeV up to $10^{19}$ eV. It will be able to separate $\nu_e$, $\nu_\mu$ and $\nu_\tau$. In addition to detecting astrophysical neutrinos, IceCube will also search for neutrinos from WIMP annihilation in the Sun and the Earth, look for low-energy (10 MeV) neutrinos from supernovae, and search for a host of exotic signatures. With the associated IceTop surface air shower array, it will study cosmic-ray air showers. IceCube construction is now 50% complete. After presenting preliminary results from the partial detector, I will discuss IceCube's future plans.Comment: Invited talk presented at Neutrino 2008; 7 page

Powerhouse Slope Behavior, Fort Peck Dam, Montana

Landslides occurred in the Bearpaw shale slope adjacent to the powerhouses at Fort Peck Dam in the geologic past. Excavation of the slope toe for construction of reservoir outlet works in 1934 initiated progressive sliding of colluvium which continued to 1974. The active slide area had an average movement rate of 4 ft/yr from 1944-1945 and average movement rates of 1-2 ft/yr from 1953-1971. These movements caused no distress to the powerhouses or other facilities. In 1974, the slope was stabilized by excavating 1.6 x 106 cu. yd. of material, resulting in a 1 on 6 overall slope. A field residual strength given by c\u27 = 0.1 ksf, Φ\u27 = 10° or c\u27 = 0, Φ\u27 = 11.5° for effective normal stresses of 3-4 ksf was calculated from the slides using 1950\u27s topography and groundwater levels

Functional metagenomic screening approach for discovery of new glycoside phosphorylases

Glycoside phosphorylases (GPs) have recently been recognized as potentially useful biocatalysts for the synthesis and biotransformation of glycans. These enzymes ordinarily carry out phosphorolysis of the glycosidic linkage by transferring a glycosyl moiety from the non-reducing end of a di- or polysaccharide substrate onto inorganic phosphate, thereby cleaving the glycosidic bond and generating a sugar-1-phosphate. GPs distinguish themselves from most carbohydrate-active enzymes in that the hydrolytic free energy associated with the ester-linkage of the sugar-1-phosphate product is roughly equivalent to that of the glycosidic linkage in the glycan substrate. Therefore, the equilibrium position can be tipped in favour of glycoside synthesis by manipulation of reaction conditions. GPs thus have considerable potential for the assembly of glycans, especially since their reversibility would allow the use of one GP to degrade an inexpensive glycan to produce a pool of sugar-1-phosphates, while a second GP could be deployed to use those sugar-1-phosphates as donors to synthesize a different, more valuable target glycan. The bottleneck in this approach, however, is the limited range of GPs available, which restricts the classes of glycan that can be assembled. To help increase the spectrum of known GPs available, we have turned to metagenomics as a means to discover new enzymes belonging to this class. We have adapted the molybdenum blue reaction to a high-throughput plate-based metagenomic screen for the discovery of GPs. Our method utilizes the reverse phosphorolysis ability of GPs by coupling inorganic phosphate released during glycan synthesis to the molybdenum blue reaction. Therefore, GP activity can be identified by incubating metagenomic clones with appropriate donor sugar-1-phosphates and acceptor glycans, then monitoring inorganic phosphate accumulation by measuring formation of molybdenum blue. Our pilot screen was optimized to identify cellulose degrading GPs and yielded 7 novel GP ORFs, all from CAZy family GH94. To our knowledge this is the first high-throughput functional metagenomic screen for GP activity. Looking ahead, we have planned to further adapt the screening method so it may identify GP activity from other CAZy families, beyond GH94. The activities that can be identified are dependent on the combination of donor and acceptor substrates used. By mixing and matching different substrates we will be able to narrow or broaden the scope of activities that can be detected within a single screen

Repurposing of Meropenem and Nadifloxacin for Treatment of Burn Patients?

The escalating number of multidrug resistant pathogens has demanded the swift development of new and potent antibiotics (ref. 2). Metallo-[beta]-lactamases (MBLs) continue to evolve, rendering the latest generation of carbapenem antibiotics useless (ref. 8). SPM-1, a recently discovered MBL, was isolated from a juvenile leukemia patient residing in a hospital in San Palo, Brazil just prior to the patient succumbing to septicemia brought on by Pseudomonas aeruginosa expressing SPM-1 (ref. 8). Screening of the Johns Hopkins Compound library of 1,514 FDA or FAD approved drugs (ref. 1) identified a novel SPM-1 inhibitor that is synergistically compatible with meropenem. Using clinically achievable concentrations, meropenem coupled with nadifloxacin inhibits Pseudomonas aeruginosa expressing SPM-1. This shotgun approach to new drug discovery provided a prompt solution to the grave problem of antibiotic resistant pathogens that are thriving in hospitals today

Multi-wavelength INTEGRAL NEtwork (MINE) observations of the microquasar GRS 1915+105

We present the international collaboration MINE (Multi-lambda Integral NEtwork) aimed at conducting multi-wavelength observations of X-ray binaries and microquasars simultaneously with the INTEGRAL gamma-ray satellite. We will focus on the 2003 March-April campaign of observations of the peculiar microquasar GRS 1915+105 gathering radio, IR and X-ray data. The source was observed 3 times in the plateau state, before and after a major radio and X-ray flare. It showed strong steady optically thick radio emission corresponding to powerful compact jets resolved in the radio images, bright near-infrared emission, a strong QPO at 2.5 Hz in the X-rays and a power law dominated spectrum without cutoff in the 3-300 keV range. We compare the different observations, their multi-wavelength light curves, including JEM-X, ISGRI and SPI, and the parameters deduced from fitting the spectra obtained with these instruments on board INTEGRAL.Comment: 4 pages, 9 fig., Proc. of the 5th INTEGRAL Workshop (Feb. 16-20 2004), to be published by ES

Simultaneous multi-wavelength observations of microquasars (the MINE collaboration)

We present the international collaboration MINE (Multi-lambda INTEGRAL NEtwork) aimed at conducting multi-wavelength observations of microquasars simultaneously with the INTEGRAL satellite. The first results on GRS 1915+105 are encouraging and those to come should help us to understand the physics of the accretion and ejection phenomena around a compact object.Comment: 2 p, 3 fig., proc. of the IAU Coll. 194, ``Compact Binaries in the Galaxy and Beyond'', Nov. 2003, La Paz, Mexico, to be published in the Conf. Series of Revista Mexicana de Astronomia y Astrofisica, Eds. G. Tovmassian & E. Sio