High fludarabine exposure and relationship with treatment-related mortality after nonmyeloablative hematopoietic cell transplantation.

Despite its common use in nonmyeloablative preparative regimens, the pharmacokinetics of fludarabine are poorly characterized in hematopoietic cell transplantation (HCT) recipients and exposure-response relationships remain undefined. The objective of this study was to evaluate the association between plasma F-ara-A exposure, the systemically circulating moiety of fludarabine, and engraftment, acute GVHD, TRM and OS after HCT. The preparative regimen consisted of CY 50 mg/kg/day i.v. day -6; plus fludarabine 30-40 mg/m²/day i.v. on days -6 to -2 and TBI 200 cGy on day -1. F-ara-A pharmacokinetics were carried out with the first dose of fludarabine in 87 adult patients. Median (range) F-ara-A area-under-the-curve (AUC((0-∞))) was 5.0 μg h/mL (2.0-11.0), clearance 15.3 L/h (6.2-36.6), C(min) 55 ng/mL (17-166) and concentration on day(zero) 16.0 ng/mL (0.1-144.1). Despite dose reductions, patients with renal insufficiency had higher F-ara-A exposures. There was strong association between high plasma concentrations of F-ara-A and increased risk of TRM and reduced OS. Patients with an AUC((0-∞)) greater than 6.5 μg h/mL had 4.56 greater risk of TRM and significantly lower OS. These data suggest that clinical strategies are needed to optimize dosing of fludarabine to prevent overexposure and toxicity in HCT

Future X-ray timing missions

Thanks to the Rossi X-ray Timing Explorer (RXTE), it is now widely recognized that fast X-ray timing can be used to probe strong gravity fields around collapsed objects and constrain the equation of state of dense matter in neutron stars. We first discuss some of the outstanding issues which could be solved with an X-ray timing mission building on the great successes of RXTE and providing an order of magnitude better sensitivity. Then we briefly describe the 'Experiment for X-ray timing and Relativistic Astrophysics' (EXTRA) recently proposed to the European Space Agency as a follow-up to RXTE and the related US mission 'Relativistic Astrophysics Explorer' (RAE).Comment: To be published in `Proceedings of the Third Microquasar Workshop: Granada Workshop on galactic relativistic jet sources', Eds A. J. Castro-Tirado, J. Greiner and J. M. Paredes, Astrophysics and Space Science, in press. More about EXTRA can be found at: http://www.cesr.fr/~barret/extra.htm

Increased artery wall stress post-stenting leads to greater intimal thickening

Since the first human procedure in the late 1980s, vascular stent implantation has been accepted as a standard form of treatment of atherosclerosis. Despite their tremendous success, these medical devices are not without their problems, as excessive neointimal hyperplasia can result in the formation of a new blockage (restenosis). Clinical data suggest that stent design is a key factor in the development of restenosis. Additionally, computational studies indicate that the biomechanical environment is strongly dependent on the geometrical configuration of the stent, and therefore possibly involved in the development of restenosis. We hypothesize that stents that induce higher stresses on the artery wall lead to a more aggressive pathobiologic response, as determined by the amount of neointimal hyperplasia. The aim of this investigation was to examine the role of solid biomechanics in the development of restenosis. A combination of computational modeling techniques and in vivo analysis were employed to investigate the pathobiologic response to two stent designs that impose greater or lesser levels of stress on the artery wall. Stent designs were implanted in a porcine model (pigs) for approximately 28 days and novel integrative pathology techniques (quantitative micro-computed tomography, histomorphometry) were utilized to quantify the pathobiologic response. Concomitantly, computational methods were used to quantify the mechanical loads that the two stents place on the artery. Results reveal a strong correlation between the computed stress values induced on the artery wall and the pathobiologic response; the stent that subjected the artery to the higher stresses had significantly more neointimal thickening at stent struts (high stress stent: 0.197 ± 0.020 mm vs. low-stress stent: 0.071 ± 0.016 mm). Therefore, we conclude that the pathobiologic differences are a direct result of the solid biomechanical environment, confirming the hypothesis that stents that impose higher wall stresses will provoke a more aggressive pathobiological response

Coping with metastatic melanoma: the last year of life.

BackgroundFew longitudinal studies have concurrently investigated cognitive appraisal, coping and psychological adjustment in patients with terminal cancer. This study aimed to (i) consider patterns of change in these variables during the last year of life and (ii) consider covariates associated with patients' psychological adjustment.Methods and patientsQuestionnaires were sent to a cohort of stage IV melanoma patients seen at the Sydney Melanoma Unit between 1991 and 1996, approximately every 3 months, for up to 2 years. A sub-sample of 110 patients completed at least one questionnaire in the last year of life. Repeated measures linear regression was used to model cognitive appraisal, coping and psychological adjustment.ResultsIn the last year of life, patients' cognitive appraisal of their disease remained relatively stable, whereas their use of active coping strategies increased (p=0. 04). There was some deterioration in psychological adjustment, particularly in patients' ability to minimize the impact of cancer on daily life (p=0.03), but this effect did not remain significant when patients' level of tiredness was included in the model. Cognitive appraisal, coping style and quality of life indicators were all associated with psychological adjustment.ConclusionThese findings suggest that while patients work hard to actively cope with their disease, they experience increasing levels of tiredness, and deterioration in their mood and ability to function in their daily lives

Adding many Baumgartner clubs

I define a homogeneous ℵ2–c.c. proper product forcing for adding many clubs of ω1 with finite conditions. I use this forcing to build models of b(ω1)=ℵ2, together with d(ω1) and 2ℵ0 large and with very strong failures of club guessing at ω1

Cognitively-inspired Agent-based Service Composition for Mobile & Pervasive Computing

Automatic service composition in mobile and pervasive computing faces many challenges due to the complex and highly dynamic nature of the environment. Common approaches consider service composition as a decision problem whose solution is usually addressed from optimization perspectives which are not feasible in practice due to the intractability of the problem, limited computational resources of smart devices, service host's mobility, and time constraints to tailor composition plans. Thus, our main contribution is the development of a cognitively-inspired agent-based service composition model focused on bounded rationality rather than optimality, which allows the system to compensate for limited resources by selectively filtering out continuous streams of data. Our approach exhibits features such as distributedness, modularity, emergent global functionality, and robustness, which endow it with capabilities to perform decentralized service composition by orchestrating manifold service providers and conflicting goals from multiple users. The evaluation of our approach shows promising results when compared against state-of-the-art service composition models.Comment: This paper will appear on AIMS'19 (International Conference on Artificial Intelligence and Mobile Services) on June 2

Predator-Induced Vertical Behavior of a Ctenophore

Although many studies have focused on Mnemiopsis leidyi predation, little is known about the role of this ctenophore as prey when abundant in native and invaded pelagic systems. We examined the response of the ctenophore M. leidyi to the predatory ctenophore Beroe ovata in an experiment in which the two species could potentially sense each other while being physically separated. On average, M. leidyi responded to the predator’s presence by increasing variability in swimming speeds and by lowering their vertical distribution. Such behavior may help explain field records of vertical migration, as well as stratified and near-bottom distributions of M. leidyi

The magnetic nature of disk accretion onto black holes

Although disk accretion onto compact objects - white dwarfs, neutron stars, and black holes - is central to much of high energy astrophysics, the mechanisms which enable this process have remained observationally elusive. Accretion disks must transfer angular momentum for matter to travel radially inward onto the compact object. Internal viscosity from magnetic processes and disk winds can in principle both transfer angular momentum, but hitherto we lacked evidence that either occurs. Here we report that an X-ray-absorbing wind discovered in an observation of the stellar-mass black hole binary GRO J1655-40 must be powered by a magnetic process that can also drive accretion through the disk. Detailed spectral analysis and modeling of the wind shows that it can only be powered by pressure generated by magnetic viscosity internal to the disk or magnetocentrifugal forces. This result demonstrates that disk accretion onto black holes is a fundamentally magnetic process.Comment: 15 pages, 2 color figures, accepted for publication in Nature. Supplemental materials may be obtained by clicking http://www.astro.lsa.umich.edu/~jonmm/nature1655.p

Using Rasch analysis to form plausible health states amenable to valuation: the development of CORE-6D from CORE-OM in order to elicit preferences for common mental health problems

Purpose: To describe a new approach for deriving a preference-based index from a condition specific measure that uses Rasch analysis to develop health states. Methods: CORE-OM is a 34-item instrument monitoring clinical outcomes of people with common mental health problems. CORE-OM is characterised by high correlation across its domains. Rasch analysis was used to reduce the number of items and response levels in order to produce a set of unidimensionally-behaving items, and to generate a credible set of health states corresponding to different levels of symptom severity using the Rasch item threshold map. Results: The proposed methodology resulted in the development of CORE-6D, a 2-dimensional health state description system consisting of a unidimensionally-behaving 5-item emotional component and a physical symptom item. Inspection of the Rasch item threshold map of the emotional component helped identify a set of 11 plausible health states, which, combined with the physical symptom item levels, will be used for the valuation of the instrument, resulting in the development of a preference-based index. Conclusions: This is a useful new approach to develop preference-based measures where the domains of a measure are characterised by high correlation. The CORE-6D preference-based index will enable calculation of Quality Adjusted Life Years in people with common mental health problems

Enrichment of Two Isomeric Heparin Oligosaccharides Exhibiting Different Affinities toward Monocyte Chemoattractant Protein-1

Chemokine-GAG interactions are crucial to facilitate chemokine immobilization, resulting in the formation of chemokine gradients that guide cell migration. Here we demonstrate chromatographic isolation and purification of two heparin hexasaccharide isomers that interact with the oligomeric chemokine Monocyte Chemoattractant Protein-1 (MCP-1)/CCL2 with different binding affinities. The sequences of these two hexasaccharides were deduced from unique MS/MS product ions and HPLC compositional analysis. Ion mobility mass spectrometry (IM-MS) showed that the two isolated oligosaccharides have different conformations and both displayed preferential binding for one of the two distinct conformations known for MCP-1 dimers. A significant shift in arrival time distribution of close to 70 Å2 was observed, indicating a more compact protein:hexasaccharide conformation. Clear differences in the MS spectra between bound and unbound protein allowed calculation of Kd values from the resulting data. The structural difference between the two hexasaccharides was defined as the differential location of a single sulfate at either C-6 of glucosamine or C-2 of uronic acid in the reducing disaccharide, resulting in a 200-fold difference in binding affinity for MCP-1. These data indicate sequence specificity for high affinity binding, supporting the view that sulfate position, and not simply the number of sulfates, is important for heparan sulfate protein binding