Meta-analysis of stomatitis in clinical studies of everolimus: incidence and relationship with efficacy.

BackgroundEverolimus, an oral mammalian target of rapamycin (mTOR) inhibitor, is used to treat solid tumors and tuberous sclerosis complex (TSC). Stomatitis, an inflammation of the mucous membranes of the mouth, is a common adverse event associated with mTOR inhibitors, including everolimus. We conducted a meta-analysis of data from seven randomized, double-blind phase 3 clinical trials of everolimus to determine the clinical impact of stomatitis on efficacy and safety.Patients and methodsData were pooled from the safety sets of solid tumor [breast cancer (BOLERO-2 and BOLERO-3), renal cell carcinoma (RECORD-1), carcinoid tumors (RADIANT-2), and pancreatic neuroendocrine tumors (RADIANT-3)] and TSC studies (EXIST-1 and EXIST-2). Data from solid tumor trials and TSC trials were analyzed separately.ResultsThe rate of stomatitis was 67% in the solid tumor trials (973/1455 patients) and 70% in the TSC trials (110/157 patients). Most stomatitis events were grade 1/2, with grade 3/4 events reported in only 9% (solid tumor trials) and 8% (TSC trials) of patients. Low TSC patient numbers prevented an in-depth evaluation of stomatitis and response. In the solid tumor trials, most first stomatitis episodes (89%; n = 870) were observed within 8 weeks of starting everolimus. Patients with stomatitis occurring within 8 weeks of everolimus initiation had longer progression-free survival (PFS) than everolimus-treated patients without stomatitis in BOLERO-2 {8.5 versus 6.9 months, respectively; hazard ratio (HR), 0.78 [95% confidence interval (CI), 0.62-1.00]} and RADIANT-3 [13.9 versus 8.3 months, respectively; HR, 0.70 (95% CI, 0.48-1.04)]. A similar trend was observed in RECORD-1 [HR, 0.90 (95% CI, 0.66-1.22)] and RADIANT-2 [HR, 0.87 (95% CI, 0.61-1.22)] but not in BOLERO-3 [HR, 1.01 (95% CI, 0.75-1.36)].ConclusionsStomatitis did not adversely affect PFS, supporting the administration of everolimus in accordance with standard management guidelines

Investigation of the Effects of Autorotative Flare Index Variation on Helicopter Flight Dynamics in Autorotation

Autorotation is a flight condition whereby the engine of a helicopter is no longer supplying power to the main rotor system, which is driven solely by the upward flow of the air moving through the rotor. For helicopters, autorotation is a common emergency procedure performed by pilots to safely land the vehicle in the event of a power failure or tail-rotor failure. In the classic analysis of dynamic stability of helicopters in powered flight, it is common practice to neglect the effect of variation of rotor angular velocity, as the rotorspeed is constant. However, this assumption is no longer justified in case of autorotative flight. Therefore, the rotorspeed becomes an additional degree-of-freedom in autorotation, giving rise to a new stability mode that couples with classical rigid-body modes. The present paper aims at understanding the role of the rotorspeed degree-of-freedom in modifying the stability characteristics in autorotation of rotor systems with different autorotative flare indexes. Results show that the helicopter dynamics are considerably affected in autorotation as a consequence of the fact that the rotorspeed degree of freedom couples with the heave subsidence mode. Therefore, autorotation requires a different control strategy by the pilot and should not be mistakenly considered only as an energy management task. Furthermore, the autorotative flare index, used to characterize the autorotative performance during the preliminary design phase of a new helicopter, provides only energy information. Indeed, this paper demonstrates that high values of this index, representative of good autorotative performance in terms of available energy over required energy, may lead to degraded stability characteristics of the helicopter in autorotation.Control & Simulatio

Quantum critical transport, duality, and M-theory

We consider charge transport properties of 2+1 dimensional conformal field theories at non-zero temperature. For theories with only Abelian U(1) charges, we describe the action of particle-vortex duality on the hydrodynamic-to-collisionless crossover function: this leads to powerful functional constraints for self-dual theories. For the n=8 supersymmetric, SU(N) Yang-Mills theory at the conformal fixed point, exact hydrodynamic-to-collisionless crossover functions of the SO(8) R-currents can be obtained in the large N limit by applying the AdS/CFT correspondence to M-theory. In the gravity theory, fluctuating currents are mapped to fluctuating gauge fields in the background of a black hole in 3+1 dimensional anti-de Sitter space. The electromagnetic self-duality of the 3+1 dimensional theory implies that the correlators of the R-currents obey a functional constraint similar to that found from particle-vortex duality in 2+1 dimensional Abelian theories. Thus the 2+1 dimensional, superconformal Yang Mills theory obeys a "holographic self duality" in the large N limit, and perhaps more generally.Comment: 35 pages, 4 figures; (v2) New appendix on CFT2, corrected normalization of gauge field action, added ref

Some closure operations in Zariski-Riemann spaces of valuation domains: a survey

In this survey we present several results concerning various topologies that were introduced in recent years on spaces of valuation domains

ABJM theory as a Fermi gas

The partition function on the three-sphere of many supersymmetric Chern-Simons-matter theories reduces, by localization, to a matrix model. We develop a new method to study these models in the M-theory limit, but at all orders in the 1/N expansion. The method is based on reformulating the matrix model as the partition function of an ideal Fermi gas with a non-trivial, one-particle quantum Hamiltonian. This new approach leads to a completely elementary derivation of the N^{3/2} behavior for ABJM theory and N=3 quiver Chern-Simons-matter theories. In addition, the full series of 1/N corrections to the original matrix integral can be simply determined by a next-to-leading calculation in the WKB or semiclassical expansion of the quantum gas, and we show that, for several quiver Chern-Simons-matter theories, it is given by an Airy function. This generalizes a recent result of Fuji, Hirano and Moriyama for ABJM theory. It turns out that the semiclassical expansion of the Fermi gas corresponds to a strong coupling expansion in type IIA theory, and it is dual to the genus expansion. This allows us to calculate explicitly non-perturbative effects due to D2-brane instantons in the AdS background.Comment: 52 pages, 11 figures. v3: references, corrections and clarifications added, plus a footnote on the relation to the recent work by Hanada et a

A Comparison of the Dynamics of S100B, S100A1, and S100A6 mRNA Expression in Hippocampal CA1 Area of Rats during Long-Term Potentiation and after Low-Frequency Stimulation

The interest in tissue- and cell-specific S100 proteins physiological roles in the brain remains high. However, necessary experimental data for the assessment of their dynamics in one of the most important brain activities, its plasticity, is not sufficient. We studied the expression of S100B, S100A1, and S100A6 mRNA in the subfield CA1 of rat hippocampal slices after tetanic and low-frequency stimulation by real-time PCR. Within 30 min after tetanization, a 2–4 fold increase of the S100B mRNA level was observed as compared to the control (intact slices) or to low-frequency stimulation. Subsequently, the S100B mRNA content gradually returned to baseline. The amount of S100A1 mRNA gradually increased during first hour and maintained at the achieved level in the course of second hour after tetanization. The level of S100A6 mRNA did not change following tetanization or low-frequency stimulation

Altered Gating of K\u3csub\u3ev\u3c/sub\u3e1.4 in the Nucleus Accumbens Suppresses Motivation for Reward

Deficient motivation contributes to numerous psychiatric disorders, including withdrawal from drug use, depression, schizophrenia, and others. Nucleus accumbens (NAc) has been implicated in motivated behavior, but it remains unclear whether motivational drive is linked to discrete neurobiological mechanisms within the NAc. To examine this, we profiled cohorts of Sprague-Dawley rats in a test of motivation to consume sucrose. We found that substantial variability in willingness to exert effort for reward was not associated with operant responding under low-effort conditions or stress levels. Instead, effort-based motivation was mirrored by a divergent NAc shell transcriptome with differential regulation at potassium and dopamine signaling genes. Functionally, motivation was inversely related to excitability of NAc principal neurons. Furthermore, neuronal and behavioral outputs associated with low motivation were linked to faster inactivation of a voltage-gated potassium channel, Kv1.4. These results raise the prospect of targeting Kv1.4 gating in psychiatric conditions associated with motivational dysfunction

Maximum Likelihood Estimator for Hidden Markov Models in continuous time

The paper studies large sample asymptotic properties of the Maximum Likelihood Estimator (MLE) for the parameter of a continuous time Markov chain, observed in white noise. Using the method of weak convergence of likelihoods due to I.Ibragimov and R.Khasminskii, consistency, asymptotic normality and convergence of moments are established for MLE under certain strong ergodicity conditions of the chain.Comment: Warning: due to a flaw in the publishing process, some of the references in the published version of the article are confuse

HIV and hepatitis C virus infections among hanka injection drug users in central Ukraine: a cross-sectional survey

<p>Abstract</p> <p>Background</p> <p>Ukraine has experienced an increase in injection drug use since the 1990s. An increase in HIV and hepatitis C virus infections has followed, but not measures of prevalence and risk factors. The purposes of this study are to estimate the prevalence of HIV, HCV, and co-infection among injection drug users (IDUs) in central Ukraine and to describe risk factors for HIV and HCV.</p> <p>Methods</p> <p>A sample of 315 IDUs was recruited using snowball sampling for a structured risk interview and HIV/HCV testing (81.9% male, 42% single, average age 28.9 years [range = 18 to 55]).</p> <p>Results</p> <p>HIV and HCV antibodies were detected in 14.0% and 73.0%, respectively, and 12.1% were seropositive for both infections. The most commonly used drug was hanka, home-made from poppy straw and often mixed with other substances including dimedrol, diazepines, and hypnotics. The average period of injecting was 8.5 years; 62.5% reported past-year sharing needles or injection equipment, and 8.0% shared with a known HIV-positive person. More than half (51.1%) reported multiple sexual partners, 12.9% buying or selling sex, and 10.5% exchanging sex and drugs in the past year. Those who shared with HIV positive partners were 3.4 times more likely to be HIV positive than those who did not. Those who front- or back-loaded were 4 times more likely to be HCV positive than those who did not.</p> <p>Conclusion</p> <p>Harm reduction, addiction treatment and HIV prevention programs should address risk factors to stop further spread of both HIV and HCV among IDUs and to the general population in central Ukraine.</p