Role and rationale for the use of milnacipran in the management of fibromyalgia

Fibromyalgia (FM) is a complex syndrome characterized by chronic widespread musculoskeletal pain which is often accompanied by multiple other symptoms, including fatigue, sleep disturbances, decreased physical functioning, and dyscognition. Due to these multiple symptoms, as well as high rates of comorbidity with other related disorders, patients with FM often report a reduced quality of life. Although the pathophysiology of FM is not completely understood, patients with FM experience pain differently from the general population, most likely due to dysfunctional pain processing in the central nervous system leading to both hyperalgesia and allodynia. In many patients with FM, this aberrant pain processing, or central sensitization, appears to involve decreased pain inhibition within the spinal tract, which is mediated by descending pathways that utilize serotonin, norepinephrine, and other neurotransmitters. The reduced serotonin and norepinephrine levels observed in patients with FM suggest that medications which increase the levels of these neurotransmitters, such as serotonin and norepinephrine reuptake inhibitors (SNRIs), may have clinically beneficial effects in FM and other chronic pain conditions. Milnacipran is an SNRI that has been approved for the management of FM. In clinical trials, treatment with milnacipran for up to 1 year has been found to improve the pain and other symptoms of FM. Because FM is characterized by multiple symptoms that all contribute to the decreased quality of life and ability to function, the milnacipran pivotal trials implemented responder analyses. These utilized a single composite endpoint to identify the proportion of patients who reported simultaneous and clinically significant improvements in pain, global disease status, and physical function. Other domains assessed during the milnacipran trials include fatigue, multidimensional functioning, mood, sleep quality, and patient-reported dyscognition. This review article provides information intended to help clinicians make informed decisions about the use of milnacipran in the clinical management of patients with FM. It draws primarily on results from 2 of the pivotal clinical trials that formed the basis of approval of milnacipran in the United States by the Food and Drug Administration

The deepest X-ray look at the Universe

The origin of the X-ray background, in particular at hard (2-10 keV) energies, has been a debated issue for more than 30 years. The Chandra deep fields provide the deepest look at the X-ray sky and are the best dataset to study the X-ray background. We searched the Chandra Deep Field South for X-ray sources with the aid of a dedicated wavelet-based algorithm. We are able to reconstruct the Log N-Log S source distribution in the soft (0.5-2 keV) and hard (2-10 keV) bands down to limiting fluxes of 2x10^{-17} erg s^{-1} cm^{-2} and 2x10^{-16} erg s^{-1} cm^{-2}, respectively. These are a factor ~5 deeper than previous investigations. We find that the soft relation continues along the extrapolation from higher fluxes, almost completely accounting for the soft X-ray background. On the contrary, the hard distribution shows a flattening below ~2x10^{-14} erg s^{-1} cm^{-2}. Nevertheless, we can account for >68% of the hard X-ray background, with the main uncertainty being the sky flux itself.Comment: Accepted for publication on ApJL. Two figures, requires emulateapj5 (included

A strongly changing accretion morphology during the outburst decay of the neutron star X-ray binary 4U 1608−52

It is commonly assumed that the properties and geometry of the accretion flow in transient low-mass X-ray binaries (LMXBs) significantly change when the X-ray luminosity decays below ∼10⁻² of the Eddington limit (L_(Edd)). However, there are few observational cases where the evolution of the accretion flow is tracked in a single X-ray binary over a wide dynamic range. In this work, we use NuSTAR and NICER observations obtained during the 2018 accretion outburst of the neutron star LMXB 4U 1608−52, to study changes in the reflection spectrum. We find that the broad Fe–Kα line and Compton hump, clearly seen during the peak of the outburst when the X-ray luminosity is ∼10³⁷ erg s⁻¹ (∼0.05 L_(Edd)), disappear during the decay of the outburst when the source luminosity drops to ∼4.5 × 10³⁵ erg s⁻¹ (∼0.002 L_(Edd)). We show that this non-detection of the reflection features cannot be explained by the lower signal-to-noise ratio at lower flux, but is instead caused by physical changes in the accretion flow. Simulating synthetic NuSTAR observations on a grid of inner disc radius, disc ionization, and reflection fraction, we find that the disappearance of the reflection features can be explained by either increased disc ionization (log ξ ≳ 4.1) or a much decreased reflection fraction. A changing disc truncation alone, however, cannot account for the lack of reprocessed Fe–Kα emission. The required increase in ionization parameter could occur if the inner accretion flow evaporates from a thin disc into a geometrically thicker flow, such as the commonly assumed formation of a radiatively inefficient accretion flow at lower mass accretion rates

Vehicle routing with soft time windows and stochastic travel times : a column generation and branch-and-price solution approach

We study a vehicle routing problem with soft time windows and stochastic travel times. In this problem, we consider stochastic travel times to obtain routes which are both efficient and reliable. In our problem setting, soft time windows allow early and late servicing at customers by incurring some penalty costs. The objective is to minimize the sum of transportation costs and service costs. Transportation costs result from three elements which are the total distance traveled, the number of vehicles used and the total expected overtime of the drivers. Service costs are incurred for early and late arrivals; these correspond to time-window violations at the customers. We apply a column generation procedure to solve this problem. The master problem can be modeled as a classical set partitioning problem. The pricing subproblem, for each vehicle, corresponds to an elementary shortest path problem with resource constraints. To generate an integer solution, we embed our column generation procedure within a branch-and-price method. Computational results obtained by experimenting with well-known problem instances are reported

Could a Local Group X-Ray Halo Affect the X-Ray and Microwave Backgrounds?

Suto et al. (1996, astro-ph/9602061 and ApJ, 461, L33) have suggested that an X-ray halo in the Local Group might explain both the observed low-energy excess in the X-ray background and the quadrupole anisotropy in the cosmic microwave background. Recent observations of poor groups of galaxies by the ROSAT PSPC set reasonable limits on how extensive and dense such a halo could be. The poor groups most similar to the Local Group do not have a detectable halo, and the upper limits of these observations suggest that any Local Group halo would be nearly two orders of magnitude too tenuous to produce the effects Suto et al. (1996) discuss. In particular, the Sunyaev-Zel'dovich effect cannot contribute significantly to the quadrupole anisotropy measured by COBE.Comment: 8 pages, to appear in The Astrophysical Journal Letters, paper can also be obtained at http://hea-www.harvard.edu/~pildis/smio.htm

Development of Ground-testable Phase Fresnel Lenses in Silicon

Diffractive/refractive optics, such as Phase Fresnel Lenses (PFL's), offer the potential to achieve excellent imaging performance in the x-ray and gamma-ray photon regimes. In principle, the angular resolution obtained with these devices can be diffraction limited. Furthermore, improvements in signal sensitivity can be achieved as virtually the entire flux incident on a lens can be concentrated onto a small detector area. In order to verify experimentally the imaging performance, we have fabricated PFL's in silicon using gray-scale lithography to produce the required Fresnel profile. These devices are to be evaluated in the recently constructed 600-meter x-ray interferometry testbed at NASA/GSFC. Profile measurements of the Fresnel structures in fabricated PFL's have been performed and have been used to obtain initial characterization of the expected PFL imaging efficiencies.Comment: Presented at GammaWave05: "Focusing Telescopes in Nuclear Astrophysics", Bonifacio, Corsica, September 2005, to be published in Experimental Astronomy, 8 pages, 3 figure

A Persistent Disk Wind in GRS 1915+105 with NICER

The bright, erratic black hole X-ray binary GRS 1915+105 has long been a target for studies of disk instabilities, radio/infrared jets, and accretion disk winds, with implications that often apply to sources that do not exhibit its exotic X-ray variability. With the launch of NICER, we have a new opportunity to study the disk wind in GRS 1915+105 and its variability on short and long timescales. Here we present our analysis of 39 NICER observations of GRS 1915+105 collected during five months of the mission data validation and verification phase, focusing on Fe XXV and Fe XXVI absorption. We report the detection of strong Fe XXVI in 32 (>80%) of these observations, with another four marginal detections; Fe XXV is less common, but both likely arise in the well-known disk wind. We explore how the properties of this wind depends on broad characteristics of the X-ray lightcurve: mean count rate, hardness ratio, and fractional RMS variability. The trends with count rate and RMS are consistent with an average wind column density that is fairly steady between observations but varies rapidly with the source on timescales of seconds. The line dependence on spectral hardness echoes known behavior of disk winds in outbursts of Galactic black holes; these results clearly indicate that NICER is a powerful tool for studying black hole winds.Comment: Accepted for publication in ApJL. Comments welcom

The resolved fraction of the Cosmic X-ray Background

We present the X-ray source number counts in two energy bands (0.5-2 and 2-10 keV) from a very large source sample: we combine data of six different surveys, both shallow wide field and deep pencil beam, performed with three different satellites (ROSAT, Chandra and XMM-Newton). The sample covers with good statistics the largest possible flux range so far: [2.4*10^-17 - 10^-11] cgs in the soft band and [2.1*10^-16 - 8*10^{-12}]cgs in the hard band. Integrating the flux distributions over this range and taking into account the (small) contribution of the brightest sources we derive the flux density generated by discrete sources in both bands. After a critical review of the literature values of the total Cosmic X--Ray Background (CXB) we conclude that, with the present data, the 94.3%, and 88.8% of the soft and hard CXB can be ascribed to discrete source emission. If we extrapolate the analytical form of the Log N--Log S distribution beyond the flux limit of our catalog in the soft band we find that the flux from discrete sources at ~3*10^-18 cgs is consistent with the entire CXB, whereas in the hard band it accounts for only 93% of the total CXB at most, hinting for a faint and obscured population to arise at even fainter fluxes.Comment: Accepted for publication in Ap