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

Durability of Therapeutic Response to Milnacipran Treatment for Fibromyalgia. Results of a Randomized, Double-Blind, Monotherapy 6-Month Extension Study

To evaluate the durability of improvement and long-term efficacy of milnacipran treatment in fibromyalgia, to assess efficacy in patients re-randomized from placebo to milnacipran, and to collect additional information on the tolerability and efficacy of long-term treatment with milnacipran.A total of 449 patients who successfully completed a 6-month lead-in study enrolled in this 6-month extension study (87.7% of eligible subjects). Patients initially receiving milnacipran 200 mg/day during the lead-in study were maintained at 200 mg/day (n = 209); patients initially assigned to placebo or milnacipran 100 mg/day were re-randomized (1:4) to either 100 mg/day (n = 48) or 200 mg/day (n = 192) of milnacipran for an additional 6 months of treatment. Efficacy assessments included visual analog scale pain ratings, Fibromyalgia Impact Questionnaire (FIQ) total score, and Patient Global Impression of Change (PGIC).Patients continuing on milnacipran demonstrated a sustained reduction in pain over the full 12-month period. Additional beneficial effects were also maintained, as indicated by the PGIC and FIQ. Patients initially assigned to either placebo or milnacipran 100 mg/day in the lead-in study and subsequently re-randomized to milnacipran 200 mg/day in the extension study experienced further improvements in their mean pain scores, FIQ total scores, and PGIC ratings at 1 year. Milnacipran treatment was generally well tolerated. The most commonly reported newly emergent adverse event was nausea.In addition to confirming that milnacipran safely and effectively improves the multiple symptoms of fibromyalgia, these data indicate that milnacipran provides 1-year durable efficacy in this patient population.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/78636/1/j.1526-4637.2009.00755.x.pd

Rapid accretion state transitions following the tidal disruption event AT2018fyk

Following a tidal disruption event (TDE), the accretion rate can evolve from quiescent to near-Eddington levels and back over months - years timescales. This provides a unique opportunity to study the formation and evolution of the accretion flow around supermassive black holes (SMBHs). We present two years of multi-wavelength monitoring observations of the TDE AT2018fyk at X-ray, UV, optical and radio wavelengths. We identify three distinct accretion states and two state transitions between them. These appear remarkably similar to the behaviour of stellar-mass black holes in outburst. The X-ray spectral properties show a transition from a soft (thermal-dominated) to a hard (power-law dominated) spectral state around L$_{\rm bol} \sim$few $\times 10^{-2}$ L$_{\rm Edd}$, and the strengthening of the corona over time $\sim$100--200 days after the UV/optical peak. Contemporaneously, the spectral energy distribution (in particular, the UV-to-X-ray spectral slope $\alpha_{ox}$) shows a pronounced softening as the outburst progresses. The X-ray timing properties also show a marked change, initially dominated by variability at long ($>$day) timescales while a high frequency ($\sim$10$^{-3}$ Hz) component emerges after the transition into the hard state. At late times ($\sim$500 days after peak), a second accretion state transition occurs, from the hard into the quiescent state, as identified by the sudden collapse of the bolometric (X-ray+UV) emission to levels below 10$^{-3.4}$ L$_{\rm Edd}$. Our findings illustrate that TDEs can be used to study the scale (in)variance of accretion processes in individual SMBHs. Consequently, they provide a new avenue to study accretion states over seven orders of magnitude in black hole mass, removing limitations inherent to commonly used ensemble studies.Comment: Accepted version following referee comments. 2 new figures compared to previous arxiv version (Figs 9 and 10). Data will be available from the journal webpages, or upon request to the author

Optical Identification of the Hardest X-ray Source in the ASCA Large Sky Survey

We report the optical identification of the hardest X-ray source (AX J131501+3141) detected in an unbiased wide-area survey in the 0.5--10 keV band, the ASCA Large Sky Survey. The X-ray spectrum of the source is very hard and is well reproduced by a power-law component (Gamma = 1.5^+0.7_-0.6) with N_H = 6^+4_-2 *10^22 cm^-2 (Sakano et al. 1998). We have found a galaxy with R=15.62 mag near the center of the error circle for the X-ray source. The optical spectrum of the galaxy shows only narrow emission lines whose ratios correspond to those of a type 2 Seyfert galaxy at z = 0.072, implying an absorption-corrected X-ray luminosity of 2*10^43 erg sec^-1 (2--10 keV) and M_B = -20.93 mag. A radio point source is also associated with the center of the galaxy. We thus identify the X-ray source with this galaxy as an obscured AGN. The hidden nature of the nucleus of the galaxy in the optical band is consistent with the X-ray spectrum. These results support the idea that the obscured AGNs/QSOs contribute significantly to the cosmic X-ray background in the hard band at the faint flux level.Comment: 20 pages with 5 postscript figures, uses aaspp4.sty, Ap.J. Accepte

NICER X-ray Observations of Eta Carinae During its Most Recent Periastron Passage

We report high-precision X-ray monitoring observations in the 0.4-10 keV band of the luminous, long-period colliding-wind binary Eta Carinae up to and through its most recent X-ray minimum/periastron passage in February 2020. Eta Carinae reached its observed maximum X-ray flux on 7 January 2020, at a flux level of $3.30 \times 10^{-10}$ ergs s$^{-1}$ cm$^{-2}$, followed by a rapid plunge to its observed minimum flux, $0.03 \times 10^{-10}$ ergs s$^{-1}$ cm$^{-2}$ near 17 February 2020. The NICER observations show an X-ray recovery from minimum of only $\sim$16 days, the shortest X-ray minimum observed so far. We provide new constraints of the "deep" and "shallow" minimum intervals. Variations in the characteristic X-ray temperature of the hottest observed X-ray emission indicate that the apex of the wind-wind "bow shock" enters the companion's wind acceleration zone about 81 days before the start of the X-ray minimum. There is a step-like increase in column density just before the X-ray minimum, probably associated with the presence of dense clumps near the shock apex. During recovery and after, the column density shows a smooth decline, which agrees with previous $N_{H}$ measurements made by SWIFT at the same orbital phase, indicating that changes in mass-loss rate are only a few percent over the two cycles. Finally, we use the variations in the X-ray flux of the outer ejecta seen by NICER to derive a kinetic X-ray luminosity of the ejecta of $\sim 10^{41}$ ergs s$^{-1}$ near the time of the "Great Eruption'

SEXTANT X-Ray Pulsar Navigation Demonstration: Additional On-Orbit Results

The Station Explorer for X-ray Timing and Navigation Technology (SEXTANT) is a technology demonstration enhancement to the Neutron-star Interior Composition Explorer (NICER) mission, a NASA Astrophysics Explorer Mission of Opportunity to the International Space Station, launched in June of 2017. In late 2017, SEXTANT successfully completed a first demonstration of in-space and autonomous X-ray pulsar navigation (XNAV). This form of navigation relies on processing faint signals from millisecond pulsars-rapidly rotating neutron stars that appear to pulsate in the X-ray band-and could potentially provide a GPS-like navigation capability applicable throughout the solar-system and beyond. In this work, we briefly review prior SEXTANT results and then present new results focusing on: making use of the high- flux but rotationally unstable Crab pulsar, and using XNAV to estimate position, velocity, and time in the presence of an imperfect local clock

A Comprehensive X-ray Report on AT2019wey

The Galactic low-mass X-ray binary AT2019wey (ATLAS19bcxp, SRGA J043520.9+552226, SRGE J043523.3+552234, ZTF19acwrvzk) was discovered as a new optical transient in Dec 2019, and independently as an X-ray transient in Mar 2020. In this paper, we present comprehensive NICER, NuSTAR, Chandra, Swift, and MAXI observations of AT2019wey from ~1 year prior to the discovery to the end of September 2020. AT2019wey appeared as a ~1 mCrab source and stayed at this flux density for several months, displaying a hard X-ray spectrum that can be modeled as a power-law with photon index Gamma~1.8. In June 2020 it started to brighten, and reached ~20 mCrab in ~2 months. The inclination of this system can be constrained to i≾30 deg by modeling the reflection spectrum. Starting from late-August (~59082 MJD), AT2019wey entered into the hard-intermediate state (HIMS), and underwent a few week-long timescale outbursts, where the brightening in soft X-rays is correlated with the enhancement of a thermal component. Low-frequency quasi-periodic oscillation (QPO) was observed in the HIMS. We detect no pulsation and in timing analysis of the NICER and NuSTAR data. The X-ray states and power spectra of AT2019wey are discussed against the landscape of low-mass X-ray binaries

STROBE-X: A probe-class mission for x-ray spectroscopy and timing on timescales from microseconds to years

We describe the Spectroscopic Time-Resolving Observatory for Broadband Energy X-rays (STROBE-X), a probeclass mission concept that will provide an unprecedented view of the X-ray sky, performing timing and spectroscopy over both a broad energy band (0.2-30 keV) and a wide range of timescales from microseconds to years. STROBE-X comprises two narrow-field instruments and a wide field monitor. The soft or low-energy band (0.2-12 keV) is covered by an array of lightweight optics (3-m focal length) that concentrate incident photons onto small solid-state detectors with CCD-level (85-175 eV) energy resolution, 100 ns time resolution, and low background rates. This technology has been fully developed for NICER and will be scaled up to take advantage of the longer focal length of STROBE-X. The higher-energy band (2-30 keV) is covered by large-area, collimated silicon drift detectors that were developed for the European LOFT mission concept. Each instrument will provide an order of magnitude improvement in effective area over its predecessor (NICER in the soft band and RXTE in the hard band). Finally, STROBE-X offers a sensitive wide-field monitor (WFM), both to act as a trigger for pointed observations of X-ray transients and also to provide high duty-cycle, high time-resolution, and high spectral-resolution monitoring of the variable X-ray sky. The WFM will boast approximately 20 times the sensitivity of the RXTE All-Sky Monitor, enabling multi-wavelength and multi-messenger investigations with a large instantaneous field of view. This mission concept will be presented to the 2020 Decadal Survey for consideration

SEXTANT X-Ray Pulsar Navigation Demonstration: Additional On-Orbit Results

No abstract availabl