Rapid spin changes around a magnetar fast radio burst.

Magnetars are neutron stars with extremely high magnetic fields (≳1014 gauss) that exhibit various X-ray phenomena such as sporadic subsecond bursts, long-term persistent flux enhancements and variable rotation-period derivative1,2. In 2020, a fast radio burst (FRB), akin to cosmological millisecond-duration radio bursts, was detected from the Galactic magnetar SGR 1935+2154 (refs. 3-5), confirming the long-suspected association between some FRBs and magnetars. However, the mechanism for FRB generation in magnetars remains unclear. Here we report the X-ray observation of two glitches in SGR 1935+2154 within a time interval of approximately nine hours, bracketing an FRB that occurred on 14 October 20226,7. Each glitch involved a significant increase in the magnetar's spin frequency, being among the largest abrupt changes in neutron-star rotation8-10 observed so far. Between the glitches, the magnetar exhibited a rapid spin-down phase, accompanied by an increase and subsequent decline in its persistent X-ray emission and burst rate. We postulate that a strong, ephemeral, magnetospheric wind11 provides the torque that rapidly slows the star's rotation. The trigger for the first glitch couples the star's crust to its magnetosphere, enhances the various X-ray signals and spawns the wind that alters magnetospheric conditions that might produce the FRB.

Searching for Gravitational Waves from Cosmological Phase Transitions with the NANOGrav 12.5-Year Dataset.

We search for a first-order phase transition gravitational wave signal in 45 pulsars from the NANOGrav 12.5-year dataset. We find that the data can be modeled in terms of a strong first order phase transition taking place at temperatures below the electroweak scale. However, we do not observe any strong preference for a phase-transition interpretation of the signal over the standard astrophysical interpretation in terms of supermassive black hole mergers; but we expect to gain additional discriminating power with future datasets, improving the signal to noise ratio and extending the sensitivity window to lower frequencies. An interesting open question is how well gravitational wave observatories could separate such signals.

Regulatory and Clinical Experiences with Biosimilar Filgrastim in the U.S., the European Union, Japan, and Canada.

Biosimilar filgrastims are primarily indicated for chemotherapy-induced neutropenia prevention. They are less expensive formulations of branded filgrastim, and biosimilar filgrastim was the first biosimilar oncology drug administered in European Union (EU) countries, Japan, and the U.S. Fourteen biosimilar filgrastims have been marketed in EU countries, Japan, the U.S., and Canada since 2008, 2012, 2015, and 2016, respectively. We reviewed experiences and policies for biosimilar filgrastim markets in EU countries and Japan, where uptake has been rapid, and in the U.S. and Canada, where experience is rapidly emerging. U.S. regulations for designating biosimilar interchangeability are under development, and such regulations have not been developed in most other countries. Pharmaceutical substitution is allowed for new filgrastim starts in some EU countries and in Canada, but not Japan and the U.S. In EU countries, biosimilar adoption is facilitated with favorable hospital tender offers. U.S. adoption is reportedly 24%, while the second filgrastim biosimilar is priced 30% lower than branded filgrastim and 20% lower than the first biosimilar filgrastim approved by the U.S. Food and Drug Administration. Utilization is about 60% in EU countries, where biosimilar filgrastim is marketed at a 30%-40% discount. In Japan, biosimilar filgrastim utilization is 45%, primarily because of 35% discounts negotiated by Central Insurance and hospital-only markets. Overall, biosimilar filgrastim adoption barriers are small in many EU countries and Japan and are diminishing in Canada in the U.S. Policies facilitating improved U.S. adoption of biosimilar filgrastim, based on positive experiences in EU countries and Japan, including favorable insurance coverage; larger price discount relative to reference filgrastim pricing; closing of the "rebate trap" with transparent pricing information; formal educational efforts of patients, physicians, caregivers, and providers; and allowance of pharmaceutical substitution of biosimilar versus reference filgrastim, should be considered. IMPLICATIONS FOR PRACTICE: We reviewed experiences and policies for biosimilar filgrastims in Europe, Japan, Canada, and the U.S. Postmarketing harmonization of regulatory policies for biosimilar filgrastims has not occurred. Acceptance of biosimilar filgrastims for branded filgrastim, increasing in the U.S. and in Canada, is commonplace in Japan and Europe. In the U.S., some factors, accepted in Europe or Japan, could improve uptake, including acceptance of biosimilars as safe and effective; larger cost savings, decreasing "rebate traps" where pharmaceutical benefit managers support branded filgrastim, decreased use of patent litigation/challenges, and allowing pharmacists to routinely substitute biosimilar for branded filgrastim.

A powerful bursting radio source towards the Galactic Centre.

Transient astronomical sources are typically powered by compact objects and usually signify highly explosive or dynamic events. Although high-time-resolution observations are often possible in radio astronomy, they are usually limited to quite narrow fields of view. The dynamic radio sky is therefore poorly sampled, in contrast to the situation in the X-ray and gamma-ray bands in which wide-field instruments routinely detect transient sources. Here we report a transient radio source, GCRT J1745-3009, which was detected during a moderately wide-field monitoring programme of the Galactic Centre region at 0.33 GHz. The characteristics of its bursts are unlike those known for any other class of radio transient. If located in or near the Galactic Centre, its brightness temperature (approximately 10(16) K) and the implied energy density within GCRT J1745-3009 vastly exceed those observed in most other classes of radio astronomical sources, and are consistent with coherent emission processes that are rarely observed. We conclude that it represents a hitherto unknown class of transient radio sources, the first of possibly many new classes that may be discovered by emerging wide-field radio telescopes.

Consequences to patients, clinicians, and manufacturers when very serious adverse drug reactions are identified (1997-2019): A qualitative analysis from the Southern Network on Adverse Reactions (SONAR).

BACKGROUND: Adverse drug/device reactions (ADRs) can result in severe patient harm. We define very serious ADRs as being associated with severe toxicity, as measured on the Common Toxicity Criteria Adverse Events (CTCAE)) scale, following use of drugs or devices with large sales, large financial settlements, and large numbers of injured persons. We report on impacts on patients, clinicians, and manufacturers following very serious ADR reporting. METHODS: We reviewed clinician identified very serious ADRs published between 1997 and 2019. Drugs and devices associated with reports of very serious ADRs were identified. Included drugs or devices had market removal discussed at Food and Drug Advisory (FDA) Advisory Committee meetings, were published by clinicians, had sales > $1 billion, were associated with CTCAE Grade 4 or 5 toxicity effects, and had either >$1 billion in settlements or >1,000 injured patients. Data sources included journals, Congressional transcripts, and news reports. We reviewed data on: 1) timing of ADR reports, Boxed warnings, and product withdrawals, and 2) patient, clinician, and manufacturer impacts. Binomial analysis was used to compare sales pre- and post-FDA Advisory Committee meetings. FINDINGS: Twenty very serious ADRs involved fifteen drugs and one device. Legal settlements totaled $38.4 billion for 753,900 injured persons. Eleven of 18 clinicians (61%) reported harms, including verbal threats from manufacturer (five) and loss of a faculty position (one). Annual sales decreased 94% from $29.1 billion pre-FDA meeting to $4.9 billion afterwards (p<0.0018). Manufacturers of four drugs paid $1.7 billion total in criminal fines for failing to inform the FDA and physicians about very serious ADRs. Following FDA approval, the median time to ADR reporting was 7.5 years (Interquartile range 3,13 years). Twelve drugs received Box warnings and one drug received a warning (median, 7.5 years following ADR reporting (IQR 5,11 years). Six drugs and 1 device were withdrawn from marketing (median, 5 years after ADR reporting (IQR 4,6 years)). INTERPRETATION: Because very serious ADRs impacts are so large, policy makers should consider developing independently funded pharmacovigilance centers of excellence to assist with clinician investigations. FUNDING: This work received support from the National Cancer Institute (1R01 CA102713 (CLB), https://www.nih.gov/about-nih/what-we-do/nih-almanac/national-cancer-institute-nci; and two Pilot Project grants from the American Cancer Society's Institutional Grant Award to the University of South Carolina (IRG-13-043-01) https://www.cancer.org/ (SH; BS).

Enhanced x-ray emission coinciding with giant radio pulses from the Crab Pulsar.

Giant radio pulses (GRPs) are sporadic bursts emitted by some pulsars that last a few microseconds and are hundreds to thousands of times brighter than regular pulses from these sources. The only GRP-associated emission outside of radio wavelengths is from the Crab Pulsar, where optical emission is enhanced by a few percentage points during GRPs. We observed the Crab Pulsar simultaneously at x-ray and radio wavelengths, finding enhancement of the x-ray emission by 3.8 ± 0.7% (a 5.4σ detection) coinciding with GRPs. This implies that the total emitted energy from GRPs is tens to hundreds of times higher than previously known. We discuss the implications for the pulsar emission mechanism and extragalactic fast radio bursts.

Return of the Big Glitcher: NICER timing and glitches of PSR J0537-6910.

PSR J0537-6910, also known as the Big Glitcher, is the most prolific glitching pulsar known, and its spin-induced pulsations are only detectable in X-ray. We present results from analysis of 2.7 years of NICER timing observations, from 2017 August to 2020 April. We obtain a rotation phase-connected timing model for the entire timespan, which overlaps with the third observing run of LIGO/Virgo, thus enabling the most sensitive gravitational wave searches of this potentially strong gravitational wave-emitting pulsar. We find that the short-term braking index between glitches decreases towards a value of 7 or lower at longer times since the preceding glitch. By combining NICER and RXTE data, we measure a long-term braking index n = -1.25 ± 0.01. Our analysis reveals 8 new glitches, the first detected since 2011, near the end of RXTE, with a total NICER and RXTE glitch activity of 8.88 × 10-7 yr-1. The new glitches follow the seemingly unique time-to-next-glitch-glitch-size correlation established previously using RXTE data, with a slope of 5 d µHz-1. For one glitch around which NICER observes two days on either side, we search for but do not see clear evidence of spectral nor pulse profile changes that may be associated with the glitch.

NICER and Fermi GBM Observations of the First Galactic Ultraluminous X-ray Pulsar Swift J0243.6+6124.

Swift J0243.6+6124 is a newly discovered Galactic Be/X-ray binary, revealed in late September 2017 in a giant outburst with a peak luminosity of 2 × 1039(d/7 kpc)2 erg s-1 (0.1-10 keV), with no formerly reported activity. At this luminosity, Swift J0243.6+6124 is the first known galactic ultraluminous X-ray pulsar. We describe Neutron star Interior Composition Explorer (NICER) and Fermi Gamma-ray Burst Monitor (GBM) timing and spectral analyses for this source. A new orbital ephemeris is obtained for the binary system using spin-frequencies measured with GBM and 15-50 keV fluxes measured with the Neil Gehrels Swift Observatory Burst Alert Telescope to model the system's intrinsic spin-up. Power spectra measured with NICER show considerable evolution with luminosity, including a quasi-periodic oscillation (QPO) near 50 mHz that is omnipresent at low luminosity and has an evolving central frequency. Pulse profiles measured over the combined 0.2-100 keV range show complex evolution that is both luminosity and energy dependent. Near the critical luminosity of L ~ 1038 erg s-1, the pulse profiles transition from single-peaked to double peaked, the pulsed fraction reaches a minimum in all energy bands, and the hardness ratios in both NICER and GBM show a turn-over to softening as the intensity increases. This behavior repeats as the outburst rises and fades, indicating two distinct accretion regimes. These two regimes are suggestive of the accretion structure on the neutron star surface transitioning from a Coulomb collisional stopping mechanism at lower luminosities to a radiation-dominated stopping mechanism at higher luminosities. This is the highest observed (to date) value of the critical luminosity, suggesting a magnetic field of B ~ 1013 G.

Economics of Malignant Gliomas: A Critical Review.

PURPOSE: Approximately 18,500 persons are diagnosed with malignant glioma in the United States annually. Few studies have investigated the comprehensive economic costs. We reviewed the literature to examine costs to patients with malignant glioma and their families, payers, and society. METHODS: A total of 18 fully extracted studies were included. Data were collected on direct and indirect costs, and cost estimates were converted to US dollars using the conversion rate calculated from the study's publication date, and updated to 2011 values after adjustment for inflation. A standardized data abstraction form was used. Data were extracted by one reviewer and checked by another. RESULTS: Before approval of effective chemotherapeutic agents for malignant gliomas, estimated total direct medical costs in the United States for surgery and radiation therapy per patient ranged from $50,600 to $92,700. The addition of temozolomide (TMZ) and bevacizumab to glioblastoma treatment regimens has resulted in increased overall costs for glioma care. Although health care costs are now less front-loaded, they have increased over the course of illness. Analysis using a willingness-to-pay threshold of $50,000 per quality-adjusted life-year suggests that the benefits of TMZ fall on the edge of acceptable therapies. Furthermore, indirect medical costs, such as productivity losses, are not trivial. CONCLUSION: With increased chemotherapy use for malignant glioma, the paradigm for treatment and associated out-of-pocket and total medical costs continue to evolve. Larger out-of-pocket costs may influence the choice of chemotherapeutic agents, the economic implications of which should be evaluated prospectively.