Summary Although low-grade gliomas (LGG) have a less aggressive course than do high-grade gliomas, the outcome of these tumours is ultimately fatal in most patients. Both the tumour and its treatment ...can cause disabling morbidity, particularly of cognitive functions. Because many patients present with seizures only, with no other signs and symptoms, maintenance of quality of life and function constitutes a particular challenge in LGG. The slow growth pattern of most LGG, and the rare radiological true responses despite a favourable clinical response to treatment, interferes with the use of progression-free survival as the primary endpoint in trials. Overall survival as an endpoint brings logistical challenges, and is sensitive to other non-investigational salvage therapies. Clinical trials for LGG need to consider other measures of patient benefit such as cognition, symptom burden, and seizure activity, to establish whether improved survival is reflected in prolonged wellbeing. This Review investigates clinical and imaging endpoints in trials of LGG, and provides response assessment in neuro-oncology (RANO) criteria for non-enhancing tumours. Additionally, other measures for patients with brain tumours that assess outcome are described. Similar considerations are relevant for trials of high-grade gliomas, although for these tumours survival is shorter and survival endpoints generally have more value than they do for LGG.
We present timing models for 20 millisecond pulsars in the Parkes Pulsar Timing Array. The precision of the parameter measurements in these models has been improved over earlier results by using ...longer data sets and modelling the non-stationary noise. We describe a new noise modelling procedure and demonstrate its effectiveness using simulated data. Our methodology includes the addition of annual dispersion measure (DM) variations to the timing models of some pulsars. We present the first significant parallax measurements for PSRs J1024−0719, J1045−4509, J1600−3053, J1603−7202, and J1730−2304, as well as the first significant measurements of some post-Keplerian orbital parameters in six binary pulsars, caused by kinematic effects. Improved Shapiro delay measurements have resulted in much improved pulsar mass measurements, particularly for PSRs J0437−4715 and J1909−3744 with M
p = 1.44 ± 0.07 and 1.47 ± 0.03 M⊙, respectively. The improved orbital period-derivative measurement for PSR J0437−4715 results in a derived distance measurement at the 0.16 per cent level of precision, D = 156.79 ± 0.25 pc, one of the most fractionally precise distance measurements of any star to date.
ABSTRACT
Pulsar timing array projects measure the pulse arrival times of millisecond pulsars for the primary purpose of detecting nanohertz-frequency gravitational waves. The measurements include ...contributions from a number of astrophysical and instrumental processes, which can either be deterministic or stochastic. It is necessary to develop robust statistical and physical models for these noise processes because incorrect models diminish sensitivity and may cause a spurious gravitational wave detection. Here we characterize noise processes for the 26 pulsars in the second data release of the Parkes Pulsar Timing Array using Bayesian inference. In addition to well-studied noise sources found previously in pulsar timing array data sets such as achromatic timing noise and dispersion measure variations, we identify new noise sources including time-correlated chromatic noise that we attribute to variations in pulse scattering. We also identify ‘exponential dip’ events in four pulsars, which we attribute to magnetospheric effects as evidenced by pulse profile shape changes observed for three of the pulsars. This includes an event in PSR J1713+0747, which had previously been attributed to interstellar propagation. We present noise models to be used in searches for gravitational waves. We outline a robust methodology to evaluate the performance of noise models and identify unknown signals in the data. The detection of variations in pulse profiles highlights the need to develop efficient profile domain timing methods.
Gravitational waves are expected to be radiated by supermassive black hole binaries formed during galaxy mergers. A stochastic superposition of gravitational waves from all such binary systems would ...modulate the arrival times of pulses from radio pulsars. Using observations of millisecond pulsars obtained with the Parkes radio telescope, we constrained the characteristic amplitude of this background, Ac,yr, to be <1.0 × 10–15 with 95% confidence. This limit excludes predicted ranges for Ac,yr from current models with 91 to 99.7% probability. We conclude that binary evolution is either stalled or dramatically accelerated by galactic-center environments and that higher-cadence and shorter-wavelength observations would be more sensitive to gravitational waves.
ABSTRACT
Long-term studies of binary millisecond pulsars (MSPs) provide precise tests of strong-field gravity, and can be used to measure neutron-star masses. PSR J1909-3744, a binary MSP has been ...the subject of several pulsar timing analyses. The edge-on orbit enables measurement of its mass using the Shapiro delay; however, there is degeneracy in the sense of the inclination angle, i, and multiple solutions for the longitude of ascending node, Ω. Radio pulsars scintillate due to inhomogeneities in the ionized interstellar medium (IISM). This can result in scintillation arcs in the power spectrum of the dynamic spectrum that can use these to study the interstellar medium and constrain binary pulsar orbits. Here, we study the scintillation of PSR J1909-3744 using observations from the 64-m Parkes Radio Telescope (Murriyang) over ≈13 yr, using techniques to study scintillation in a lower signal-to-noise regime. By monitoring annual and orbital variations of the arc-curvature measurements, we are able to characterize the velocity of the IISM. We find that the statistics of the IISM remained stationary over this time and a slightly anisotropic model (axial ratio ≳1.2) is preferred. We measure the relative distance to a single dominant thin scattering screen at s = 0.49 ± 0.04, or Ds = 590 ± 50 pc, with an angle of anisotropy ζ = 85 ± 6° (East of North) and velocity in the direction of anisotropy VIISM,ζ = 14 ± 10 km s−1. By combining a physical model of the IISM and current pulsar timing results, we also constrain Ω = 225 ± 3° and i = 86.46 ± 0.05°.
ABSTRACT
The main goal of pulsar timing array experiments is to detect correlated signals such as nanohertz-frequency gravitational waves. Pulsar timing data collected in dense monitoring campaigns ...can also be used to study the stars themselves, their binary companions, and the intervening ionized interstellar medium. Timing observations are extraordinarily sensitive to changes in path-length between the pulsar and the Earth, enabling precise measurements of the pulsar positions, distances and velocities, and the shapes of their orbits. Here we present a timing analysis of 25 pulsars observed as part of the Parkes Pulsar Timing Array (PPTA) project over time spans of up to 24 yr. The data are from the second data release of the PPTA, which we have extended by including legacy data. We make the first detection of Shapiro delay in four Southern pulsars (PSRs J1017−7156, J1125−6014, J1545−4550, and J1732−5049), and of parallax in six pulsars. The prominent Shapiro delay of PSR J1125−6014 implies a neutron star mass of Mp = 1.5 ± 0.2 M⊙ (68 per cent credibility interval). Measurements of both Shapiro delay and relativistic periastron advance in PSR J1600−3053 yield a large but uncertain pulsar mass of $M_p = 2.06^{+0.44}_{-0.41}$ M⊙ (68 per cent credibility interval). We measure the distance to PSR J1909−3744 to a precision of 10 lyr, indicating that for gravitational wave periods over a decade, the pulsar provides a coherent baseline for pulsar timing array experiments.
Abstract Since 2005, the standard of care for patients with newly diagnosed glioblastoma (GBM) has consisted of maximal resection followed by radiotherapy plus daily temozolomide (TMZ), followed by ...maintenance TMZ. In patients selected for clinical trials, median overall survival (OS) and progression-free survival (PFS) with this regimen is 15 to 17 months and 6 to 7 months, respectively. There have been various, largely unsuccessful attempts to improve on this standard of care. With the FDA approval of the tumor-treating fields (TTFields) device, Optune, for recurrent GBM (2011), and the more recent EF-14 interim trial results and approval for newly diagnosed GBM patients, several questions have arisen. A roundtable of experts was convened at the 2015 ASCO meeting to engage in an open conversation and debate of the EF-14 results presented at that meeting and their implications for neuro-oncology practice and clinical research. In October 2015, subsequent to the roundtable discussion, TTFields received FDA approval for newly diagnosed GBM.
Abstract
A nanohertz-frequency stochastic gravitational-wave background can potentially be detected through the precise timing of an array of millisecond pulsars. This background produces ...low-frequency noise in the pulse arrival times that would have a characteristic spectrum common to all pulsars and a well-defined spatial correlation. Recently the North American Nanohertz Observatory for Gravitational Waves collaboration (NANOGrav) found evidence for the common-spectrum component in their 12.5 yr data set. Here we report on a search for the background using the second data release of the Parkes Pulsar Timing Array. If we are forced to choose between the two NANOGrav models—one with a common-spectrum process and one without—we find strong support for the common-spectrum process. However, in this paper, we consider the possibility that the analysis suffers from model misspecification. In particular, we present simulated data sets that contain noise with distinctive spectra but show strong evidence for a common-spectrum process under the standard assumptions. The Parkes data show no significant evidence for, or against, the spatially correlated Hellings–Downs signature of the gravitational-wave background. Assuming we did observe the process underlying the spatially uncorrelated component of the background, we infer its amplitude to be
A
=
2.2
−
0.3
+
0.4
×
10
−
15
in units of gravitational-wave strain at a frequency of 1 yr
−1
. Extensions and combinations of existing and new data sets will improve the prospects of identifying spatial correlations that are necessary to claim a detection of the gravitational-wave background.
ABSTRACT
We present the first 2.5 yr of data from the MeerKAT Pulsar Timing Array (MPTA), part of MeerTime, a MeerKAT Large Survey Project. The MPTA aims to precisely measure pulse arrival times from ...an ensemble of 88 pulsars visible from the Southern hemisphere, with the goal of contributing to the search, detection, and study of nanohertz-frequency gravitational waves as part of the International Pulsar Timing Array. This project makes use of the MeerKAT telescope and operates with a typical observing cadence of 2 weeks using the L-band receiver that records data from 856 to 1712 MHz. We provide a comprehensive description of the observing system, software, and pipelines used and developed for the MeerTime project. The data products made available as part of this data release are from the 78 pulsars that had at least 30 observations between the start of the MeerTime programme in February 2019 and October 2021. These include both sub-banded and band-averaged arrival times and the initial timing ephemerides, noise models, and the frequency-dependent standard templates (portraits) used to derive pulse arrival times. After accounting for detected noise processes in the data, the frequency-averaged residuals of 67 of the pulsars achieved a root-mean-square residual precision of $\lt 1 \, \mu \rm {s}$. We also present a novel recovery of the clock correction waveform solely from pulsar timing residuals and an exploration into preliminary findings of interest to the international pulsar timing community. The arrival times, standards, and full Stokes parameter-calibrated pulsar timing archives are publicly available.
Abstract Background Despite the documented survival benefit conferred by neoadjuvant (NAC) and adjuvant chemotherapy (AC), there has been a slow adoption of guideline recommendations for the use of ...perioperative chemotherapy (POC) in patients with muscle-invasive bladder cancer (MIBC). Objective To evaluate temporal trends in POC utilization and identify factors influencing POC delivery in a representative cohort of patients with MIBC. Design, setting, and participants Retrospective cohort study identifying factors associated with receipt of POC and evaluating temporal changes in NAC and AC utilization. We included patients from the National Cancer Data Base (NCDB) with no prior malignancy who ultimately underwent radical cystectomy for ≥cT2/cN0/cM0 MIBC between 2006 and 2010. Outcome measurements and statistical analysis Relationships between demographic and hospital factors and the likelihood of receiving POC were evaluated using Pearson chi-square and Wilcoxon rank-sum tests, and multivariable logistic regression. Temporal changes in NAC and AC use were detected using a linear test of trend. Results and limitations A total of 5692 patients met our inclusion criteria. POC use increased from 29.5% in 2006 to 39.8% in 2010 ( p < 0.001). NAC use increased from 10.1% in 2006 to 20.8% in 2010 ( p = 0.005); AC remained stable between 18.1% and 21.3% ( p = 0.68). Multivariable modeling revealed advanced age, increasing comorbidity, lack of insurance, increased travel distance, geographic location outside the northeastern United States, and lower income as negatively associated with POC receipt (all p < 0.05). Limitations include retrospective design and potential sampling bias, excluding patients treated at non-NCDB facilities. Conclusions POC use for MIBC increased from 2006 to 2010, with this increase disproportionately due to rising NAC utilization. Nonetheless, there is persistent variation in the likelihood of receiving POC secondary to nonclinical factors. Patient summary When retrospectively analyzing a representative cohort of patients undergoing radical cystectomy for muscle-invasive bladder cancer between 2006 and 2010, we noted that preoperative chemotherapy rates increased steadily while use of chemotherapy after surgery remained stable. Factors related to access to care significantly influenced receipt of chemotherapy.
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