ABSTRACT
Emulation of the Global (sky-averaged) 21-cm signal with neural networks has been shown to be an essential tool for physical signal modelling. In this paper, we present globalemu, a Global ...21-cm signal emulator that uses redshift as a character-defining variable alongside a set of astrophysical parameters to estimate the signal brightness temperature. Combined with physically motivated data pre-processing, this makes for a reliable and fast emulator that is relatively insensitive to the network design. globalemu can emulate a high-resolution signal in 1.3 ms in comparison to 133 ms, a factor of 102 improvement, when using the existing public state-of-the-art 21cmGEM. We illustrate, with the standard astrophysical models used to train 21cmGEM, that globalemu is almost twice as accurate and for a test set of ≈1700 signals we achieve a mean root mean squared error of 2.52 mK across the band z = 7–28 ≈10 per cent the expected noise of the Radio Experiment for the Analysis of Cosmic Hydrogen (REACH). The models are parametrized by the star formation efficiency, f*, minimum virial circular velocity, Vc, X-ray efficiency, fX, cosmic microwave background optical depth, τ, the slope and low energy cut-off of the X-ray spectral energy density, α and νmin, respectively, and the mean free path of ionizing photons, Rmfp. globalemu provides a flexible framework for easily emulating updated simulations of the Global signal and in addition the neutral fraction history. The emulator is pip installable and available at https://github.com/htjb/globalemu. globalemu will be used extensively by the REACH collaboration.
Many studies have focused on the role of programmed death receptor ligand 1 (PD-L1) expression in predicting immunotherapy outcomes. Limited clinical data are available regarding the role of ...programmed death receptor 1 (PD-1; the PD-L1 receptor) expressing tumor-infiltrating lymphocytes (TILs) in PD-1/PD-L1 antibody responsiveness. However, preclinical studies demonstrate that TILs expressing PD-1 contribute to tumor immune evasion.
This study analyzed the association between TIL-PD-1 status and outcome after immune checkpoint blockade (ICB) therapy. We evaluated 123 patients with various solid tumors treated with monoclonal antibodies targeting the PD-1/PD-L1 signaling axis. Additionally, 8706 solid tumor specimens were assessed for TIL-PD-1 and tumor mutational burden (TMB) status.
The presence of PD-1-expressing TILs in tumors was associated with increased median progression-free survival (7.0 vs 1.9 months;
= 0.006) and overall survival (18.1 vs 8.0 months;
= 0.04) after treatment with ICB. TIL-PD-1-positive patients had an objective response rate (ORR) of 41% (95% CI, 24-61;
= 12/29) compared with 17% (95% CI, 4-43;
= 3/17) for TIL-PD-1-negative patients (
= 0.18). Analyzed as continuous variables, TIL-PD-1 and TMB showed a weak correlation in 8706 solid tumor samples (Pearson
= 0.074); when analyzed as categorical variables (cutoffs: TIL-PD-1 ≥ 1% and TMB ≥ 10 mutations/Mb), the two variables are correlated (
< 0.0001). TIL-PD-1-positive status is also associated with enrichment of pathologic variants within several genes, most notably
(adjusted
< 0.05).
TIL-PD-1 positivity in tumors (≥ 1%) is associated with significantly longer progression-free and overall survival after ICB.
.
Measurements of thermal neutrons and gamma rays using multiple <inline-formula> <tex-math notation="LaTeX">{\mathrm{ Cs}}_{2}{\mathrm{ LiYCl}}_{6}:{\mathrm{ Ce}}^{3+} </tex-math></inline-formula> ...(CLYC) crystals with photomultiplier tube (PMT) and silicon photomultiplier (SiPM) are compared. The first set of measurements used three single-sided crystals (two made from 95% enriched 6 Li and one made with 99% enriched 7 Li) mated with the PMT and SiPM to compare the energy resolutions and figures of merit (FOM) for the pulse shape discrimination of gamma rays and neutrons. All crystals and photomultipliers were able to resolve full-energy photopeaks for 137 Cs and 60 Co and distinguish gamma-ray interactions from neutron interactions (<inline-formula> <tex-math notation="LaTeX">\text {FOM} > 1 </tex-math></inline-formula> in all cases) while operating in a thermal neutron environment. Measurements made with the PMT had better energy resolution, and switching to the SiPM degraded the energy resolution by an average of 34.0± 0.7% (at 662 keV). The second set of measurements used a CLYC crystal with two optical windows to enable simultaneous measurements with the PMT and SiPM. Once again, both photomultipliers were able to distinguish gamma rays from neutrons, and the PMT had the best energy resolution. However, in this case, the SiPM was not able to resolve the 137 Cs full-energy photopeak, and neither photomultiplier could resolve any photopeaks if 60 Co was used simultaneously. The degradation in energy resolution was due to the relative splitting of scintillation light intensity between each photomultiplier depending on the position of the interaction site within the crystal. Each pair of waveforms recorded from the PMT and SiPM, corresponding to a single interaction within the double-sided crystal, were combined to improve the energy resolution at 662 keV from 15.9 ± 0.9% to 12.7 ± 0.3% and the FOM from 1.850 ± 0.004 to 2.117 ± 0.003 when compared to the data just from the PMT.
Immune checkpoint blockade is effective for only a subset of cancers. Targeting T-cell priming markers (TPMs) may enhance activity, but proper application of these agents in the clinic is challenging ...due to immune complexity and heterogeneity. We interrogated transcriptomics of 15 TPMs (CD137, CD27, CD28, CD80, CD86, CD40, CD40LG, GITR, ICOS, ICOSLG, OX40, OX40LG, GZMB, IFNG, and TBX21) in a pan-cancer cohort (N = 514 patients, 30 types of cancer). TPM expression was analyzed for correlation with histological type, microsatellite instability high (MSI-H), tumor mutational burden (TMB), and programmed death-ligand 1 (PD-L1) expression. Among 514 patients, the most common histological types were colorectal (27%), pancreatic (11%), and breast cancer (10%). No statistically significant association between histological type and TPM expression was seen. In contrast, expression of GZMB (granzyme B, a serine protease stored in activated T and NK cells that induces cancer cell apoptosis) and IFNG (activates cytotoxic T cells) were significantly higher in tumors with MSI-H, TMB ≥ 10 mutations/mb and PD-L1 ≥ 1%. PD-L1 ≥ 1% was also associated with significantly higher CD137, GITR, and ICOS expression. Patients' tumors were classified into "Hot", "Mixed", or "Cold" clusters based on TPM expression using hierarchical clustering. The cold cluster showed a significantly lower proportion of tumors with PD-L1 ≥ 1%. Overall, 502 patients (98%) had individually distinct patterns of TPM expression. Diverse expression patterns of TPMs independent of histological type but correlating with other immunotherapy biomarkers (PD-L1 ≥ 1%, MSI-H and TMB ≥ 10 mutations/mb) were observed. Individualized selection of patients based on TPM immunomic profiles may potentially help with immunotherapy optimization.
An organic glass scintillator developed by Sandia National Laboratories was characterized in terms of its light output and pulse shape discrimination (PSD) properties and compared to commercial ...liquid (EJ-309) and plastic (EJ-276) organic scintillators. The electron light output was determined through relative comparison of the 137Cs Compton edge location. The proton light yield was measured using a double time-of-flight technique at the 88-Inch Cyclotron at Lawrence Berkeley National Laboratory. Using a tunable broad-spectrum neutron source and an array of pulse-shape-discriminating observation scintillators, a continuous measurement of the proton light yield was performed for EJ-309 (200 keV–3.2 MeV), EJ-276 (170 keV–4.9 MeV), and the organic glass (50 keV–20 MeV) . Finally, the PSD properties of the organic glass, EJ-309, and EJ-276 were evaluated using an AmBe source and compared via a figure-of-merit metric. The organic glass exhibited a higher electron light output than both EJ-309 and EJ-276. Its proton light yield and PSD performance were comparable to EJ-309 and superior to that of EJ-276. With these performance characteristics, the organic glass scintillator is well poised to replace current state-of-the-art PSD-capable scintillators in a range of fast neutron detection applications.
Abstract
Objectives
We analyzed test volume data to identify low-value test utilization. We subsequently tracked the efficacy of interventions to improve test utilization by decreasing low-value ...testing.
Methods
Test volume data for analytes included in the Choosing Wisely guidelines were analyzed to identify population outliers. Outliers were defined by test volume ratios of either analyte to sodium or paired analytes to correct for variation in patient volumes at each site. Interventions to improve test utilization were targeted to outlier sites. Relative efficacy in reducing low-value testing was tracked at those sites.
Results
After appropriate data cleaning, test volume ratios for 17 analytes paired with sodium and 8 pairs of analytes were acquired from 108 national sites. A site with abnormally high Clostridium difficile/sodium ratio was selected for intervention, leading to a 71% decrease in C difficile tests. Two different interventions to decrease creatine kinase MB isoform (CKMB) testing were performed at two unique sites with abnormally high CKMB/troponin ratios. These interventions decreased CKMB by 11% and 98% at the different sites, showing the efficacy of the different kinds of interventions.
Conclusions
Test volume ratio analysis and benchmarking enable identification of low-value test utilization.
ABSTRACT
Maximally Smooth Functions (MSFs) are a form of constrained functions in which there are no inflection points or zero crossings in high-order derivatives. Consequently, they have ...applications to signal recovery in experiments where signals of interest are expected to be non-smooth features masked by larger smooth signals or foregrounds. They can also act as a powerful tool for diagnosing the presence of systematics. The constrained nature of MSFs makes fitting these functions a non-trivial task. We introduce maxsmooth, an open-source package that uses quadratic programming to rapidly fit MSFs. We demonstrate the efficiency and reliability of maxsmooth by comparison to commonly used fitting routines and show that we can reduce the fitting time by approximately two orders of magnitude. We introduce and implement with maxsmooth Partially Smooth Functions, which are useful for describing elements of non-smooth structure in foregrounds. This work has been motivated by the problem of foreground modelling in 21-cm cosmology. We discuss applications of maxsmooth to 21-cm cosmology and highlight this with examples using data from the Experiment to Detect the Global Epoch of Reionization Signature (EDGES) and the Large-aperture Experiment to Detect the Dark Ages (LEDA) experiments. We demonstrate the presence of a sinusoidal systematic in the EDGES data with a log-evidence difference of 86.19 ± 0.12 when compared to a pure foreground fit. MSFs are applied to data from LEDA for the first time in this paper and we identify the presence of sinusoidal systematics. maxsmooth is pip installable and available for download at https://github.com/htjb/maxsmooth.
Objectives: The analytical sensitivity of high-sensitivity cardiac troponin T (hsTnT) assays has enabled rapid myocardial infarction rule-out algorithms for emergency department (ED) presentations. ...Few studies have analyzed the real-world impact of hsTnT algorithms on outcomes and operations. Methods: Comparison of ED length of stay (LOS) and 30-day outcomes (return to ED, inpatient admission, and mortality) for patients presenting with chest pain during 2 separate 208-day periods using a 0/1-hour hsTnT-enabled algorithm or fourth-generation TnT. Results: Discharge, 30-day readmission, and 30-day mortality rates were not significantly different with fourth-generation TnT vs hsTnT. Thirty-day return rates were significantly decreased with hsTnT (17.4% vs 14.9%; P <.01). For encounters with TnT measured at least twice and resulting in discharge, median ED LOS decreased by 61 minutes with the use of hsTnT (488 vs 427 minutes; P <.0001). Median time between first and second TnT results decreased by 82 minutes with hsTnT (202 vs 120 minutes; P <.0001), suggesting that the 0/1-hour algorithm was incompletely adopted. Conclusions: Implementation of the hsTnT algorithm was associated with decreased 30-day return rates and decreased ED LOS for a subset of patients, despite incomplete adoption of the 0/1-hour algorithm. KEY WORDS Troponin; Sensitive; Acute myocardial infarction; Cardiac biomarkers
Abstract Background The metacarpophalangeal is commonly affected by rheumatoid arthritis. This may lead to joint replacement with a flexible prosthesis. The aims of this study were to determine the ...effects of rheumatoid arthritis on joint motion and to determine whether joint replacement needs to restore the full range of motion. Methods Three-dimensional motion analysis was used to measure the range of motion of the metacarpophalangeal joint in rheumatoid patients with and without a flexible silicone arthroplasty, when performing pinch and key grips, when making a fist and when spreading the fingers. The results were compared with those from younger and older normal subjects. Findings There appeared to be a trend for a decrease in range of motion from younger normal to older normal to rheumatoid (no prosthesis) to rheumatoid (with prosthesis) subject groups. However, statistically different ( p < 0.05) results were only observed for some movements (mostly involved in making a fist), in some fingers and between some subject groups. The only exception to this apparent trend was in flexion/extension when spreading the fingers into abduction. Interpretation Making a fist is the most sensitive simple measure of range of motion in the metacarpophalangeal joint. Successful replacement of the metacarpophalangeal joint in patients with rheumatoid arthritis need not restore the normal range of motion.
ABSTRACT
Bayesian analysis has become an indispensable tool across many different cosmological fields, including the study of gravitational waves, the cosmic microwave background, and the 21-cm ...signal from the Cosmic Dawn, among other phenomena. The method provides a way to fit complex models to data describing key cosmological and astrophysical signals and a whole host of contaminating signals and instrumental effects modelled with ‘nuisance parameters’. In this paper, we summarize a method that uses masked autoregressive flows and kernel density estimators to learn marginal posterior densities corresponding to core science parameters. We find that the marginal or ‘nuisance-free’ posteriors and the associated likelihoods have an abundance of applications, including the calculation of previously intractable marginal Kullback–Leibler divergences and marginal Bayesian model dimensionalities, likelihood emulation, and prior emulation. We demonstrate each application using toy examples, examples from the field of 21-cm cosmology, and samples from the Dark Energy Survey. We discuss how marginal summary statistics like the Kullback–Leibler divergences and Bayesian model dimensionalities can be used to examine the constraining power of different experiments and how we can perform efficient joint analysis by taking advantage of marginal prior and likelihood emulators. We package our multipurpose code up in the pip-installable code margarine for use in the wider scientific community.
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