Immune checkpoint blockade with Programmed cell death 1 (PD-1)/PD-L1 inhibitors has been effective in various malignancies and is considered as a standard treatment modality for patients with ...non-small-cell lung cancer (NSCLC). However, emerging evidence show that PD-1/PD-L1 blockade can lead to hyperprogressive disease (HPD), a flair-up of tumor growth linked to dismal prognosis. This study aimed to evaluate the incidence of HPD and identify the determinants associated with HPD in patients with NSCLC treated with PD-1/PD-L1 blockade.
We enrolled patients with recurrent and/or metastatic NSCLC treated with PD-1/PD-L1 inhibitors between April 2014 and November 2018. Clinicopathologic variables, dynamics of tumor growth, and treatment outcomes were analyzed in patients with NSCLC who received PD-1/PD-L1 blockade. HPD was defined according to tumor growth kinetics (TGK), tumor growth rate (TGR), and time to treatment failure (TTF). Immunophenotyping of peripheral blood CD8+ T lymphocytes was conducted to explore the potential predictive biomarkers of HPD.
A total of 263 patients were analyzed. HPD was observed in 55 (20.9%), 54 (20.5%), and 98 (37.3%) patients according to the TGK, TGR, and TTF. HPD meeting both TGK and TGR criteria was associated with worse progression-free survival hazard ratio (HR) 4.619; 95% confidence interval (CI) 2.868–7.440 and overall survival (HR, 5.079; 95% CI, 3.136–8.226) than progressive disease without HPD. There were no clinicopathologic variables specific for HPD. In the exploratory biomarker analysis with peripheral blood CD8+ T lymphocytes, a lower frequency of effector/memory subsets (CCR7−CD45RA− T cells among the total CD8+ T cells) and a higher frequency of severely exhausted populations (TIGIT+ T cells among PD-1+CD8+ T cells) were associated with HPD and inferior survival rate.
HPD is common in NSCLC patients treated with PD-1/PD-L1 inhibitors. Biomarkers derived from rationally designed analysis may successfully predict HPD and worse outcomes, meriting further investigation of HPD.
ABSTRACT
We present an improved measurement of the Hubble constant (H0) using the ‘inverse distance ladder’ method, which adds the information from 207 Type Ia supernovae (SNe Ia) from the Dark ...Energy Survey (DES) at redshift 0.018 < z < 0.85 to existing distance measurements of 122 low-redshift (z < 0.07) SNe Ia (Low-z) and measurements of Baryon Acoustic Oscillations (BAOs). Whereas traditional measurements of H0 with SNe Ia use a distance ladder of parallax and Cepheid variable stars, the inverse distance ladder relies on absolute distance measurements from the BAOs to calibrate the intrinsic magnitude of the SNe Ia. We find H0 = 67.8 ± 1.3 km s−1 Mpc−1 (statistical and systematic uncertainties, 68 per cent confidence). Our measurement makes minimal assumptions about the underlying cosmological model, and our analysis was blinded to reduce confirmation bias. We examine possible systematic uncertainties and all are below the statistical uncertainties. Our H0 value is consistent with estimates derived from the Cosmic Microwave Background assuming a ΛCDM universe.
We report the results from a search for z > 6.5 quasars using the Dark Energy Survey (DES) Year 3 data set combined with the VISTA Hemisphere Survey (VHS) and WISE All-Sky Survey. Our photometric ...selection method is shown to be highly efficient in identifying clean samples of high-redshift quasars, leading to spectroscopic confirmation of three new quasars – VDES J0244-5008 (z = 6.724), VDES J0020-3653 (z = 6.834), and VDES J0246-5219 (z = 6.90) – which were selected as the highest priority candidates in the survey data without any need for additional follow-up observations. Here, we have obtained spectroscopic observations in the near-infrared for VDES J0244-5008 and VDES J0020-3653 as well as our previously identified quasar, VDES J0224-4711 at z = 6.50 from Reed et al. We use the near-infrared spectra to derive virial black hole masses from the full width at half-maximum of the Mg ii line. These black hole masses are ≃1–2 × 109 M⊙. Combined with the bolometric luminosities of these quasars of Lbol ≃ 1–3 × 1047, these imply that the Eddington ratios are high, ≃0.6–1.1. We consider the C iv emission line properties of the sample and demonstrate that our high-redshift quasars do not have unusual C iv line properties when compared to carefully matched low-redshift samples. Our new DES + VHS z > 6.5 quasars now add to the growing census of luminous, rapidly accreting supermassive black holes seen well into the epoch of reionization.
Pressure-driven shock waves in solid materials can cause extreme damage and deformation. Understanding this deformation and the associated defects that are created in the material is crucial in the ...study of a wide range of phenomena, including planetary formation and asteroid impact sites, the formation of interstellar dust clouds, ballistic penetrators, spacecraft shielding and ductility in high-performance ceramics. At the lattice level, the basic mechanisms of plastic deformation are twinning (whereby crystallites with a mirror-image lattice form) and slip (whereby lattice dislocations are generated and move), but determining which of these mechanisms is active during deformation is challenging. Experiments that characterized lattice defects have typically examined the microstructure of samples after deformation, and so are complicated by post-shock annealing and reverberations. In addition, measurements have been limited to relatively modest pressures (less than 100 gigapascals). In situ X-ray diffraction experiments can provide insights into the dynamic behaviour of materials, but have only recently been applied to plasticity during shock compression and have yet to provide detailed insight into competing deformation mechanisms. Here we present X-ray diffraction experiments with femtosecond resolution that capture in situ, lattice-level information on the microstructural processes that drive shock-wave-driven deformation. To demonstrate this method we shock-compress the body-centred-cubic material tantalum-an important material for high-energy-density physics owing to its high shock impedance and high X-ray opacity. Tantalum is also a material for which previous shock compression simulations and experiments have provided conflicting information about the dominant deformation mechanism. Our experiments reveal twinning and related lattice rotation occurring on the timescale of tens of picoseconds. In addition, despite the common association between twinning and strong shocks, we find a transition from twinning to dislocation-slip-dominated plasticity at high pressure (more than 150 gigapascals), a regime that recovery experiments cannot accurately access. The techniques demonstrated here will be useful for studying shock waves and other high-strain-rate phenomena, as well as a broad range of processes induced by plasticity.
We estimate total mass (M500), intracluster medium (ICM) mass (MICM), and stellar mass (M*) in a Sunyaev–Zel’dovich effect (SZE) selected sample of 91 galaxy clusters with masses M500 ≳ 2.5 × 1014 M⊙ ...and redshift 0.2 < z < 1.25 from the 2500 deg^2 South Pole Telescope SPT-SZ survey. The total masses M500 are estimatedfrom the SZE observable, the ICM masses MICM are obtained from the analysis of Chandra X-ray observations, and the stellar masses M* are derived by fitting spectral energy distribution templates to Dark Energy Survey griz optical photometry and WISE or Spitzer near-infrared photometry. We study trends in the stellar mass, the ICM mass, the total baryonic mass, and the cold baryonic fraction with cluster halo mass and redshift. We find significant departures from self-similarity in the mass scaling for all quantities, while the redshift trends are all statistically consistent with zero, indicating that the baryon content of clusters at fixed mass has changed remarkably little over the past ≈9 Gyr. We compare our results to the mean baryon fraction (and the stellar mass fraction) in the field, finding that these values lie above (below) those in cluster virial regions in all but the most massive clusters at low redshift. Using a simple model of the matter assembly of clusters from infalling groups with lower masses and from infalling material from the low-density environment or field surrounding the parent haloes, we show that the measured mass trends without strong redshift trends in the stellar mass scaling relation could be explained by a mass and redshift dependent fractional contribution from field material. Similar analyses of the ICM and baryon mass scaling relations provide evidence for the so-called ‘missing baryons’ outside cluster virial regions.
ABSTRACT
We implement the first blind analysis of cluster abundance data to derive cosmological constraints from the abundance and weak lensing signal of redMaPPer clusters in the Sloan Digital Sky ...Survey (SDSS). We simultaneously fit for cosmological parameters and the richness–mass relation of the clusters. For a flat Λ cold dark matter cosmological model with massive neutrinos, we find $S_8 \equiv \sigma _{8}(\Omega _\mathrm{ m}/0.3)^{0.5}=0.79^{+0.05}_{-0.04}$. This value is both consistent and competitive with that derived from cluster catalogues selected in different wavelengths. Our result is also consistent with the combined probes analyses by the Dark Energy Survey (DES), the Kilo-Degree Survey (KiDS), and with the cosmic microwave background (CMB) anisotropies as measured by Planck. We demonstrate that the cosmological posteriors are robust against variation of the richness–mass relation model and to systematics associated with the calibration of the selection function. In combination with baryon acoustic oscillation data and big bang nucleosynthesis data (Cooke et al.), we constrain the Hubble rate to be h = 0.66 ± 0.02, independent of the CMB. Future work aimed at improving our understanding of the scatter of the richness–mass relation has the potential to significantly improve the precision of our cosmological posteriors. The methods described in this work were developed for use in the forthcoming analysis of cluster abundances in the DES. Our SDSS analysis constitutes the first part of a staged-unblinding analysis of the full DES data set.
We present the first demonstration of THz driven bunch compression and timing stabilization of a relativistic electron beam. Quasi-single-cycle strong field THz radiation is used in a shorted ...parallel-plate structure to compress a few-fC beam with 2.5 MeV kinetic energy by a factor of 2.7, producing a 39 fs rms bunch length and a reduction in timing jitter by more than a factor of 2 to 31 fs rms. This THz driven technique offers a significant improvement to beam performance for applications like ultrafast electron diffraction, providing a critical step towards unprecedented timing resolution in ultrafast sciences, and other accelerator applications using femtosecond-scale electron beams.
We present the analysis underpinning the measurement of cosmological parameters from 207 spectroscopically classified SNe Ia from the first 3 years of the Dark Energy Survey Supernova Program ...(DES-SN), spanning a redshift range of 0.017 < z < 0.849. We combine the DES-SN sample with an external sample of 122 low-redshift (z < 0.1) SNe Ia, resulting in a "DES-SN3YR" sample of 329 SNe Ia. Our cosmological analyses are blinded: after combining our DES-SN3YR distances with constraints from the Cosmic Microwave Background, our uncertainties in the measurement of the dark energy equation-of-state parameter, w, are 0.042 (stat) and 0.059 (stat+syst) at 68% confidence. We provide a detailed systematic uncertainty budget, which has nearly equal contributions from photometric calibration, astrophysical bias corrections, and instrumental bias corrections. We also include several new sources of systematic uncertainty. While our sample is less than one-third the size of the Pantheon sample, our constraints on w are only larger by 1.4×, showing the impact of the DES-SN Ia light-curve quality. We find that the traditional stretch and color standardization parameters of the DES-SNe Ia are in agreement with earlier SN Ia samples such as Pan-STARRS1 and the Supernova Legacy Survey. However, we find smaller intrinsic scatter about the Hubble diagram (0.077 mag). Interestingly, we find no evidence for a Hubble residual step (0.007 0.018 mag) as a function of host-galaxy mass for the DES subset, in 2.4 tension with previous measurements. We also present novel validation methods of our sample using simulated SNe Ia inserted in DECam images and using large catalog-level simulations to test for biases in our analysis pipelines.
The aims of this study were to investigate the effects of either hearing, vision or dual sensory impairment on depressive symptoms and to identify subgroups that are vulnerable and significantly ...affected.
Data from the 2006-2014 Korean Longitudinal Study of Aging (KLoSA) were used and a total of 5832 individuals were included in this study. Depressive symptoms were assessed using the Center for Epidemiologic Studies Depression (CES-D10) scale. Sensory impairment was assessed according to the levels of self-reported hearing or vision, which were categorised as either good (excellent, very good or good) or poor (fair or poor). The changes in hearing or vision from records of previous survey were investigated. Changes from good to poor, which indicates new onset, were defined as hearing impairment or vision impairment. Interactions of changes in hearing and vision were considered in the analysis. Dual sensory impairment was indicated when hearing impairment and vision impairment both developed at the same time. Demographic, socioeconomic and health-related factors were considered as potential confounders and were adjusted for in the generalised estimating equation model.
Individuals with hearing impairment demonstrated significantly more severe depressive symptoms β = 0.434, standard errors (s.e.) = 0.097, p < 0.001 than those who had good hearing. Those with vision impairment also showed significantly elevated depressive symptoms (β = 0.253, s.e. = 0.058, p < 0.001) than those with good vision. When the interactions between hearing and vision were considered, participants with dual sensory impairment showed significantly more severe depressive symptoms (β = 0.768, s.e. = 0.197, p < 0.001) than those with good hearing and vision. The effect of a single and dual sensory impairment on depressive symptoms was significant in both sexes and across age groups, except for vision impairment in male participants.
Hearing, vision and dual sensory impairment are significantly associated with depressive symptoms. Our results suggest that treatment or rehabilitation of either hearing or vision impairment would help prevent depression.
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