Atezolizumab, a humanized immunoglobulin G1 (IgG1) monoclonal antibody targeting human programmed death‐ligand 1 (PD‐L1), is US Food and Drug Administration (FDA) approved in metastatic urothelial ...carcinoma (MUC) and is being investigated in various malignancies. This analysis based upon 906 patients from two phase I and one phase II MUC studies, is the first report of the clinical pharmacokinetics (PK) and pharmacodynamics (PD) of atezolizumab. Atezolizumab exhibited linear PK over a dose range of 1–20 mg/kg, including the labeled 1,200 mg dose. The clearance, volume of distribution, and terminal half‐life estimates from population pharmacokinetic (PopPK) analysis of 0.200 L/day, 6.91 L, and 27 days, respectively, were as expected for an IgG1. Exposure‐response analyses did not identify statistically significant relationships with either objective response rate or adverse events of grades 3–5 or of special interest. None of the statistically significant covariates from PopPK (body weight, gender, antitherapeutic antibody, albumin, and tumor burden) would require dose adjustment.
We present a classification of galaxies in the Pan-STARRS1 (PS1) 3π survey based on their recent star formation history and morphology. Specifically, we train and test two Random Forest (RF) ...classifiers using photometric features (colors and moments) from the PS1 data release 2. The labels for the morphological classification are taken from Huertas-Company et al., while labels for the star formation fraction (SFF) are from the Blanton et al. catalog. We find that colors provide more predictive accuracy than photometric moments. We morphologically classify galaxies as either early- or late-type, and our RF model achieves a 78% classification accuracy. Our second model classifies galaxies as having either a low-to-moderate or high SFF. This model achieves an 89% classification accuracy. We apply both RF classifiers to the entire PS1 3π dataset, which allows us to assign two scores to each PS1 source: PHSFF, which quantifies the probability of having a high SFF; and Pspiral, which quantifies the probability of having a late-type morphology. Finally, as a proof of concept, we apply our classification framework to supernova (SN) host galaxies from the Zwicky Transient Factory and the Lick Observatory Supernova Search samples. We show that by selecting PHSFF or Pspiral, it is possible to significantly enhance or suppress the fraction of core-collapse SNe (or thermonuclear SNe) in the sample with respect to random guessing. This result demonstrates how contextual information can aid transient classifications at the time of first detection. In the current era of spectroscopically starved time-domain astronomy, prompt automated classification is paramount. Our table is available at 10.5281/zenodo.3990545.
Abstract
We present the results from a multiyear radio campaign of the superluminous supernova (SLSN) SN 2017ens, which yielded the earliest radio detection of an SLSN to date at the age of ∼3.3 yr ...after explosion. SN 2017ens was not detected at radio frequencies in the first ∼300 days but reached
L
ν
≈ 10
28
erg s
−1
cm
−2
Hz
−1
at
ν
∼ 6 GHz, ∼1250 days post explosion. Interpreting the radio observations in the context of synchrotron radiation from the supernova shock interaction with the circumstellar medium (CSM), we infer an effective mass-loss rate
M
̇
≈
10
−
4
M
☉
yr
−
1
at
r
∼ 10
17
cm from the explosion’s site, for a wind speed of
v
w
= 50–60 km s
−1
as measured from optical spectra. These findings are consistent with the spectroscopic metamorphosis of SN 2017ens from hydrogen poor to hydrogen rich ∼190 days after explosion reported by Chen et al. SN 2017ens is thus an addition to the sample of hydrogen-poor massive progenitors that explode shortly after having lost their hydrogen envelope. The inferred circumstellar densities, implying a CSM mass up to ∼0.5
M
☉
, and low velocity of the ejection suggest that binary interactions (in the form of common-envelope evolution and subsequent envelope ejection) play a role in shaping the evolution of the stellar progenitors of SLSNe in the ≲500 yr preceding core collapse.
This paper engages with Isaac Levi's approach to justifying changes in our states of full belief and offers a Peircean criticism of his strategy for resolving conflicts between the results of what ...inquirers deem to be the most reliable programs for a given situation and the settled beliefs about which we have no doubts. In the first section, I discuss the central features of Levi's theory of justifying changes to our state of full belief. In the second section, I present a Peircean approach to evaluating the reliability of these programs for routine expansion of belief, and I argue that there is a conflict between Levi's approach to situations where an inquirer has expanded her beliefs into inconsistency and Peirce's criticisms of non-scientific methods for settling opinion. The third section presents two potential objections to the Peircean approach, objections that emphasize the importance of our concern to avoid error, and in the fourth section, I propose an original supplement to the Peircean approach that better addresses that concern. Ultimately, my aim is to develop and defend a Peircean approach that is in opposition to Levi's views about when it is appropriate to question the reliability of our programs for routine expansion of belief but that also addresses his legitimate worries about underemphasizing our concern to avoid error.
We present the first results from the Bulge Asymmetries and Dynamic Evolution (BAaDE) survey. Though only a subset of the complete survey (∼2700 out of ∼20,000 final sources), our data comprise the ...largest radio kinematic survey to date of stellar SiO masers observed toward the Galactic bulge and plane from −15° < l < +12° and −6° < b < +6°. Our sources include a substantial number of line-of-sight velocities in high extinction regions within 1° of the Galactic plane. When matched with 2MASS photometry, our radio-detected sample lies significantly brighter than and redward of the first red giant branch tip, reaching extremes of (J − Ks)0 > 8, colors consistent with Mira variables and mass-losing AGB stars. We see a clean division into two kinematic populations: a kinematically cold ( ∼ 50 km s−1) population that we propose is in the foreground disk, consisting of giants with 2MASS Ks < 5.5, and a kinematically hot ( ∼ 100 km s−1) candidate bulge/bar population for most giants with Ks > 5.5. Only the kinematically hot giants with Ks > 5.5 include the reddest stars. Adopting 8.3 kpc to the Galactic center, and correcting for foreground extinction, we find that most of the sources have Mbol ∼ −5, consistent with their being luminous and possibly intermediate-age AGB stars. We note some tension between the possible intermediate age of the kinematically hot population, and its high-velocity dispersion compared to the disk.
Mosquitoes are the deadliest organisms in the world, killing an estimated 750,000 people per year due to the pathogens they can transmit. Mosquitoes also pose a major threat to other vertebrate ...animals. Culex territans is a mosquito species found in temperate zones worldwide that feeds almost exclusively on amphibians and can transmit parasites; however, little is known about its ability to transmit other pathogens, including fungi. Batrachochytrium dendrobatidis (Bd) is a topical pathogenic fungus that spreads through contact. With amphibian populations around the world experiencing mass die-offs and extinctions due to this pathogen, it is critical to study all potential modes of transmission. Because Cx. territans mosquitoes are in contact with their hosts for long periods of time while blood-feeding, we hypothesize that they can transmit and pick up Bd. In this study, we first assessed Cx. territans ability to transfer the fungus from an infected surface to a clean one under laboratory conditions. We also conducted a surveillance study of Bd infections in frogs and mosquitoes in the field (Mountain Lake Biological station, VA, USA). In parallel, we determined Cx. territans host preference via blood meal analysis of field caught mosquitoes. We found that this mosquito species can carry the fungus to an uninfected surface, implying that they may have the ability to transmit Bd to their amphibian hosts. We also found that Cx. territans feed primarily on green frogs (Rana clamitans) and bullfrogs (Rana catesbeiana) and that the prevalence of Bd within the frog population at our field site varied between years. This study provides critical insights into understanding the role of amphibian-biting mosquitoes in transmitting pathogens, which can be applied to disease ecology of susceptible amphibian populations worldwide.
We assessed the feasibility of the Molecular Transducers of Physical Activity Consortium (MoTrPAC) human adult clinical exercise protocols, while also documenting select cardiovascular, metabolic, ...and molecular responses to these protocols. After phenotyping and familiarization sessions, 20 subjects (25 ± 2 yr, 12 M, 8 W) completed an endurance exercise bout (
= 8, 40 min cycling at 70% V̇o
), a resistance exercise bout (
= 6, ∼45 min, 3 sets of ∼10 repetition maximum, 8 exercises), or a resting control period (
= 6, 40 min rest). Blood samples were taken before, during, and after (10 min, 2 h, and 3.5 h) exercise or rest for levels of catecholamines, cortisol, glucagon, insulin, glucose, free fatty acids, and lactate. Heart rate was recorded throughout exercise (or rest). Skeletal muscle (vastus lateralis) and adipose (periumbilical) biopsies were taken before and ∼4 h following exercise or rest for mRNA levels of genes related to energy metabolism, growth, angiogenesis, and circadian processes. Coordination of the timing of procedural components (e.g., local anesthetic delivery, biopsy incisions, tumescent delivery, intravenous line flushes, sample collection and processing, exercise transitions, and team dynamics) was reasonable to orchestrate while considering subject burden and scientific objectives. The cardiovascular and metabolic alterations reflected a dynamic and unique response to endurance and resistance exercise, whereas skeletal muscle was transcriptionally more responsive than adipose 4 h postexercise. In summary, the current report provides the first evidence of protocol execution and feasibility of key components of the MoTrPAC human adult clinical exercise protocols. Scientists should consider designing exercise studies in various populations to interface with the MoTrPAC protocols and DataHub.
This study highlights the feasibility of key aspects of the MoTrPAC adult human clinical protocols. This initial preview of what can be expected from acute exercise trial data from MoTrPAC provides an impetus for scientists to design exercise studies to interlace with the rich phenotypic and -omics data that will populate the MoTrPAC DataHub at the completion of the parent protocol.
Nonnative species are a key agent of global change. However, nonnative invertebrates remain understudied at the community scales where they are most likely to drive local extirpations. We use the ...North American NEON pitfall trapping network to document the number of nonnative species from 51 invertebrate communities, testing four classes of drivers. We sequenced samples using the eDNA from the sample's storage ethanol. We used AICc informed regression to evaluate how native species richness, productivity, habitat, temperature, and human population density and vehicular traffic account for continent‐wide variation in the number of nonnative species in a local community. The percentage of nonnatives varied 3‐fold among habitat types and over 10‐fold (0%–14%) overall. We found evidence for two types of constraints on nonnative diversity. Consistent with Capacity rules (i.e., how the number of niches and individuals reflect the number of species an ecosystem can support) nonnatives increased with existing native species richness and ecosystem productivity. Consistent with Establishment Rules (i.e., how the dispersal rate of nonnative propagules and the number of open sites limits nonnative species richness) nonnatives increased with automobile traffic—a measure of human‐generated propagule pressure—and were twice as common in pastures than native grasslands. After accounting for drivers associated with a community's ability to support native species (native species richness and productivity), nonnatives are more common in communities that are regularly seasonally disturbed (pastures and, potentially deciduous forests) and those experiencing more vehicular traffic. These baseline values across the US North America will allow NEON's monitoring mission to document how anthropogenic change—from disturbance to propagule transport, from temperature to trends in local extinction—further shape biotic homogenization.
We use the North American NEON pitfall trapping network to document the number of nonnative species from 51 invertebrate communities, testing four classes of drivers. We found evidence for two types of constraints on nonnative diversity. Consistent with Capacity rules (i.e., how the number of niches and individuals reflect the number of species an ecosystem can support) nonnatives increased with existing native species richness and ecosystem productivity. Consistent with Establishment Rules (i.e., how the dispersal rate of nonnative propagules and the number of open sites limits nonnative species richness) nonnatives increased with automobile traffic—a measure of human‐generated propagule pressure—and were twice as common in pastures than native grasslands.
We present the results of a series of radio, optical, X-ray, and γ-ray observations of the BL Lac object S50716+714 carried out between April 2007 and January 2011. The multifrequency observations ...were obtained using several ground- and space-based facilities. The intense optical monitoring of the source reveals faster repetitive variations superimposed on a long-term variability trend on a time scale of ~350 days. Episodes of fast variability recur on time scales of ~60−70 days. The intense and simultaneous activity at optical and γ-ray frequencies favors the synchrotron self-Compton mechanism for the production of the high-energy emission. Two major low-peaking radio flares were observed during this high optical/γ-ray activity period. The radio flares are characterized by a rising and a decaying stage and agrees with the formation of a shock and its evolution. We found that the evolution of the radio flares requires a geometrical variation in addition to intrinsic variations of the source. Different estimates yield robust and self-consistent lower limits of δ ≥ 20 and equipartition magnetic field Beq ≥ 0.36 G. Causality arguments constrain the size of emission region θ ≤ 0.004 mas. We found a significant correlation between flux variations at radio frequencies with those at optical and γ-rays. Theoptical/GeV flux variations lead the radio variability by ~65 days. The longer time delays between low-peaking radio outbursts and optical flares imply that optical flares are the precursors of radio ones. An orphan X-ray flare challenges the simple, one-zone emission models, rendering them too simple. Here we also describe the spectral energy distribution modeling of the source from simultaneous data taken through different activity periods.
Therapeutic drug monitoring (TDM) aims to maintain circulating drug concentrations at a desired level to optimize clinical outcome. The vast majority of marketed drugs do not require TDM, suggesting ...the clinical benefit of TDM has not been sufficiently demonstrated in most cases. With the continued emergence and prominence of monoclonal antibodies (mAbs) as drugs, especially in inflammation and cancer therapeutic areas, we are at a juncture to consider applicability of TDM for mAbs.
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