Conventional criteria for tumor progression may not fully reflect the clinical benefit of immunotherapy or appropriately guide treatment decisions. The phase II IMvigor210 study demonstrated the ...efficacy and safety of atezolizumab, a programmed death-ligand 1-directed antibody, in patients with platinum-treated locally advanced or metastatic urothelial carcinoma. Patients could continue atezolizumab beyond Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 progression at the investigator’s discretion: this analysis assessed post-progression outcomes in these patients.
Patients were treated with atezolizumab 1200 mg i.v. every 3 weeks until loss of clinical benefit. Efficacy and safety outcomes in patients who experienced RECIST v1.1 progression and did, or did not, continue atezolizumab were analyzed descriptively.
In total, 220 patients who experienced progression from the overall cohort (n = 310) were analyzed: 137 continued atezolizumab for ≥ 1 dose after progression, 19 received other systemic therapy, and 64 received no further systemic therapy. Compared with those who discontinued, patients continuing atezolizumab beyond progression were more likely to have had a baseline Eastern Cooperative Oncology Group performance status of 0 (43.1% versus 31.3%), less likely to have had baseline liver metastases (27.0% versus 41.0%), and more likely to have had an initial response to atezolizumab (responses in 11.7% versus 1.2%). Five patients (3.6%) continuing atezolizumab after progression had subsequent responses compared with baseline measurements. Median post-progression overall survival was 8.6 months in patients continuing atezolizumab, 6.8 months in those receiving another treatment, and 1.2 months in those receiving no further treatment. Atezolizumab exposure-adjusted adverse event frequencies were generally similar before and following progression.
In this single-arm study, patients who continued atezolizumab beyond RECIST v1.1 progression derived prolonged clinical benefit without additional safety signals. Identification of patients most likely to benefit from atezolizumab beyond progression remains an important challenge in the management of metastatic urothelial carcinoma.
NCT02108652.
The branched-chain amino acids (BCAAs Ile, Leu, and Val) represent important nutrients in bacterial physiology, with roles that range from supporting protein synthesis to signaling and fine-tuning ...the adaptation to amino acid starvation. In some pathogenic bacteria, the adaptation to amino acid starvation includes induction of virulence gene expression: thus, BCAAs support not only proliferation during infection, but also the evasion of host defenses. A body of research has accumulated over the years to describe the multifaceted physiological roles of BCAAs and the mechanisms bacteria use to maintain their intracellular levels. More recent studies have focused on understanding how fluctuations in their intracellular levels impact global regulatory pathways that coordinate the adaptation to nutrient limitation, especially in pathogenic bacteria. In this minireview, we discuss how these studies have refined the individual roles of BCAAs, shed light on how BCAA auxotrophy might promote higher sensitivity to exogenous BCAA levels, and revealed pathogen-specific responses to BCAA deprivation. These advancements improve our understanding of how bacteria meet their nutritional requirements for growth while simultaneously remaining responsive to changes in environmental nutrient availability to promote their survival in a range of environments.
Background and purpose
The Gugging Swallowing Screen (GUSS) is a tool to screen aspiration risk in acute stroke. We aimed to replicate its validity in a larger second cohort of patients with acute ...stroke, including the more severe with a National Institutes of Health Stroke Scale (NIHSS) ≥ 15.
Methods
In a prospective, double‐blind design, the GUSS was validated with the Fiberoptic Endoscopic Evaluation of Swallowing scale. Patients were categorized into different stroke severities as assessed by the NIHSS, and the diagnostic properties were calculated separately for each subgroup.
Results
A total of 100 patients with acute stroke were evaluated consecutively at a mean 1.7 ± 2.2 days after stroke. With the GUSS cut‐off value of 14 points, the GUSS screened aspiration risk with a 96.5% sensitivity and 55.8% specificity (area under the curve, 0.76; 95% CI, 0.67–0.84), which corresponded well with the original publication. In the NIHSS < 5 group, the sensitivity and specificity levels were 71.4% and 88.8%, respectively. In the NIHSS ≥ 15 group, these levels changed to 100% and 20%, respectively. The high failure rate in completing the first part of the GUSS in the latter group was related to the low specificity. Diet recommendations following the GUSS were more conservative than those after Fiberoptic Endoscopic Evaluation of Swallowing. In particular, the GUSS overestimated the need for nasogastric tube feeding.
Conclusions
This is the first time that a swallowing screening tool for patients with acute stroke has been revalidated in a larger population from another stroke center. The validity of a swallow screening test may vary according to different stroke severities.
Understanding the neural basis of behavior requires monitoring and manipulating combinations of physiological elements and their interactions in behaving animals. We developed a thermal tapering ...process enabling fabrication of low-cost, flexible probes combining ultrafine features: dense electrodes, optical waveguides, and microfluidic channels. Furthermore, we developed a semi-automated backend connection allowing scalable assembly. We demonstrate T-DOpE (Tapered Drug delivery, Optical stimulation, and Electrophysiology) probes achieve in single neuron-scale devices (1) high-fidelity electrophysiological recording (2) focal drug delivery and (3) optical stimulation. The device tip can be miniaturized (as small as 50 µm) to minimize tissue damage while the ~20 times larger backend allows for industrial-scale connectorization. T-DOpE probes implanted in mouse hippocampus revealed canonical neuronal activity at the level of local field potentials (LFP) and neural spiking. Taking advantage of the triple-functionality of these probes, we monitored LFP while manipulating cannabinoid receptors (CB1R; microfluidic agonist delivery) and CA1 neuronal activity (optogenetics). Focal infusion of CB1R agonist downregulated theta and sharp wave-ripple oscillations (SPW-Rs). Furthermore, we found that CB1R activation reduces sharp wave-ripples by impairing the innate SPW-R-generating ability of the CA1 circuit.
We demonstrate a plasmonic Mach-Zehnder (MZ) modulator with a flat frequency response exceeding 170 GHz. The modulator comprises two phase modulators exploiting the Pockels effect of an organic ...electro-optic material in plasmonic slot waveguides. We further show modulation at 100 GBd NRZ and 60 GBd PAM-4. The electrical drive signals were generated using a 100 GSa/s digital to analog converter (DAC). The high-speed and small-scale devices are relevant for next-generation optical interconnects.
The prevalence of radio-loud active galactic nucleus (AGN) activity in present-day massive haloes is determined using a sample of 625 nearby groups and clusters selected from the Sloan Digital Sky ...Survey. Brightest group and cluster galaxies (BCGs) are more likely to host a radio-loud AGN than other galaxies of the same stellar mass (by below a factor of 2 at a stellar mass of ∼5 × 1011 M⊙, but rising to over an order of magnitude below 1011 M⊙). The distribution of radio luminosities for BCGs does not depend on mass, however, and is similar to that of field galaxies of the same stellar mass. Neither the radio-loud fraction nor the radio luminosity distribution of BCGs depends strongly on the velocity dispersion of the host cluster. The radio-AGN fraction is also studied as a function of distance from the cluster centre. Only within 0.2r200 do cluster galaxies exhibit an enhanced likelihood of radio-loud AGN activity, which approaches that of the BCGs. In contrast to the radio properties, the fraction of galaxies with optical emission-line AGN activity is suppressed within r200 in groups and clusters, decreasing monotonically towards the cluster centre. It is argued that the radio-loud AGN properties of both BCGs and non-BCGs can naturally be explained if this activity is fuelled by cooling from hot gas surrounding the galaxy. Using observational estimates of the mechanical output of the radio jets, the time-averaged energy output associated with recurrent radio source activity is estimated for all group and cluster galaxies. Within the cooling radius of the cluster, the radio-mode heating associated with the BCG dominates over that of all other galaxies combined. The scaling between total radio-AGN energy output and cluster velocity dispersion is observed to be considerably shallower than the ∼σ4v scaling of the radiative cooling rate. Thus, unless either the mechanical-to-radio luminosity ratio or the efficiency of converting AGN mechanical energy into heating increases by 2–3 orders of magnitude between groups and rich clusters, radio-mode heating will not balance radiative cooling in systems of all masses. In groups, radio-AGN heating probably overcompensates the radiative cooling losses, and this may account for the observed entropy floor in these systems. In the most massive clusters, an additional heating process (most likely thermal conduction) may be required to supplement the AGN heating.
ABSTRACT
Flat radio spectra with large brightness temperatures at the core of active galactic nuclei and X‐ray binaries are usually interpreted as the partially self‐absorbed bases of jet flows ...emitting synchrotron radiation. Here we extend previous models of jets propagating at large angles to our line of sight to self‐consistently include the effects of energy losses of the relativistic electrons due to the synchrotron process itself and the adiabatic expansion of the jet flow. We also take into account energy gains through self‐absorption. Two model classes are presented. The ballistic jet flows, with the jet material travelling along straight trajectories, and adiabatic jets. Despite the energy losses, both scenarios can result in flat emission spectra; however, the adiabatic jets require a specific geometry. No re‐acceleration process along the jet is needed for the electrons. We apply the models to observational data of the X‐ray binary Cygnus X‐1. Both models can be made consistent with the observations. The resulting ballistic jet is extremely narrow with a jet opening angle of only 5 arcsec. Its energy transport rate is small compared to the time‐averaged jet power and therefore suggests the presence of non‐radiating protons in the jet flow. The adiabatic jets require a strong departure from energy equipartition between the magnetic field and the relativistic electrons. These models also imply a jet power of two orders of magnitude higher than the Eddington limiting luminosity of a 10‐M⊙ black hole. The models put strong constraints on the physical conditions in the jet flows on scales well below achievable resolution limits.
Evolution of Buoyant Bubbles in M87 Churazov, E; Brüggen, M; Kaiser, C. R ...
The Astrophysical journal,
06/2001, Letnik:
554, Številka:
1
Journal Article
The granular retrosplenial cortex (gRSC) exhibits high-frequency oscillations (HFOs; ∼150 Hz), which can be driven by a hippocampus-subiculum pathway. How the cellular-synaptic and laminar ...organization of gRSC facilitates HFOs is unknown. Here, we probe gRSC HFO generation and coupling with hippocampal rhythms using focal optogenetics and silicon-probe recordings in behaving mice. ChR2-mediated excitation of CaMKII-expressing cells in L2/3 or L5 induces HFOs, but spontaneous HFOs are found only in L2/3, where HFO power is highest. HFOs couple to CA1 sharp wave-ripples (SPW-Rs) during rest and the descending phase of theta. gRSC HFO current sources and sinks are the same for events during both SPW-Rs and theta oscillations. Independent component analysis shows that high gamma (50–100 Hz) in CA1 stratum lacunosum moleculare is comodulated with HFO power. HFOs may thus facilitate interregional communication of a multisynaptic loop between the gRSC, hippocampus, and medial entorhinal cortex during distinct brain and behavioral states.
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•Endogenous high-frequency oscillations (HFOs) occur in gRSC layer 2/3•HFOs can be induced in gRSC L2/3 and L5 by optogenetic excitation•CA1 high gamma in stratum lacunosum moleculare is comodulated with HFOs during theta
Arndt et al. demonstrate that gRSC high-frequency oscillations (HFOs) occur in layer 2/3 aligned with hippocampal sharp wave ripples or the descending phase of the theta oscillation (HOR). Focal excitation of L2/3 or L5 produces local HFOs. HORs are associated with a current sink and high gamma in stratum lacunosum moleculare.
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