Recipients of extended‐criteria donor (ECD) kidneys have poorer long‐term outcomes compared to standard‐criteria donor kidney recipients. We report 3‐year outcomes from a randomized, phase III study ...in recipients of de novo ECD kidneys (n = 543) assigned (1:1:1) to either a more intensive (MI) or less intensive (LI) belatacept regimen, or cyclosporine. Three hundred twenty‐three patients completed treatment by year 3. Patient survival with a functioning graft was comparable between groups (80% in MI, 82% in LI, 80% in cyclosporine). Mean calculated GFR (cGFR) was 11 mL/min higher in belatacept‐treated versus cyclosporine‐treated patients (42.7 in MI, 42.2 in LI, 31.5 mL/min in cyclosporine). More cyclosporine‐treated patients (44%) progressed to GFR <30 mL/min (chronic kidney disease CKD stage 4/5) than belatacept‐treated patients (27–30%). Acute rejection rates were similar between groups. Posttransplant lymphoproliferative disorder (PTLD) occurrence was higher in belatacept‐treated patients (two in MI, three in LI), most of which occurred during the first 18 months; four additional cases (3 in LI, 1 in cyclosporine) occurred after 3 years. Tuberculosis was reported in two MI, four LI and no cyclosporine patients. In conclusion, at 3 years after transplantation, immunosuppression with belatacept resulted in similar patient survival, graft survival and acute rejection, with better renal function compared with cyclosporine. As previously reported, PTLD and tuberculosis were the principal safety findings associated with belatacept in this study population.
Three‐year results from the BENEFIT‐EXT study confirm the durability of the renal function benefits of belatacept over time compared to cyclosporine, while providing comparable 3‐year patient/graft survival and balancing risks associated with belatacept in recipients of extended criteria donor kidneys.
Mindfulness describes a state of consciousness in which individuals attend to ongoing events and experiences in a receptive and non-judgmental way. The present research investigated the idea that ...mindfulness reduces emotional exhaustion and improves job satisfaction. The authors further suggest that these associations are mediated by the emotion regulation strategy of surface acting. Study 1 was a 5-day diary study with 219 employees and revealed that mindfulness negatively related to emotional exhaustion and positively related to job satisfaction at both the within- and the between-person levels. Both relationships were mediated by surface acting at both levels of analysis. Study 2 was an experimental field study, in which participants (N = 64) were randomly assigned to a self-training mindfulness intervention group or a control group. Results revealed that participants in the mindfulness intervention group experienced significantly less emotional exhaustion and more job satisfaction than participants in the control group. The causal effect of mindfulness self-training on emotional exhaustion was mediated by surface acting. Implications for using mindfulness and mindfulness training interventions in organizational research and practice are discussed in conclusion.
When two indistinguishable single photons impinge at the two inputs of a beam splitter they coalesce into a pair of photons appearing in either one of its two outputs. This effect is due to the ...bosonic nature of photons and was first experimentally observed by Hong, Ou and Mandel. Here, we present the observation of the Hong-Ou-Mandel effect with two independent single-photon sources in the microwave frequency domain. We probe the indistinguishability of single photons, created with a controllable delay, in time-resolved second-order cross- and auto-correlation function measurements. Using quadrature amplitude detection we are able to resolve different photon numbers and detect coherence in and between the output arms. This scheme allows us to fully characterize the two-mode entanglement of the spatially separated beam-splitter output modes. Our experiments constitute a first step towards using two-photon interference at microwave frequencies for quantum communication and information processing.
A reliable and precise in situ CO2 and CO analysis system has been developed and deployed at eight sites in the NOAA Earth System Research Laboratory's (ESRL) Global Greenhouse Gas Reference Network. ...The network uses very tall (> 300 m) television and radio transmitter towers that provide a convenient platform for mid-boundary-layer trace-gas sampling. Each analyzer has three sample inlets for profile sampling, and a complete vertical profile is obtained every 15 min. The instrument suite at one site has been augmented with a cavity ring-down spectrometer for measuring CO2 and CH4 . The long-term stability of the systems in the field is typically better than 0.1 ppm for CO2 , 6 ppb for CO, and 0.5 ppb for CH4 , as determined from repeated standard gas measurements. The instrumentation is fully automated and includes sensors for measuring a variety of status parameters, such as temperatures, pressures, and flow rates, that are inputs for automated alerts and quality control algorithms. Detailed and time-dependent uncertainty estimates have been constructed for all of the gases, and the uncertainty framework could be readily adapted to other species or analysis systems. The design emphasizes use of off-the-shelf parts and modularity to facilitate network operations and ease of maintenance. The systems report high-quality data with > 93% uptime. Recurrent problems and limitations of the current system are discussed along with general recommendations for high-accuracy trace-gas monitoring. The network is a key component of the North American Carbon Program and a useful model for future research-grade operational greenhouse gas monitoring efforts.
Background
Depression is prevalent and typically has its onset in adolescence. Resting‐state fMRI could help create a better understanding of the underlying neurobiological mechanisms during this ...critical period. In this study, resting‐state functional connectivity (RSFC) is examined using seed regions‐of‐interest (ROIs) associated with three networks: the limbic network, the default mode network (DMN) and the salience network.
Methods
Twenty‐six treatment‐naïve, clinically depressed adolescents of whom 18 had comorbid anxiety, and 26 pair‐wise matched healthy controls underwent resting‐state fMRI. The three networks were investigated using a seed‐based ROI approach with seeds in the bilateral amygdala (limbic network), bilateral dorsal anterior cingulate cortex (dACC; salience network) and bilateral posterior cingulate cortex (default mode network).
Results
Compared to healthy controls, clinically depressed adolescents showed increased RSFC of the left amygdala with right parietal cortical areas, and decreased right amygdala RSFC with left frontal cortical areas including the ACC, as well as with right occipito‐parietal areas. The bilateral dACC showed decreased RSFC with the right middle frontal gyrus, frontal pole, and inferior frontal gyrus in clinically depressed adolescents. No abnormalities in DMN RSFC were found, and differences in RSFC did not correlate with clinical measures.
Conclusions
The aberrant RSFC of the amygdala network and the dACC network may be related to altered emotion processing and regulation in depressed adolescents. Our results provide new insights into RSFC in clinically depressed adolescents and future models on adolescent depression may include abnormalities in the connectivity of salience network.
Human betacoronaviruses OC43 and HKU1 are endemic respiratory pathogens and, while related, originated from independent zoonotic introductions. OC43 is in fact a host-range variant of the species ...Betacoronavirus-1, and more closely related to bovine coronavirus (BCoV)—its presumptive ancestor—and porcine hemagglutinating encephalomyelitis virus (PHEV). The β1-coronaviruses (β1CoVs) and HKU1 employ glycan-based receptors carrying 9-O-acetylated sialic acid (9-O-Ac-Sia). Receptor binding is mediated by spike protein S, the main determinant of coronavirus host specificity. For BCoV, a crystal structure for the receptor-binding domain S1A is available and for HKU1 a cryoelectron microscopy structure of the complete S ectodomain. However, the location of the receptor-binding site (RBS), arguably the single-most important piece of information, is unknown. Here we solved the 3.0-Å crystal structure of PHEV S1A. We then took a comparative structural analysis approach to map the β1CoV S RBS, using the general design of 9-O-Ac-Sia-binding sites as blueprint, backed-up by automated ligand docking, structure-guided mutagenesis of OC43, BCoV, and PHEV S1A, and infectivity assays with BCoV-S–pseudotyped vesicular stomatitis viruses. The RBS is not exclusive to OC43 and related animal viruses, but is apparently conserved and functional also in HKU1 S1A. The binding affinity of the HKU1 S RBS toward short sialoglycans is significantly lower than that of OC43, which we attribute to differences in local architecture and accessibility, and which may be indicative for differences between the two viruses in receptor fine-specificity. Our findings challenge reports that would map the OC43 RBS elsewhere in S1A and that of HKU1 in domain S1B.
We report the detection of pulsed gamma rays from the Crab pulsar at energies above 100 giga—electron volts (GeV) with the Very Energetic Radiation Imaging Telescope Array System (VERITAS) array of ...atmospheric Cherenkov telescopes. The detection cannot be explained on the basis of current pulsar models. The photon spectrum of pulsed emission between 100 mega—electron volts and 400 GeV is described by a broken power law that is statistically preferred over a power law with an exponential cutoff. It is unlikely that the observation can be explained by invoking curvature radiation as the origin of the observed gamma rays above 100 GeV. Our findings require that these gamma rays be produced more than 10 stellar radii from the neutron star.
Constraint-induced movement therapy (CIMT) is among the most developed training approaches for motor restoration of the upper extremity (UE).
Very Early Constraint-Induced Movement during Stroke ...Rehabilitation (VECTORS) was a single-blind phase II trial of CIMT during acute inpatient rehabilitation comparing traditional UE therapy with dose-matched and high-intensity CIMT protocols. Participants were adaptively randomized on rehabilitation admission, and received 2 weeks of study-related treatments. The primary endpoint was the total Action Research Arm Test (ARAT) score on the more affected side at 90 days after stroke onset. A mixed model analysis was performed.
A total of 52 participants (mean age 63.9 +/- 14 years) were randomized 9.65 +/- 4.5 days after onset. Mean NIHSS was 5.3 +/- 1.8; mean total ARAT score was 22.5 +/- 15.6; 77% had ischemic stroke. Groups were equivalent at baseline on all randomization variables. As expected, all groups improved with time on the total ARAT score. There was a significant time x group interaction (F = 3.1, p < 0.01), such that the high intensity CIT group had significantly less improvement at day 90. No significant differences were found between the dose-matched CIMT and control groups at day 90. MRI of a subsample showed no evidence of activity-dependent lesion enlargement.
Constraint-induced movement therapy (CIMT) was equally as effective but not superior to an equal dose of traditional therapy during inpatient stroke rehabilitation. Higher intensity CIMT resulted in less motor improvement at 90 days, indicating an inverse dose-response relationship. Motor intervention trials should control for dose, and higher doses of motor training cannot be assumed to be more beneficial, particularly early after stroke.
Sacituzumab govitecan (SG), a trophoblast cell surface antigen-2 (Trop-2)-directed antibody-drug conjugate, has demonstrated antitumor efficacy and acceptable tolerability in a phase I/II multicenter ...trial (NCT01631552) in patients with advanced epithelial cancers. This report summarizes the safety data from the overall safety population (OSP) and efficacy data, including additional disease cohorts not published previously.
Patients with refractory metastatic epithelial cancers received intravenous SG (8, 10, 12, or 18 mg/kg) on days 1 and 8 of 21-day cycles until disease progression or unacceptable toxicity. Endpoints for the OSP included safety and pharmacokinetic parameters with investigator-evaluated objective response rate (ORR per RECIST 1.1), duration of response, clinical benefit rate, progression-free survival, and overall survival evaluated for cohorts (n > 10 patients) of small-cell lung, colorectal, esophageal, endometrial, pancreatic ductal adenocarcinoma, and castrate-resistant prostate cancer.
In the OSP (n = 495, median age 61 years, 68% female; UGT1A1∗28 homozygous, n = 46; 9.3%), 41 (8.3%) permanently discontinued treatment due to adverse events (AEs). Most common treatment-related AEs were nausea (62.6%), diarrhea (56.2%), fatigue (48.3%), alopecia (40.4%), and neutropenia (57.8%). Most common treatment-related serious AEs (n = 75; 15.2%) were febrile neutropenia (4.0%) and diarrhea (2.8%). Grade ≥3 neutropenia and febrile neutropenia occurred in 42.4% and 5.3% of patients, respectively. Neutropenia (all grades) was numerically more frequent in UGT1A1∗28 homozygotes (28/46; 60.9%) than heterozygotes (69/180; 38.3%) or UGT1A1∗1 wild type (59/177; 33.3%). There was one treatment-related death due to an AE of aspiration pneumonia. Partial responses were seen in endometrial cancer (4/18, 22.2% ORR) and small-cell lung cancer (11/62, 17.7% ORR), and one castrate-resistant prostate cancer patient had a complete response (n = 1/11; 9.1% ORR).
SG demonstrated a toxicity profile consistent with previous published reports. Efficacy was seen in several cancer cohorts, which validates Trop-2 as a broad target in solid tumors.
•Sacituzumab govitecan (SG) is a Trop-2-directed antibody-drug conjugate with a hydrolyzable linker and an SN-38 payload.•The most frequent treatment-related adverse events (TRAEs) were nausea, diarrhea, neutropenia, alopecia, and fatigue.•Grade ≥3 TRAEs were infrequent except for treatment-related grade ≥3 neutropenia; discontinuation due to AEs was 8.3%.•AEs with SG parallel those of chemotherapy and can be managed with proactive intervention per established guidelines.•Objective response rates, coupled with disease control, are apparent across small disease cohorts, warranting further study.
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