At the hundredth anniversary of the Tunguska event in Siberia it is appropriate to discuss measures to avoid such occurrences in the future. Recent discussions about detecting, tracking, cataloguing, ...and characterizing near-Earth objects (NEOs) center on objects larger than about 140 m in size. However, objects smaller than 100 m are more frequent and can cause significant regional destruction of civil infrastructures and population centers. The cosmic object responsible for the Tunguska event provides a graphic example: although it is thought to have been only about 50 to 60 m in size, it devastated an area of about 2000 km
2
. Ongoing surveys aimed at early detection of a potentially hazardous object (PHO: asteroid or comet nucleus that approaches the Earth’s orbit within 0.05 AU) are only a first step toward applying countermeasures to prevent an impact on Earth. Because “early” may mean only a few weeks or days in the case of a Tunguska-sized object or a longperiod comet, deflecting the object by changing its orbit is beyond the means of current technology, and destruction and dispersal of its fragments may be the only reasonable solution. Highly capable countermeasures- always at the ready—are essential to defending against an object with such short warning time, and therefore short reaction time between discovery and impending impact. We present an outline for a comprehensive plan for countermeasures that includes smaller (Tunguska-sized) objects and long-period comets, focuses on short warning times, uses non-nuclear methods (e.g., hyper-velocity impactor devices and conventional explosives) whenever possible, uses nuclear munitions only when needed, and launches from the ground. The plan calls for international collaboration for action against a truly global threat.
To estimate prevalence of and identify risk factors for fecal Salmonella shedding among hospitalized horses with signs of gastrointestinal tract disease.
Cross-sectional study.
465 hospitalized ...horses with gastrointestinal tract disease.
Horses were classified as positive or negative for fecal Salmonella shedding during hospitalization by means of standard aerobic bacteriologic methods. The relationship between investigated exposure factors and fecal Salmonella shedding was examined by means of logistic regression.
The overall prevalence of fecal Salmonella shedding was 13%. Salmonella serotype Newport was the most commonly isolated serotype (12/60 20%), followed by Anatum (8/60 13%), Java (13%), and Saint-paul (13%). Foals with gastrointestinal tract disease were 3.27 times as likely to be shedding Salmonella organisms as were adult horses with gastrointestinal tract disease. Adult horses that had been treated with antimicrobial drugs prior to hospitalization were 3.09 times as likely to be shedding Salmonella organisms as were adult horses that had not been treated with antimicrobial drugs prior to hospitalization. Adult horses that underwent abdominal surgery were 2.09 times as likely to be shedding Salmonella organisms as were adult horses that did not undergo abdominal surgery.
Results suggest that a history of exposure to antimicrobial drugs prior to hospitalization and abdominal surgery during hospitalization were associated with Salmonella shedding in adult horses with gastrointestinal tract disease. Foals with gastrointestinal tract disease were more likely to shed Salmonella organisms than were adult horses with gastrointestinal tract disease.
Summary Background Results from phase 2 and 3 trials in patients with advanced melanoma have shown significant improvements in the proportion of patients achieving an objective response and prolonged ...progression-free survival with the combination of nivolumab (an anti-PD-1 antibody) plus ipilimumab (an anti-CTLA-4 antibody) compared with ipilimumab alone. We report 2-year overall survival data from a randomised controlled trial assessing this treatment in previously untreated advanced melanoma. Methods In this multicentre, double-blind, randomised, controlled, phase 2 trial (CheckMate 069) we recruited patients from 19 specialist cancer centres in two countries (France and the USA). Eligible patients were aged 18 years or older with previously untreated, unresectable stage III or IV melanoma and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned 2:1 to receive an intravenous infusion of nivolumab 1 mg/kg plus ipilimumab 3 mg/kg or ipilimumab 3 mg/kg plus placebo, every 3 weeks for four doses. Subsequently, patients assigned to nivolumab plus ipilimumab received nivolumab 3 mg/kg every 2 weeks until disease progression or unacceptable toxicity, whereas patients allocated to ipilimumab alone received placebo every 2 weeks during this phase. Randomisation was done via an interactive voice response system with a permuted block schedule (block size of six) and stratification by BRAF mutation status. The study funder, patients, investigators, and study site staff were masked to treatment assignment. The primary endpoint, which has been reported previously, was the proportion of patients with BRAFV600 wild-type melanoma achieving an investigator-assessed objective response. Overall survival was an exploratory endpoint and is reported in this Article. Efficacy analyses were done on the intention-to-treat population, whereas safety was assessed in all treated patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov , number NCT01927419 , and is ongoing but no longer enrolling patients. Findings Between Sept 16, 2013, and Feb 6, 2014, we screened 179 patients and enrolled 142, randomly assigning 95 patients to nivolumab plus ipilimumab and 47 to ipilimumab alone. In each treatment group, one patient no longer met the study criteria following randomisation and thus did not receive study drug. At a median follow-up of 24·5 months (IQR 9·1–25·7), 2-year overall survival was 63·8% (95% CI 53·3–72·6) for those assigned to nivolumab plus ipilimumab and 53·6% (95% CI 38·1–66·8) for those assigned to ipilimumab alone; median overall survival had not been reached in either group (hazard ratio 0·74, 95% CI 0·43–1·26; p=0·26). Treatment-related grade 3–4 adverse events were reported in 51 (54%) of 94 patients who received nivolumab plus ipilimumab compared with nine (20%) of 46 patients who received ipilimumab alone. The most common treatment-related grade 3–4 adverse events were colitis (12 13% of 94 patients) and increased alanine aminotransferase (ten 11%) in the combination group and diarrhoea (five 11% of 46 patients) and hypophysitis (two 4%) in the ipilimumab alone group. Serious grade 3–4 treatment-related adverse events were reported in 34 (36%) of 94 patients who received nivolumab plus ipilimumab (including colitis in ten 11% of 94 patients, and diarrhoea in five 5%) compared with four (9%) of 46 patients who received ipilimumab alone (including diarrhoea in two 4% of 46 patients, colitis in one 2%, and hypophysitis in one 2%). No new types of treatment-related adverse events or treatment-related deaths occurred in this updated analysis. Interpretation Although follow-up of the patients in this study is ongoing, the results of this analysis suggest that the combination of first-line nivolumab plus ipilimumab might lead to improved outcomes compared with first-line ipilimumab alone in patients with advanced melanoma. The results suggest encouraging survival outcomes with immunotherapy in this population of patients. Funding Bristol-Myers Squibb.
Introduction
Recent longitudinal studies point towards the existence of a positive relationship between cannabis use and violence in people with severe mental disorders. However, the existence of a ...dose-response relationship between the frequency and/or the severity of cannabis use and violence has seldom been investigated.
Objectives
This study aimed to determine if a dose-response relationship between cannabis use and violence exists in a psychiatric population.
Methods
This observational study was conducted at the
Institut universitaire de santé mentale de Montréal
(Montréal, Canada). A total of 98 outpatients (81 males and 17 females, all over 18 years of age) with severe mental disorders were included in the analyses. Clinical evaluations were conducted every 3 months for a year. Substance use, violent behaviors, and potential covariables were assessed through self-reported assessments, urinary testing, as well as clinical, criminal, and police records. Using generalized estimating equations, the association between cannabis use frequency (non-users, occasional, regular, and frequent users, assessed using the Time-Line Follow-Back and confirmed with urinary testing) and violence was investigated, as well as the association between the severity of cannabis use (measured using the Cannabis Use Problems Identification Test – CUPIT) and violent behaviors.
Results
Cannabis use frequency and severity were significant predictors of violent behaviors. After adjustment for time, age, sex, ethnicity, psychiatric diagnoses, impulsivity and use of alcohol and stimulants, odds ratios were of 1.91 (p <0.001) between each frequency profile, and 1.040 (p <0.001) for each increase of one point of the severity of cannabis use score (0 to 79).
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Conclusions
These findings have important implications for clinicians, demonstrating that cannabis use may have serious adverse consequences in a psychiatric population. Nevertheless, the mechanisms underlying this association remain unclear.
Disclosure of Interest
None Declared
We study the distribution of cold dark matter (CDM) in cosmological simulations from the FIRE (Feedback In Realistic Environments) project, for M
* ∼ 104–11 M⊙ galaxies in M
h ∼ 109–12 M⊙ haloes. ...FIRE incorporates explicit stellar feedback in the multiphase interstellar medium, with energetics from stellar population models. We find that stellar feedback, without ‘fine-tuned’ parameters, greatly alleviates small-scale problems in CDM. Feedback causes bursts of star formation and outflows, altering the DM distribution. As a result, the inner slope of the DM halo profile (α) shows a strong mass dependence: profiles are shallow at M
h ∼ 1010–1011 M⊙ and steepen at higher/lower masses. The resulting core sizes and slopes are consistent with observations. This is broadly consistent with previous work using simpler feedback schemes, but we find steeper mass dependence of α, and relatively late growth of cores. Because the star formation efficiency M
*/M
h is strongly halo mass dependent, a rapid change in α occurs around M
h ∼ 1010 M⊙ (M
* ∼ 106–107 M⊙), as sufficient feedback energy becomes available to perturb the DM. Large cores are not established during the period of rapid growth of haloes because of ongoing DM mass accumulation. Instead, cores require several bursts of star formation after the rapid build-up has completed. Stellar feedback dramatically reduces circular velocities in the inner kpc of massive dwarfs; this could be sufficient to explain the ‘Too Big To Fail’ problem without invoking non-standard DM. Finally, feedback and baryonic contraction in Milky Way-mass haloes produce DM profiles slightly shallower than the Navarro–Frenk–White profile, consistent with the normalization of the observed Tully–Fisher relation.
In a phase 1 dose-escalation study, combined inhibition of T-cell checkpoint pathways by nivolumab and ipilimumab was associated with a high rate of objective response, including complete responses, ...among patients with advanced melanoma.
In this double-blind study involving 142 patients with metastatic melanoma who had not previously received treatment, we randomly assigned patients in a 2:1 ratio to receive ipilimumab (3 mg per kilogram of body weight) combined with either nivolumab (1 mg per kilogram) or placebo once every 3 weeks for four doses, followed by nivolumab (3 mg per kilogram) or placebo every 2 weeks until the occurrence of disease progression or unacceptable toxic effects. The primary end point was the rate of investigator-assessed, confirmed objective response among patients with BRAF V600 wild-type tumors.
Among patients with BRAF wild-type tumors, the rate of confirmed objective response was 61% (44 of 72 patients) in the group that received both ipilimumab and nivolumab (combination group) versus 11% (4 of 37 patients) in the group that received ipilimumab and placebo (ipilimumab-monotherapy group) (P<0.001), with complete responses reported in 16 patients (22%) in the combination group and no patients in the ipilimumab-monotherapy group. The median duration of response was not reached in either group. The median progression-free survival was not reached with the combination therapy and was 4.4 months with ipilimumab monotherapy (hazard ratio associated with combination therapy as compared with ipilimumab monotherapy for disease progression or death, 0.40; 95% confidence interval, 0.23 to 0.68; P<0.001). Similar results for response rate and progression-free survival were observed in 33 patients with BRAF mutation-positive tumors. Drug-related adverse events of grade 3 or 4 were reported in 54% of the patients who received the combination therapy as compared with 24% of the patients who received ipilimumab monotherapy. Select adverse events with potential immunologic causes were consistent with those in a phase 1 study, and most of these events resolved with immune-modulating medication.
The objective-response rate and the progression-free survival among patients with advanced melanoma who had not previously received treatment were significantly greater with nivolumab combined with ipilimumab than with ipilimumab monotherapy. Combination therapy had an acceptable safety profile. (Funded by Bristol-Myers Squibb; ClinicalTrials.gov number, NCT01927419.).
The mitochondrial protein MAVS (also known as IPS-1, VISA, and CARDIF) interacts with RIG-I-like receptors (RLRs) to induce type I interferon (IFN-I). NLRX1 is a mitochondrial nucleotide-binding, ...leucine-rich repeats (NLR)-containing protein that attenuates MAVS-RLR signaling. Using Nlrx1−/− cells, we confirmed that NLRX1 attenuated IFN-I production, but additionally promoted autophagy during viral infection. This dual function of NLRX1 paralleled the previously described functions of the autophagy-related proteins Atg5-Atg12, but NLRX1 did not associate with Atg5-Atg12. High-throughput quantitative mass spectrometry and endogenous protein-protein interaction revealed an NLRX1-interacting partner, mitochondrial Tu translation elongation factor (TUFM). TUFM interacted with Atg5-Atg12 and Atg16L1 and has similar functions as NLRX1 by inhibiting RLR-induced IFN-I but promoting autophagy. In the absence of NLRX1, increased IFN-I and decreased autophagy provide an advantage for host defense against vesicular stomatitis virus. This study establishes a link between an NLR protein and the viral-induced autophagic machinery via an intermediary partner, TUFM.
► NLRX1 suppresses VSV-mediated type 1 IFN production but enhances autophagy ► TUFM works with NLRX1 to inhibit RLR-induced type 1 IFN signaling ► TUFM enhances autophagy and interacts with Atg5-Atg12 and Atg16L1 ► NLRX1-mediated autophagy and IFN-I inhibition enhance VSV replication
This paper describes a tactile probe designed for surface identification in a context of all-terrain low-velocity mobile robotics. The proposed tactile probe is made of a small metallic rod with a ...single-axis accelerometer attached near its tip. Surface identification is based on analyzing acceleration patterns induced at the tip of this mechanically robust tactile probe, while it is passively dragged along a surface. A training dataset was collected over ten different indoor and outdoor surfaces. Classification results for an artificial neural network were positive, with an 89.9% and 94.6% success rate for 1- and 4-s time windows of data, respectively. We also demonstrated that the same tactile probe can be used for unsupervised learning of terrains. For 1-s time windows of data, the classification success rate was only reduced to 74.1%. Finally, a blind mobile robot, performing real-time classification of surfaces, demonstrated the feasibility of this tactile probe as a guidance mechanism.
The CHIRON optical high-resolution echelle spectrometer was commissioned at the 1.5 m telescope at CTIO in 2011. The instrument was designed for high throughput and stability, with the goal of ...monitoring radial velocities of bright stars with high precision and high cadence for the discovery of low-mass exoplanets. Spectral resolution of R = 79 000 is attained when using a slicer with a total (including telescope and detector) efficiency of 6% or higher, while a resolution of R = 136 000 is available for bright stars. A fixed spectral range of 415-880 nm is covered. The echelle grating is housed in a vacuum enclosure and the instrument temperature is stabilized to ± 0.2°. Stable illumination is provided by an octagonal multimode fiber with excellent light-scrambling properties. An iodine cell is used for wavelength calibration. We describe the main optics, fiber feed, detector, exposure-meter, and other aspects of the instrument, as well as the observing procedure and data reduction.
The bolometric quasar luminosity function at z = 0–7 Shen, Xuejian; Hopkins, Philip F; Faucher-Giguère, Claude-André ...
Monthly notices of the Royal Astronomical Society,
07/2020, Letnik:
495, Številka:
3
Journal Article
Recenzirano
Odprti dostop
ABSTRACT
In this paper, we provide updated constraints on the bolometric quasar luminosity function (QLF) from z = 0 to z = 7. The constraints are based on an observational compilation that includes ...observations in the rest-frame IR, B band, UV, soft, and hard X-ray in past decades. Our method follows Hopkins et al. with an updated quasar SED model and bolometric and extinction corrections. The new best-fitting bolometric quasar luminosity function behaves qualitatively different from the old Hopkins model at high redshift. Compared with the old model, the number density normalization decreases towards higher redshift and the bright-end slope is steeper at z ≳ 2. Due to the paucity of measurements at the faint end, the faint end slope at z ≳ 5 is quite uncertain. We present two models, one featuring a progressively steeper faint-end slope at higher redshift and the other featuring a shallow faint-end slope at z ≳ 5. Further multiband observations of the faint-end QLF are needed to distinguish between these models. The evolutionary pattern of the bolometric QLF can be interpreted as an early phase likely dominated by the hierarchical assembly of structures and a late phase likely dominated by the quenching of galaxies. We explore the implications of this model on the ionizing photon production by quasars, the CXB spectrum, the SMBH mass density, and mass functions. The predicted hydrogen photoionization rate contributed by quasars is subdominant during the epoch of reionization and only becomes important at z ≲ 3. The predicted CXB spectrum, cosmic SMBH mass density, and SMBH mass function are generally consistent with existing observations.
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