•Exacerbation treatment outcomes for STOP2 subjects with P. aeruginosa were studied.•Outcomes were compared across number of antipseudomonal classes used.•Lung function and symptom changes and future ...exacerbation risks were compared.•Patients receiving one class fared no worse than those receiving two or more classes.
Cystic fibrosis (CF) pulmonary exacerbation (PEx) treatment guidelines suggest that Pseudomonas aeruginosa (Pa) airway infection be treated with two antipseudomonal agents.
We retrospectively studied treatment responses for STOP2 PEx treatment trial (NCT02781610) participants with a history of Pa infection. Mean lung function and symptom changes from intravenous (IV) antimicrobial treatment start to Visit 2 (7 to 10 days later) were compared between those receiving one, two, and three+ antipseudomonal classes before Visit 2 by ANCOVA. Odds of PEx retreatment with IV antimicrobials within 30 days and future IV-treated PEx hazard were modeled by logistic and Cox proportional hazards regression, respectively. Sensitivity analyses limited to the most common one-, two-, and three-class regimens, to only IV/oral antipseudomonal treatments, and with more stringent Pa infection definitions were conducted.
Among 751 participants, 50 (6.7%) were treated with one antipseudomonal class before Visit 2, while 552 (73.5%) and 149 (19.8%) were treated with two and with three+ classes, respectively. Females and participants with a negative Pa culture in the prior month were more likely to be treated with a single class. The most common single, double, and triple class regimens were beta-lactam (BL; n = 42), BL/aminoglycoside (AG; n = 459), and BL/AG/fluoroquinolone (FQ; n = 73). No lung function or symptom response, odds of retreatment, or future PEx hazard differences were observed by number of antipseudomonal classes administered in primary or sensitivity analyses.
We were unable to identify additional benefit when multiple antipseudomonal classes are used to treat PEx in people with CF and Pa.
Guidelines currently recommend targeting light sedation with dexmedetomidine or propofol for adults receiving mechanical ventilation. Differences exist between these sedatives in arousability, ...immunity, and inflammation. Whether they affect outcomes differentially in mechanically ventilated adults with sepsis undergoing light sedation is unknown.
In a multicenter, double-blind trial, we randomly assigned mechanically ventilated adults with sepsis to receive dexmedetomidine (0.2 to 1.5 μg per kilogram of body weight per hour) or propofol (5 to 50 μg per kilogram per minute), with doses adjusted by bedside nurses to achieve target sedation goals set by clinicians according to the Richmond Agitation-Sedation Scale (RASS, on which scores range from -5 unresponsive to +4 combative). The primary end point was days alive without delirium or coma during the 14-day intervention period. Secondary end points were ventilator-free days at 28 days, death at 90 days, and age-adjusted total score on the Telephone Interview for Cognitive Status questionnaire (TICS-T; scores range from 0 to 100, with a mean of 50±10 and lower scores indicating worse cognition) at 6 months.
Of 432 patients who underwent randomization, 422 were assigned to receive a trial drug and were included in the analyses - 214 patients received dexmedetomidine at a median dose of 0.27 μg per kilogram per hour, and 208 received propofol at a median dose of 10.21 μg per kilogram per minute. The median duration of receipt of the trial drugs was 3.0 days (interquartile range, 2.0 to 6.0), and the median RASS score was -2.0 (interquartile range, -3.0 to -1.0). We found no difference between dexmedetomidine and propofol in the number of days alive without delirium or coma (adjusted median, 10.7 vs. 10.8 days; odds ratio, 0.96; 95% confidence interval CI, 0.74 to 1.26), ventilator-free days (adjusted median, 23.7 vs. 24.0 days; odds ratio, 0.98; 95% CI, 0.63 to 1.51), death at 90 days (38% vs. 39%; hazard ratio, 1.06; 95% CI, 0.74 to 1.52), or TICS-T score at 6 months (adjusted median score, 40.9 vs. 41.4; odds ratio, 0.94; 95% CI, 0.66 to 1.33). Safety end points were similar in the two groups.
Among mechanically ventilated adults with sepsis who were being treated with recommended light-sedation approaches, outcomes in patients who received dexmedetomidine did not differ from outcomes in those who received propofol. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT01739933.).
Abstract Background Despite advances in therapeutic interventions AF remains a progressive and symptomatic disease. Therefore, novel therapeutic interventions targeting the underlying arrhythmogenic ...substrate for AF is needed. Atrial fibrosis is an important component of the arrhythmogenic substrate of AF and may be initiated by aldosterone binding to the mineralocorticoid receptor. We hypothesized that aldosterone pathway blockade with mineralocorticoid receptor antagonists (MRA) reduces atrial fibrosis, and thus AF. Methods We searched OVID MEDLINE, OVID EMBASE and the Cochrane Central Register of Controlled Trials from inception to June 10th, 2016 for randomized controlled trials (RCT) and observational studies addressing MRA and providing information on AF occurrence. Two independent reviewers selected and appraised the data. We performed fixed-effects or random-effects meta-analyses as appropriate. Summary odds ratios (OR) with 95% confidence intervals (CI) were calculated. Results We included 14 studies, 5 RCT and 9 observational cohorts, with a cumulative number of 5332 patients (male: 74.9%, age: 65.3 years); 2397 (45.0%) received an MRA (spironolactone or eplerenone). During follow-up, 204 (8.5%) patients treated with MRAs, developed AF, compared to 547 (18.6%) patients, without MRA treatment. Meta-analyses showed a significant overall reduction of AF risk in MRA treated patients (OR: 0.48 CI: 0.38–0.60 p < 0.001), including a reduction of new-onset AF (OR: 0.52 CI: 0.37–0.74 p < 0.001) and recurrent AF (OR: 0.37 CI: 0.24–0.57 p < 0.001), but not post-operative AF (POAF) (OR: 0.60 CI: 0.33–1.09 p = 0.09). Conclusions MRAs significantly reduce new-onset AF and recurrent AF, but not POAF. MRA treatment can be considered an additive therapeutic strategy in AF.
ABSTRACT We present the GALEX detection of a UV burst at the time of explosion of an optically normal supernova (SN) IIP (PS1-13arp) from the Pan-STARRS1 survey at z = 0.1665. The temperature and ...luminosity of the UV burst match the theoretical predictions for shock breakout in a red supergiant (RSG), but with a duration a factor of ∼50 longer than expected. We compare the NUV light curve of PS1-13arp to previous GALEX detections of SNe IIP and find clear distinctions that indicate that the UV emission is powered by shock breakout, and not by the subsequent cooling envelope emission previously detected in these systems. We interpret the ∼1 day duration of the UV signal with a shock breakout in the wind of an RSG with a pre-explosion mass-loss rate of yr−1. This mass-loss rate is enough to prolong the duration of the shock breakout signal, but not enough to produce an excess in the optical plateau light curve or narrow emission lines powered by circumstellar interaction. This detection of non-standard, potentially episodic high mass loss in an RSG SN progenitor has favorable consequences for the prospects of future wide-field UV surveys to detect shock breakout directly in these systems, and provide a sensitive probe of the pre-explosion conditions of SN progenitors.
Historically, light curve studies of supernovae (SNe) and other transient classes have focused on individual objects with copious and high signal-to-noise observations. In the nascent era of wide ...field transient searches, objects with detailed observations are decreasing as a fraction of the overall known SN population, and this strategy sacrifices the majority of the information contained in the data about the underlying population of transients. A population level modeling approach, simultaneously fitting all available observations of objects in a transient sub-class of interest, fully mines the data to infer the properties of the population and avoids certain systematic biases. We present a novel hierarchical Bayesian statistical model for population level modeling of transient light curves, and discuss its implementation using an efficient Hamiltonian Monte Carlo technique. As a test case, we apply this model to the Type IIP SN sample from the Pan-STARRS1 Medium Deep Survey, consisting of 18,837 photometric observations of 76 SNe, corresponding to a joint posterior distribution with 9176 parameters under our model. Our hierarchical model fits provide improved constraints on light curve parameters relevant to the physical properties of their progenitor stars relative to modeling individual light curves alone. Moreover, we directly evaluate the probability for occurrence rates of unseen light curve characteristics from the model hyperparameters, addressing observational biases in survey methodology. We view this modeling framework as an unsupervised machine learning technique with the ability to maximize scientific returns from data to be collected by future wide field transient searches like LSST.
Aims. We provide an in-depth analysis of the COSMOS-Web ring, an Einstein ring at z ≈ 2 that we serendipitously discovered during the data reduction of the COSMOS-Web survey and that could be the ...most distant lens discovered to date. Methods. We extracted the visible and near-infrared photometry of the source and the lens from more than 25 bands. We combined these observations with far-infrared detections to study the dusty nature of the source and we derived the photometric redshifts and physical properties of both the lens and the source with three different spectral energy distribution (SED) fitting codes. Using JWST/NIRCam images, we also produced two lens models to (i) recover the total mass of the lens, (ii) derive the magnification of the system, (iii) reconstruct the morphology of the lensed source, and (iv) measure the slope of the total mass density profile of the lens. Results. We find the lens to be a very massive elliptical galaxy at z = 2.02 ± 0.02 with a total mass within the Einstein radius of M tot (< θ Ein = (3.66 ± 0.36) × 10 11 M ⊙ and a total stellar mass of M ⋆ = 1.37 −0.11 +0.14 × 10 11 M ⊙ . We also estimate it to be compact and quiescent with a specific star formation rate below 10 −13 yr. Compared to stellar-to-halo mass relations from the literature, we find that the total mass of the lens within the Einstein radius is consistent with the presence of a dark matter (DM) halo of total mass M h = 1.09 −0.57 +1.46 × 10 13 M ⊙ . In addition, the background source is a M ⋆ = (1.26 ± 0.17) × 10 10 M ⊙ star-forming galaxy (SFR ≈ (78 ± 15) M ⊙ yr) at z = 5.48 ± 0.06. The morphology reconstructed in the source plane shows two clear components with different colors. Dust attenuation values from SED fitting and nearby detections in the far infrared also suggest that the background source could be at least partially dust-obscured. Conclusions. We find the lens at z ≈ 2. Its total, stellar, and DM halo masses are consistent within the Einstein ring, so we do not need any unexpected changes in our description of the lens such as changing its initial mass function or including a non-negligible gas contribution. The most likely solution for the lensed source is at z ≈ 5.5. Its reconstructed morphology is complex and highly wavelength dependent, possibly because it is a merger or a main sequence galaxy with a heterogeneous dust distribution.
We report on our discovery and observations of the Pan-STARRS1 supernova (SN) PS1-12sk, a transient with properties that indicate atypical star formation in its host galaxy cluster or pose a ...challenge to popular progenitor system models for this class of explosion. The optical spectra of PS1-12sk classify it as a Type Ibn SN (SN Ibn; cf. SN 2006jc), dominated by intermediate-width (3 x 10 super(3) km s super(-1)) and time variable He I emission. Our multi-wavelength monitoring establishes the rise time dt ~ 9-23 days and shows an NUV-NIR spectral energy distribution with temperature > ~17 x 10 super(3) K and a peak magnitude of M sub(z) = -18.88 + or - 0.02 mag. SN Ibn spectroscopic properties are commonly interpreted as the signature of a massive star (17-100 M sub(middot in circle)) explosion within an He-enriched circumstellar medium. However, unlike previous SNe Ibn, PS1-12sk is associated with an elliptical brightest cluster galaxy, CGCG 208-042 (z = 0.054) in cluster RXC J0844.9+4258. The expected probability of an event like PS1-12sk in such environments is low given the measured infrequency of core-collapse SNe in red-sequence galaxies compounded by the low volumetric rate of SN Ibn. Furthermore, we find no evidence of star formation at the explosion site to sensitive limits (Sigma sub(Halpha) <, ~ 2 x 10 super(-3) M sub(middot in circle) yr super(-1) kpc super(-2)). We therefore discuss white dwarf binary systems as a possible progenitor channel for SNe Ibn. We conclude that PSl-12sk represents either a fortuitous and statistically unlikely discovery, evidence for a top-heavy initial mass function in galaxy cluster cooling flow filaments, or the first clue suggesting an alternate progenitor channel for SNe Ibn.
Type 1 interferon (IFN-1) promotes regulatory T-cell function to suppress inflammation in the mouse intestine, but little is known about IFN-1 in the human gut. We therefore assessed the influence of ...IFN-1 on CD4+ T-cells isolated from human colon tissue obtained from healthy controls or patients with inflammatory bowel disease (IBD). Immunofluorescent imaging revealed constitutive expression of IFNβ in human intestinal tissue, and colonic T-cells were responsive to exogenous IFN-1 as assessed by phosphorylation of signal transduction and activator of transcription 1 (pSTAT1) and induction of interferon stimulated genes (ISGs). Unlike their blood counterparts, intestinal T-cells from non-inflamed regions of IBD colon displayed enhanced responsiveness to IFN-1, increased frequency of pSTAT1+ cells, and greater induction of ISGs upon IFN-1 exposure in vitro. In healthy tissue, antibody neutralization of IFNβ selectively reduced T-cell production of the pro-regulatory cytokine interleukin-10 (IL-10) and increased IFNγ synthesis. In contrast, neutralization of IFNβ in IBD tissue cultures increased the frequency of T-cells producing inflammatory cytokines but did not alter IL-10 expression. These data support a role for endogenous IFN-1 as a context-dependent modulator of T-cell function that promotes regulatory activity in healthy human intestine, but indicate that the IFN-1/STAT1 pathway is dysregulated in inflammatory bowel disease.
We present Very Long Baseline Array (VLBA) observations of the nucleus of NGC 1275, the central, dominant galaxy in the Perseus cluster of galaxies. These are the first observations to resolve the ...linearly polarized emission from 3C 84, and from them we determine a Faraday rotation measure (RM) ranging from 6500 to 7500 rad m−2 across the tip of the bright southern jet component. At 22 GHz some polarization is also detected from the central pc of 3C 84, indicating the presence of even more extreme RMs that depolarize the core at lower frequencies. The nature of the Faraday screen is most consistent with being produced by magnetic fields associated with the optical filaments of ionized gas in the Perseus cluster.
An algorithm setup for the operational Aerosol Layer Height product for TROPOMI on the Sentinel-5 Precursor mission is described and discussed, applied to GOME-2A data, and evaluated with lidar ...measurements. The algorithm makes a spectral fit of reflectance at theO2 A band in the near-infrared and the fit window runs from 758 to 770 nm. The aerosol profile is parameterised by a scattering layer with constant aerosol volume extinction coefficient and aerosol single scattering albedo and with a fixed pressure thickness. The algorithm's target parameter is the height of this layer. In this paper, we apply the algorithm to observations from GOME-2A in a number of systematic and extensive case studies, and we compare retrieved aerosol layer heights with lidar measurements. Aerosol scenes cover various aerosol types, both elevated and boundary layer aerosols, and land and sea surfaces. The aerosol optical thicknesses for these scenes are relatively moderate. Retrieval experiments with GOME-2A spectra are used to investigate various sensitivities, in which particular attention is given to the role of the surface albedo.From retrieval simulations with the single-layer model, we learn that the surface albedo should be a fit parameter when retrieving aerosol layer height from the O2 A band. Current uncertainties in surface albedo climatologies cause biases and non-convergences when the surface albedo is fixed in the retrieval. Biases disappear and convergence improves when the surface albedo is fitted, while precision of retrieved aerosol layer pressure is still largely within requirement levels. Moreover, we show that fitting the surface albedo helps to ameliorate biases in retrieved aerosol layer height when the assumed aerosol model is inaccurate. Subsequent retrievals with GOME-2A spectra confirm that convergence is better when the surface albedo is retrieved simultaneously with aerosol parameters. However, retrieved aerosol layer pressures are systematically low (i.e., layer high in the atmosphere) to the extent that retrieved values no longer realistically represent actual extinction profiles. When the surface albedo is fixed in retrievals with GOME-2A spectra, convergence deteriorates as expected, but retrieved aerosol layer pressures become much higher (i.e., layer lower in atmosphere). The comparison with lidar measurements indicates that retrieved aerosol layer heights are indeed representative of the underlying profile in that case. Finally, subsequent retrieval simulations with two-layer aerosol profiles show that a model error in the assumed profile (two layers in the simulation but only one in the retrieval) is partly absorbed by the surface albedo when this parameter is fitted. This is expected in view of the correlations between errors in fit parameters and the effect is relatively small for elevated layers (less than 100 hPa). If one of the scattering layers is near the surface (boundary layer aerosols), the effect becomes surprisingly large, in such a way that the retrieved height of the single layer is above the two-layer profile.Furthermore, we find that the retrieval solution, once retrieval converges, hardly depends on the starting values for the fit. Sensitivity experiments with GOME-2A spectra also show that aerosol layer height is indeed relatively robust against inaccuracies in the assumed aerosol model, even when the surface albedo is not fitted. We show spectral fit residuals, which can be used for further investigations. Fit residuals may be partly explained by spectroscopic uncertainties, which is suggested by an experiment showing the improvement of convergence when the absorption cross section is scaled in agreement with Butz et al. (2013) and Crisp et al. (2012), and a temperature offset to the a priori ECMWF temperature profile is fitted. Retrieved temperature offsets are always negative and quite large (ranging between -4 and -8 K), which is not expected if temperature offsets absorb remaining inaccuracies in meteorological data. Other sensitivity experiments investigate fitting of stray light and fluorescence emissions. We find negative radiance offsets and negative fluorescence emissions, also for non-vegetated areas, but from the results it is not clear whether fitting these parameters improves the retrieval.Based on the present results, the operational baseline for the Aerosol Layer Height product currently will not fit the surface albedo. The product will be particularly suited for elevated, optically thick aerosol layers. In addition to its scientific value in climate research, anticipated applications of the product for TROPOMI are providing aerosol height information for aviation safety and improving interpretation of the Absorbing Aerosol Index.
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