The goal of this study is to create a predictive, interpretable model of early hospital respiratory failure among emergency department (ED) patients admitted with coronavirus disease 2019 (COVID-19).
...This was an observational, retrospective, cohort study from a 9-ED health system of admitted adult patients with severe acute respiratory syndrome coronavirus 2 (COVID-19) and an oxygen requirement less than or equal to 6 L/min. We sought to predict respiratory failure within 24 hours of admission as defined by oxygen requirement of greater than 10 L/min by low-flow device, high-flow device, noninvasive or invasive ventilation, or death. Predictive models were compared with the Elixhauser Comorbidity Index, quick Sequential Sepsis-related Organ Failure Assessment, and the CURB-65 pneumonia severity score.
During the study period, from March 1 to April 27, 2020, 1,792 patients were admitted with COVID-19, 620 (35%) of whom had respiratory failure in the ED. Of the remaining 1,172 admitted patients, 144 (12.3%) met the composite endpoint within the first 24 hours of hospitalization. On the independent test cohort, both a novel bedside scoring system, the quick COVID-19 Severity Index (area under receiver operating characteristic curve mean 0.81 95% confidence interval {CI} 0.73 to 0.89), and a machine-learning model, the COVID-19 Severity Index (mean 0.76 95% CI 0.65 to 0.86), outperformed the Elixhauser mortality index (mean 0.61 95% CI 0.51 to 0.70), CURB-65 (0.50 95% CI 0.40 to 0.60), and quick Sequential Sepsis-related Organ Failure Assessment (0.59 95% CI 0.50 to 0.68). A low quick COVID-19 Severity Index score was associated with a less than 5% risk of respiratory decompensation in the validation cohort.
A significant proportion of admitted COVID-19 patients progress to respiratory failure within 24 hours of admission. These events are accurately predicted with bedside respiratory examination findings within a simple scoring system.
To assess the clinical effectiveness and cost-effectiveness of buprenorphine maintenance therapy (BMT) and methadone maintenance therapy (MMT) for the management of opioid-dependent individuals.
...Major electronic databases were searched from inception to August 2005. Industry submissions to the National Institute for Health and Clinical Excellence were accessed.
The assessment of clinical effectiveness was based on a review of existing reviews plus an updated search for randomised controlled trials (RCTs). A decision tree with Monte Carlo simulation model was developed to assess the cost-effectiveness of BMT and MMT. Retention in treatment and opiate abuse parameters were sourced from the meta-analysis of RCTs directly comparing flexible MMT with flexible dose BMT. Utilities were derived from a panel representing a societal perspective.
Most of the included systematic reviews and RCTs were of moderate to good quality, and focused on short-term (up to 1-year follow-up) outcomes of retention in treatment and the level of opiate use (self-report or urinalysis). Most studies employed a trial design that compared a fixed-dose strategy (i.e. all individuals received a standard dose) of MMT or BMT and were conducted in predominantly young men who fulfilled criteria as opiate-dependent or heroin-dependent users, without significant co-morbidities. RCT meta-analyses have shown that a fixed dose of MMT or BMT has superior levels of retention in treatment and opiate use than placebo or no treatment, with higher fixed doses being more effective than lower fixed doses. There was evidence, primarily from non-randomised observational studies, that fixed-dose MMT reduces mortality, HIV risk behaviour and levels of crime compared with no therapy and one small RCT has shown the level of mortality with fixed-dose BMT to be significantly less than with placebo. Flexible dosing (i.e. individualised doses) of MMT and BMT is more reflective of real-world practice. Retention in treatment was superior for flexible MMT than flexible BMT dosing but there was no significant difference in opiate use. Indirect comparison of data from population cross-sectional studies suggests that mortality with BMT may be lower than that with MMT. A pooled RCT analysis showed no significant difference in serious adverse events with MMT compared with BMT. Although treatment modifier evidence was limited, adjunct psychosocial and contingency interventions (e.g. financial incentives for opiate-free urine samples) appeared to enhance the effects of both MMT and BMT. Also, MMT and BMT appear to be similarly effective whether delivered in a primary care or outpatient clinic setting. Although most of the included economic evaluations were considered to be of high quality, none used all of the appropriate parameters, effectiveness data, perspective and comparators required to make their results generalisable to the NHS context. One company (Schering-Plough) submitted cost-effectiveness evidence based on an economic model that had a 1-year time horizon and sourced data from a single RCT of flexible-dose MMT compared with flexible-dose BMT and utility values obtained from the literature; the results showed that for MMT vs no drug therapy, the incremental cost-effectiveness ratio (ICER) was pound 12,584/quality-adjusted life-year (QALY), for BMT versus no drug therapy, the ICER was pound 30,048/QALY and in a direct comparison, MMT was found to be slightly more effective and less costly than BMT. The assessment group model found for MMT versus no drug therapy that the ICER was pound 13,697/QALY, for BMT versus no drug therapy that the ICER was pound 26,429/QALY and, as with the industry model, in direct comparison, MMT was slightly more effective and less costly than BMT. When considering social costs, both MMT and BMT gave more health gain and were less costly than no drug treatment. These findings were robust to deterministic and probabilistic sensitivity analyses.
Both flexible-dose MMT and BMT are more clinically effective and more cost-effective than no drug therapy in dependent opiate users. In direct comparison, a flexible dosing strategy with MMT was found be somewhat more effective in maintaining individuals in treatment than flexible-dose BMT and therefore associated with a slightly higher health gain and lower costs. However, this needs to be balanced by the more recent experience of clinicians in the use of buprenorphine, the possible risk of higher mortality of MMT and individual opiate-dependent users' preferences. Future research should be directed towards the safety and effectiveness of MMT and BMT; potential safety concerns regarding methadone and buprenorphine, specifically mortality and key drug interactions; efficacy of substitution medications (in particular patient subgroups, such as within the criminal justice system, or within young people); and uncertainties in cost-effectiveness identified by current economic models.
Elements of celestial conformal field theory Fan, Wei; Fotopoulos, Angelos; Stieberger, Stephan ...
The journal of high energy physics,
08/2022, Letnik:
2022, Številka:
8
Journal Article
Recenzirano
Odprti dostop
A
bstract
In celestial holography, four-dimensional scattering amplitudes are considered as two-dimensional conformal correlators of a putative two-dimensional celestial conformal field theory ...(CCFT). The simplest way of converting momentum space amplitudes into CCFT correlators is by taking their Mellin transforms with respect to light-cone energies. For massless particles, like gluons, however, such a construction leads to three-point and four-point correlators that vanish everywhere except for a measure zero hypersurface of celestial coordinates. This is due to the four-dimensional momentum conservation law that constrains the insertion points of the operators associated with massless particles. These correlators are reminiscent of Coulomb gas correlators that, in the absence of background charges, vanish due to charge conservation. We supply the background momentum by coupling Yang-Mills theory to a background dilaton field, with the (complex) dilaton source localized on the celestial sphere. This picture emerges from the physical interpretation of the solutions of the system of differential equations discovered by Banerjee and Ghosh. We show that the solutions can be written as Mellin transforms of the amplitudes evaluated in such a dilaton background. The resultant three-gluon and four-gluon amplitudes are single-valued functions of celestial coordinates enjoying crossing symmetry and all other properties expected from standard CFT correlators. We use them to extract OPEs and compare them with the OPEs extracted from multi-gluon celestial amplitudes without a dilaton background. We perform the conformal block decomposition of the four-gluon single-valued correlator and determine the dimensions, spin and group representations of the entire primary field spectrum of the Yang-Mills sector of CCFT.
Abstract
We calculate the properties, occurrence rates and detection prospects of individually resolvable ‘single sources’ in the low-frequency gravitational wave (GW) spectrum. Our simulations use ...the population of galaxies and massive black hole binaries from the Illustris cosmological hydrodynamic simulations, coupled to comprehensive semi-analytic models of the binary merger process. Using mock pulsar timing arrays (PTA) with, for the first time, varying red-noise models, we calculate plausible detection prospects for GW single sources and the stochastic GW background (GWB). Contrary to previous results, we find that single sources are at least as detectable as the GW background. Using mock PTA, we find that these ‘foreground’ sources (also ‘deterministic’/‘continuous’) are likely to be detected with ∼20 yr total observing baselines. Detection prospects, and indeed the overall properties of single sources, are only moderately sensitive to binary evolution parameters – namely eccentricity and environmental coupling, which can lead to differences of ∼5 yr in times to detection. Red noise has a stronger effect, roughly doubling the time to detection of the foreground between a white-noise only model (∼10–15 yr) and severe red noise (∼20–30 yr). The effect of red noise on the GWB is even stronger, suggesting that single source detections may be more robust. We find that typical signal-to-noise ratios for the foreground peak near f = 0.1 yr−1, and are much less sensitive to the continued addition of new pulsars to PTA.
Cryptococcus neoformans was first described as a human fungal pathogen more than a century ago. One aspect of the C. neoformans infectious life cycle that has been the subject of earnest debate is ...whether the spores are pathogenic. Despite much speculation, no direct evidence has been presented to resolve this outstanding question. We present evidence that C. neoformans spores are pathogenic in a mouse intranasal inhalation model of infection. In addition, we provide mechanistic insights into spore-host interactions. We found that C. neoformans spores were phagocytosed by alveolar macrophages via interactions between fungal β-(1,3)-glucan and the host receptors Dectin-1 and CD11b. Moreover, we discovered an important link between spore survival and macrophage activation state: intracellular spores were susceptible to reactive oxygen-nitrogen species. We anticipate these results will serve as the basis for a model to further investigate the pathogenic implications of infections caused by fungal spores.
Diabetes initiates inflammation that can impair the retinal vasculature, and lead to diabetic retinopathy; one of the leading causes of blindness. Inflammatory pathways have been examined as ...potential therapeutic targets for diabetic retinopathy, but there is still a need for early-stage treatments. We hypothesized that the CD40-TNF Receptor Associated Factor 6 (TRAF6) axis plays a pivotal role in the onset of diabetic retinopathy, and that the CD40-TRAF6 axis would be a prime therapeutic target for early-stage non-proliferative diabetic retinopathy. The CD40-TRAF6 complex can initiate NFκB activation, inflammation, and tissue damage. Further, CD40 and TRAF6 are constitutively expressed on Muller glia, and upregulated in the diabetic retina. Yet the role of the CD40-TRAF6 complex in the onset of diabetic retinopathy is still unclear. In the current study, we examined the CD40-TRAF6 axis in diabetic retinopathy using a small molecule inhibitor (SMI-6877002) on streptozotocin-induced diabetic mice. When CD40-TRAF6-dependent inflammation was inhibited, retinal vascular leakage and capillary degeneration was ameliorated in diabetic mice. Collectively, these data suggest that the CD40-TRAF6 axis plays a pivotal role in the onset of diabetic retinopathy, and could be a novel therapeutic target for early diabetic retinopathy.
In an application of the social cognitive model of career self-management (Lent & Brown, 2013), we assessed the primary experiential sources of self-efficacy and outcome expectations relative to ...career exploration and decision-making activities. These sources included personal mastery, verbal persuasion, vicarious learning, and affect (both positive and negative) experienced in relation to career exploration and decision-making. Participants were 324 college students, who completed an experiential sources measure along with domain-correspondent measures of self-efficacy, outcome expectations, goals, and level of career decidedness. A confirmatory factor analysis offered support for a 5-factor representation of the experiential sources, though the personal mastery and verbal persuasion sources were substantially interrelated. As a set, the source variables accounted for a larger portion of the variance in self-efficacy than outcome expectations, with much of their relation to outcome expectations being mediated by self-efficacy. Good support was also found for a path model including the source variables in the prediction of career exploration goals and level of career decidedness. Though the sources were generally linked to goals indirectly, mastery and positive affect both produced significant direct paths to level of decidedness. The findings are interpreted in light of social cognitive career theory and their implications for further research and practice are discussed.
•Extended a social cognitive model to career exploration and decision-making•Developed a measure of the sources of self-efficacy and outcome expectations•The measure produced adequate reliability and validity estimates.•Used the measure in a test of the social cognitive model of career self-management•The self-management model fit the data well, especially with slight modification.
Bacteria play an indispensable role in marine biogeochemistry by recycling dissolved organic matter. Motile species can exploit small, ephemeral solute patches through chemotaxis and thereby gain a ...fitness advantage over nonmotile competitors. This competition occurs in a turbulent environment yet turbulence is generally considered inconsequential for bacterial uptake. In contrast, we show that turbulence affects uptake by stirring nutrient patches into networks of thin filaments that motile bacteria can readily exploit. We find that chemotactic motility is subject to a trade-off between the uptake benefit due to chemotaxis and the cost of locomotion, resulting in an optimal swimming speed. A second trade-off results from the competing effects of stirring and mixing and leads to the prediction that chemotaxis is optimally favored at intermediate turbulence intensities.
High rates of relapse to drug use during abstinence is a defining feature of human drug addiction. This clinical scenario has been studied at the preclinical level using different animal models in ...which relapse to drug seeking is assessed after cessation of operant drug self-administration in rodents and monkeys. In our Society for Neuroscience (SFN) session entitled "Circuit and Synaptic Plasticity Mechanisms of Drug Relapse," we will discuss new developments of our understanding of circuits and synaptic plasticity mechanisms of drug relapse from studies combining established and novel animal models with state-of-the-art cellular, electrophysiology, anatomical, chemogenetic, and optogenetic methods. We will also discuss the translational implications of these new developments. In the mini-review that introduces our SFN session, we summarize results from our laboratories on behavioral, cellular, and circuit mechanisms of drug relapse within the context of our session.
A comprehensive database of zircon composition in West Australian magmatic rocks reveals negative correlations between both U and Th zircon/whole rock ratio and the zircon saturation temperature, ...with the observed change with temperature less for U(zircon/whole rock) than for Th(zircon/whole rock). This observation implies a systematic increase in the zircon/rock ratio with falling crystallisation temperature, a result which replicates findings from experimental partition coefficient studies. Under equilibrium conditions there is a trend to lower zircon Th/U with increasing melt temperature which can be attributed to lattice strain. However, within a fractionating magma, Ti-in-zircon temperatures yield the opposite relationship of lower zircon Th/U in cooler melts. This is due to zircon growth under non-equilibrium conditions with greater incompatibility of Th relative to U, and the removal and segregation of mineral precipitates. These observations can be used as a tool to determine whether zircon growth was in a liquid of similar composition to the observed whole rock. We present an equation that estimates the degree of fractionation between the whole rock composition and the zircon parental liquid. This parameter demonstrates the dissimilarity between the liquid from which the zircon grew and the whole rock composition and aids in distinguishing mesostasis growth in fractionated melt versus cumulate growth in less fractionated magma. We use this ratio to investigate zircon growth in igneous rocks of the Musgrave Province. For a suite of c. 1200Ma magmas that become progressively more fractionated, based on whole rock La/Sm, the fractionation index demonstrates increasing compositional differences between the whole rock and the zircon growth liquid. In the most extreme case independent petrographic evidence indicates mesostasis growth of zircon, whereas in the least fractionated melt zircon growth is established to be close to equilibrium with a zircon saturation temperature of c. 900°C likely being accurate. In contrast, zircon crystals from a rhyolite of the c. 1070Ma Giles Supervolcano have distinctive compositional discordances indicative of antecrystic components. The fractionation factor in this rock implies some zircon growth under higher temperature conditions than the whole rock zircon saturation temperature.
•We present >10,000 zircon Th/U ratios from chemically classified igneous rocks.•Zircon Th/U ratio decreases with whole rock zircon saturation temperatures.•Zircon Th/U ratio increases with Ti-in-zircon temperatures.•Difference due to equilibrium versus fractional crystallisation.•Provide equation with case studies to understand the zircon growth mechanism.
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