Awareness with paralysis and symptoms of post-traumatic stress disorder among mechanically ventilated emergency department survivors (ED-AWARENESS-2 Trial): study protocol for a pragmatic, multicenter, stepped wedge cluster randomized trial.

BACKGROUND: Awareness with paralysis (AWP) is memory recall during neuromuscular blockade (NMB) and can cause significant psychological harm. Decades of effort and rigorous trials have been conducted to prevent AWP in the operating room, where prevalence is 0.1-0.2%. By contrast, AWP in mechanically ventilated emergency department (ED) patients is common, with estimated prevalence of 3.3-7.4% among survivors given NMB. Longer-acting NMB use is a critical risk for AWP, and we have shown an association between ED rocuronium use and increased AWP prevalence. As NMB are given to more than 90% of ED patients during tracheal intubation, this trial provides a platform to test an intervention aimed at reducing AWP. The overall objective is to test the hypothesis that limiting ED rocuronium exposure will significantly reduce the proportion of patients experiencing AWP. METHODS: This is a pragmatic, stepped wedge cluster randomized trial conducted in five academic EDs, and will enroll 3090 patients. Per the design, all sites begin in a control phase, under observational conditions. At 6-month intervals, sites sequentially enter a 2-month transition phase, during which we will implement the multifaceted intervention, which will rely on use of nudges and defaults to change clinician decisions regarding ED NMB use. During the intervention phase, succinylcholine will be the default NMB over rocuronium. The primary outcome is AWP, assessed with the modified Brice questionnaire, adjudicated by three independent, blinded experts. The secondary outcome is the proportion of patients developing clinically significant symptoms of post-traumatic stress disorder at 30 and 180 days after hospital discharge. We will also assess for symptoms of depression and anxiety, and health-related quality of life. A generalized linear model, adjusted for time and cluster interactions, will be used to compare AWP in control versus intervention phases, analyzed by intention-to-treat. DISCUSSION: The ED-AWARENESS-2 Trial will be the first ED-based trial aimed at preventing AWP, a critical threat to patient safety. Results could shape clinical use of NMB in the ED and prevent more than 10,000 annual cases of AWP related to ED care. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT05534243 . Registered 06, September 2022

The DEEP2 Galaxy Redshift Survey: Clustering of Groups and Group Galaxies at z~1

We study the clustering properties of groups and of galaxies in groups in the DEEP2 Galaxy Redshift Survey dataset at z~1. Four clustering measures are presented: 1) the group correlation function for 460 groups with estimated velocity dispersions of sigma>200 km/s, 2) the galaxy correlation for the full galaxy sample, using a flux-limited sample of 9800 objects between 0.7<z<1.0, 3) the galaxy correlation for galaxies in groups, and 4) the group-galaxy cross-correlation function. Using the observed number density and clustering amplitude of the groups, the estimated minimum group dark matter halo mass is M_min~6 10^12 h^-1 M_Sun for a flat LCDM cosmology. Groups are more clustered than galaxies, with a relative bias of b=1.7 +/-0.04 on scales r_p=0.5-15 Mpc/h. Galaxies in groups are also more clustered than the full galaxy sample, with a scale-dependent relative bias which falls from b~2.5 +/-0.3 at r_p=0.1 Mpc/h to b~1 +/-0.5 at r_p=10 Mpc/h. The correlation functions for all galaxies and galaxies in groups can be fit by a power-law on scales r_p=0.05-20 Mpc/h. We empirically measure the contribution to the projected correlation function for galaxies in groups from a `one-halo' term and a `two-halo' term by counting pairs of galaxies in the same or in different groups. The projected cross-correlation between shows that red galaxies are more centrally concentrated in groups than blue galaxies at z~1. DEEP2 galaxies in groups appear to have a shallower radial distribution than that of mock galaxy catalogs made from N-body simulations, which assume a central galaxy surrounded by satellite galaxies with an NFW profile. We show that the clustering of galaxies in groups can be used to place tighter constraints on the halo model than can be gained from using the usual galaxy correlation function alone.Comment: 22 pages, 12 figures, in emulateapj format, accepted to ApJ, minor changes made to match published versio

Akt kinase C-terminal modifications control activation loop dephosphorylation and enhance insulin response.

The Akt protein kinase, also known as protein kinase B, plays key roles in insulin receptor signalling and regulates cell growth, survival and metabolism. Recently, we described a mechanism to enhance Akt phosphorylation that restricts access of cellular phosphatases to the Akt activation loop (Thr(308) in Akt1 or protein kinase B isoform alpha) in an ATP-dependent manner. In the present paper, we describe a distinct mechanism to control Thr(308) dephosphorylation and thus Akt deactivation that depends on intramolecular interactions of Akt C-terminal sequences with its kinase domain. Modifications of amino acids surrounding the Akt1 C-terminal mTORC2 (mammalian target of rapamycin complex 2) phosphorylation site (Ser(473)) increased phosphatase resistance of the phosphorylated activation loop (pThr(308)) and amplified Akt phosphorylation. Furthermore, the phosphatase-resistant Akt was refractory to ceramide-dependent dephosphorylation and amplified insulin-dependent Thr(308) phosphorylation in a regulated fashion. Collectively, these results suggest that the Akt C-terminal hydrophobic groove is a target for the development of agents that enhance Akt phosphorylation by insulin

Genomic analysis of expressed sequence tags in American black bear Ursus americanus

<p>Abstract</p> <p>Background</p> <p>Species of the bear family (<it>Ursidae</it>) are important organisms for research in molecular evolution, comparative physiology and conservation biology, but relatively little genetic sequence information is available for this group. Here we report the development and analyses of the first large scale Expressed Sequence Tag (EST) resource for the American black bear (<it>Ursus americanus</it>).</p> <p>Results</p> <p>Comprehensive analyses of molecular functions, alternative splicing, and tissue-specific expression of 38,757 black bear EST sequences were conducted using the dog genome as a reference. We identified 18 genes, involved in functions such as lipid catabolism, cell cycle, and vesicle-mediated transport, that are showing rapid evolution in the bear lineage Three genes, Phospholamban (<it>PLN</it>), cysteine glycine-rich protein 3 (<it>CSRP3</it>) and Troponin I type 3 (<it>TNNI3</it>), are related to heart contraction, and defects in these genes in humans lead to heart disease. Two genes, biphenyl hydrolase-like (<it>BPHL</it>) and <it>CSRP3</it>, contain positively selected sites in bear. Global analysis of evolution rates of hibernation-related genes in bear showed that they are largely conserved and slowly evolving genes, rather than novel and fast-evolving genes.</p> <p>Conclusion</p> <p>We provide a genomic resource for an important mammalian organism and our study sheds new light on the possible functions and evolution of bear genes.</p

Polymyxin Resistance in Acinetobacter baumannii: Genetic Mutations and Transcriptomic Changes in Response to Clinically Relevant Dosage Regimens

Polymyxins are often last-line therapeutic agents used to treat infections caused by multidrug-resistant A. baumannii. Recent reports of polymyxin-resistant A. baumannii highlight the urgent need for research into mechanisms of polymyxin resistance. This study employed genomic and transcriptomic analyses to investigate the mechanisms of polymyxin resistance in A. baumannii AB307-0294 using an in vitro dynamic model to mimic four different clinically relevant dosage regimens of polymyxin B and colistin over 96 h. Polymyxin B dosage regimens that achieved peak concentrations above 1 mg/L within 1 h caused significant bacterial killing (~5 log10CFU/mL), while the gradual accumulation of colistin resulted in no bacterial killing. Polymyxin resistance was observed across all dosage regimens; partial reversion to susceptibility was observed in 6 of 8 bacterial samples during drug-free passaging. Stable polymyxin-resistant samples contained a mutation in pmrB. The transcriptomes of stable and non-stable polymyxin-resistant samples were not substantially different and featured altered expression of genes associated with outer membrane structure and biogenesis. These findings were further supported via integrated analysis of previously published transcriptomics data from strain ATCC19606. Our results provide a foundation for understanding the mechanisms of polymyxin resistance following exposure to polymyxins and the need to explore effective combination therapies

The DEEP2 Galaxy Redshift Survey: The Evolution of Void Statistics from z~1 to z~0

We present measurements of the void probability function (VPF) at z~1 using data from the DEEP2 Redshift Survey and its evolution to z~0 using data from the Sloan Digital Sky Survey (SDSS). We measure the VPF as a function of galaxy color and luminosity in both surveys and find that it mimics trends displayed in the two-point correlation function, $\xi$; namely that samples of brighter, red galaxies have larger voids (i.e. are more strongly clustered) than fainter, blue galaxies. We also clearly detect evolution in the VPF with cosmic time, with voids being larger in comoving units at z~0. We find that the reduced VPF matches the predictions of a `negative binomial' model for galaxies of all colors, luminosities, and redshifts studied. This model lacks a physical motivation, but produces a simple analytic prediction for sources of any number density and integrated two-point correlation function, \bar{\xi}. This implies that differences in the VPF across different galaxy populations are consistent with being due entirely to differences in the population number density and \bar{\xi}. The robust result that all galaxy populations follow the negative binomial model appears to be due to primarily to the clustering of dark matter halos. The reduced VPF is insensitive to changes in the parameters of the halo occupation distribution, in the sense that halo models with the same \bar{\xi} will produce the same VPF. For the wide range of galaxies studied, the VPF therefore does not appear to provide useful constraints on galaxy evolution models that cannot be gleaned from studies of \bar{\xi} alone. (abridged)Comment: 17 pages, 15 figures, ApJ accepte

Processing Images from the Zwicky Transient Facility

The Zwicky Transient Facility is a new robotic-observing program, in which a newly engineered 600-MP digital camera with a pioneeringly large field of view, 47~square degrees, will be installed into the 48-inch Samuel Oschin Telescope at the Palomar Observatory. The camera will generate $\sim 1$~petabyte of raw image data over three years of operations. In parallel related work, new hardware and software systems are being developed to process these data in real time and build a long-term archive for the processed products. The first public release of archived products is planned for early 2019, which will include processed images and astronomical-source catalogs of the northern sky in the $g$ and $r$ bands. Source catalogs based on two different methods will be generated for the archive: aperture photometry and point-spread-function fitting.Comment: 6 pages, 4 figures, submitted to RTSRE Proceedings (www.rtsre.org

Growth and puberty in a 2-year open-label study of lisdexamfetamine dimesylate in children and adolescents with attention-deficit/hyperactivity disorder

Background: Stimulant medications for the treatment of attention-deficit/hyperactivity disorder have a history of safe and effective use; however, concerns exist that they may adversely affect growth trajectories in children and adolescents. Objective: The objective of this study was to evaluate the longer-term effects of lisdexamfetamine dimesylate on weight, height, body mass index and pubertal development in children and adolescents with attention-deficit/hyperactivity disorder. Methods: Children and adolescents aged 6–17 years with attention-deficit/hyperactivity disorder took open-label lisdexamfetamine dimesylate (30, 50 or 70 mg/day) in this open-label 2-year safety and efficacy study. Safety evaluations included treatment-emergent adverse events, measurement of weight, height and body mass index, and selfreported pubertal status using Tanner staging. Results: The safety analysis population comprised all enrolled participants (N = 314) and 191 (60.8%) completed the study. Weight decrease was reported as a treatmentemergent adverse event in 63 participants (20.1%) and two participants (0.6%) discontinued the study as a result of treatment-emergent adverse events of weight decrease

SDSS-IV MaNGA: Modeling the Spectral Line Spread Function to Sub-Percent Accuracy

The SDSS-IV Mapping Nearby Galaxies at APO (MaNGA) program has been operating from 2014-2020, and has now observed a sample of 9,269 galaxies in the low redshift universe (z ~ 0.05) with integral-field spectroscopy. With rest-optical (\lambda\lambda 0.36 - 1.0 um) spectral resolution R ~ 2000 the instrumental spectral line-spread function (LSF) typically has 1sigma width of about 70 km/s, which poses a challenge for the study of the typically 20-30 km/s velocity dispersion of the ionized gas in present-day disk galaxies. In this contribution, we present a major revision of the MaNGA data pipeline architecture, focusing particularly on a variety of factors impacting the effective LSF (e.g., undersampling, spectral rectification, and data cube construction). Through comparison with external assessments of the MaNGA data provided by substantially higher-resolution R ~ 10,000 instruments we demonstrate that the revised MPL-10 pipeline measures the instrumental line spread function sufficiently accurately (<= 0.6% systematic, 2% random around the wavelength of Halpha) that it enables reliable measurements of astrophysical velocity dispersions sigma_Halpha ~ 20 km/s for spaxels with emission lines detected at SNR > 50. Velocity dispersions derived from [O II], Hbeta, [O III], [N II], and [S II] are consistent with those derived from Halpha to within about 2% at sigma_Halpha > 30 km/s. Although the impact of these changes to the estimated LSF will be minimal at velocity dispersions greater than about 100 km/s, scientific results from previous data releases that are based on dispersions far below the instrumental resolution should be reevaulated.Comment: 26 pages, 23 figures. Accepted for publication in A

Capsule carbohydrate structure determines virulence in Acinetobacter baumannii

Acinetobacter baumannii is a highly antibiotic-resistant bacterial pathogen for which novel therapeutic approaches are needed. Unfortunately, the drivers of virulence in A. baumannii remain uncertain. By comparing genomes among a panel of A. baumannii strains we identified a specific gene variation in the capsule locus that correlated with altered virulence. While less virulent strains possessed the intact gene gtr6, a hypervirulent clinical isolate contained a spontaneous transposon insertion in the same gene, resulting in the loss of a branchpoint in capsular carbohydrate structure. By constructing isogenic gtr6 mutants, we confirmed that gtr6-disrupted strains were protected from phagocytosis in vitro and displayed higher bacterial burden and lethality in vivo. Gtr6+ strains were phagocytized more readily and caused lower bacterial burden and no clinical illness in vivo. We found that the CR3 receptor mediated phagocytosis of gtr6+, but not gtr6-, strains in a complement-dependent manner. Furthermore, hypovirulent gtr6+ strains demonstrated increased virulence in vivo when CR3 function was abrogated. In summary, loss-of-function in a single capsule assembly gene dramatically altered virulence by inhibiting complement deposition and recognition by phagocytes across multiple A. baumannii strains. Thus, capsular structure can determine virulence among A. baumannii strains by altering bacterial interactions with host complement-mediated opsonophagocytosis