Decreasing delirium through music (DDM) in critically ill, mechanically ventilated patients in the intensive care unit: Protocol for a randomized controlled trial

Background Delirium is a highly prevalent and morbid syndrome in intensive care units (ICUs). Changing the stressful environment within the ICU via music may be an effective and a scalable way to reduce the burden of delirium. Methods/design The Decreasing Delirium through Music (DDM) study is a three-arm, single-blind, randomized controlled feasibility trial. Sixty patients admitted to the ICU with respiratory failure requiring mechanical ventilation will be randomized to one of three arms (20 participants per arm): (1) personalized music, (2) non-personalized relaxing music, or (3) attention-control. Music preferences will be obtained from all enrolled participants or their family caregivers. Participants will receive two 1-h audio sessions a day through noise-cancelling headphones and mp3 players. Our primary aim is to determine the feasibility of the trial design (recruitment, adherence, participant retention, design and delivery of the music intervention). Our secondary aim is to estimate the potential effect size of patient-preferred music listening in reducing delirium, as measured by the Confusion Assessment Method for the ICU (CAM-ICU). Participants will receive twice daily assessments for level of sedation and presence of delirium. Enrolled participants will be followed in the hospital until death, discharge, or up to 28 days, and seen in the Critical Care Recovery Clinic at 90 days. Discussion DDM is a feasibility trial to provide personalized and non-personalized music interventions for critically ill, mechanically ventilated patients. Our trial will also estimate the preliminary efficacy of music interventions on reducing delirium incidence and severity. Trial registration ClinicalTrials.gov, Identifier: NCT03095443. Registered on 23 March 2017

A New Milky Way Dwarf Galaxy in Ursa Major

In this Letter, we report the discovery of a new dwarf satellite to the Milky Way, located at ($\alpha_{2000}, \delta_{2000}$) $=$ (158.72,51.92) in the constellation of Ursa Major. This object was detected as an overdensity of red, resolved stars in Sloan Digital Sky Survey data. The color-magnitude diagram of the Ursa Major dwarf looks remarkably similar to that of Sextans, the lowest surface brightness Milky Way companion known, but with approximately an order of magnitude fewer stars. Deeper follow-up imaging confirms this object has an old and metal-poor stellar population and is $\sim$ 100 kpc away. We roughly estimate M$_V =$ -6.75 and $r_{1/2} =$ 250 pc for this dwarf. Its luminosity is several times fainter than the faintest known Milky Way dwarf. However, its physical size is typical for dSphs. Even though its absolute magnitude and size are presently quite uncertain, Ursa Major is likely the lowest luminosity and lowest surface brightness galaxy yet known.Comment: Replaced with ApJL accepted version. Includes some additional details, corrected references, and minor changes to Figure

Ram pressure feeding super-massive black holes

When supermassive black holes at the center of galaxies accrete matter (usually gas), they give rise to highly energetic phenomena named Active Galactic Nuclei (AGN). A number of physical processes have been proposed to account for the funneling of gas towards the galaxy centers to feed the AGN. There are also several physical processes that can strip gas from a galaxy, and one of them is ram pressure stripping in galaxy clusters due to the hot and dense gas filling the space between galaxies. We report the discovery of a strong connection between severe ram pressure stripping and the presence of AGN activity. Searching in galaxy clusters at low redshift, we have selected the most extreme examples of jellyfish galaxies, which are galaxies with long tentacles of material extending for dozens of kpc beyond the galaxy disk. Using the MUSE spectrograph on the ESO Very Large Telescope, we find that 6 out of the 7 galaxies of this sample host a central AGN, and two of them also have galactic-scale AGN ionization cones. The high incidence of AGN among the most striking jellyfishes may be due to ram pressure causing gas to flow towards the center and triggering the AGN activity, or to an enhancement of the stripping caused by AGN energy injection, or both. Our analysis of the galaxy position and velocity relative to the cluster strongly supports the first hypothesis, and puts forward ram pressure as another, yet unforeseen, possible mechanism for feeding the central supermassive black hole with gas.Comment: published in Nature, Vol.548, Number 7667, pag.30

Omnibus Sequences, Coupon Collection, and Missing Word Counts

An {\it Omnibus Sequence} of length $n$ is one that has each possible "message" of length $k$ embedded in it as a subsequence. We study various properties of Omnibus Sequences in this paper, making connections, whenever possible, to the classical coupon collector problem.Comment: 26 page

Increased S-nitrosylation and proteasomal degradation of caspase-3 during infection contribute to the persistence of adherent invasive escherichia coli (AIEC) in immune cells

Adherent invasive Escherichia coli (AIEC) have been implicated as a causative agent of Crohn's disease (CD) due to their isolation from the intestines of CD sufferers and their ability to persist in macrophages inducing granulomas. The rapid intracellular multiplication of AIEC sets it apart from other enteric pathogens such as Salmonella Typhimurium which after limited replication induce programmed cell death (PCD). Understanding the response of infected cells to the increased AIEC bacterial load and associated metabolic stress may offer insights into AIEC pathogenesis and its association with CD. Here we show that AIEC persistence within macrophages and dendritic cells is facilitated by increased proteasomal degradation of caspase-3. In addition S-nitrosylation of pro- and active forms of caspase-3, which can inhibit the enzymes activity, is increased in AIEC infected macrophages. This S-nitrosylated caspase-3 was seen to accumulate upon inhibition of the proteasome indicating an additional role for S-nitrosylation in inducing caspase-3 degradation in a manner independent of ubiquitination. In addition to the autophagic genetic defects that are linked to CD, this delay in apoptosis mediated in AIEC infected cells through increased degradation of caspase-3, may be an essential factor in its prolonged persistence in CD patients

Differences in proteome perturbations caused by the Wolbachia strain wAu suggest multiple mechanisms of Wolbachia-mediated antiviral activity

Some strains of the inherited bacterium Wolbachia have been shown to be effective at reducing the transmission of dengue virus (DENV) and other RNA viruses by Aedes aegypti in both laboratory and field settings and are being deployed for DENV control. The degree of virus inhibition varies between Wolbachia strains. Density and tissue tropism can contribute to these differences but there are also indications that this is not the only factor involved: for example, strains wAu and wAlbA are maintained at similar intracellular densities but only wAu produces strong DENV inhibition. We previously reported perturbations in lipid transport dynamics, including sequestration of cholesterol in lipid droplets, with strains wMel/wMelPop in Ae. aegypti. To further investigate the cellular basis underlying these differences, proteomic analysis of midguts was carried out on Ae. aegypti lines carrying strains wAu and wAlbA: with the hypothesis that differences in perturbations may underline Wolbachia-mediated antiviral activity. Surprisingly, wAu-carrying midguts not only showed distinct proteome perturbations when compared to non-Wolbachia carrying and wAlbA-carrying midguts but also wMel-carrying midguts. There are changes in RNA processing pathways and upregulation of a specific set of RNA-binding proteins in the wAu-carrying line, including genes with known antiviral activity. Lipid transport and metabolism proteome changes also differ between strains, and we show that strain wAu does not produce the same cholesterol sequestration phenotype as wMel. Moreover, in contrast to wMel, wAu antiviral activity was not rescued by cyclodextrin treatment. Together these results suggest that wAu could show unique features in its inhibition of arboviruses compared to previously characterized Wolbachia strains

Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead.

Lifestyle factors are responsible for a considerable portion of cancer incidence worldwide, but credible estimates from the World Health Organization and the International Agency for Research on Cancer (IARC) suggest that the fraction of cancers attributable to toxic environmental exposures is between 7% and 19%. To explore the hypothesis that low-dose exposures to mixtures of chemicals in the environment may be combining to contribute to environmental carcinogenesis, we reviewed 11 hallmark phenotypes of cancer, multiple priority target sites for disruption in each area and prototypical chemical disruptors for all targets, this included dose-response characterizations, evidence of low-dose effects and cross-hallmark effects for all targets and chemicals. In total, 85 examples of chemicals were reviewed for actions on key pathways/mechanisms related to carcinogenesis. Only 15% (13/85) were found to have evidence of a dose-response threshold, whereas 59% (50/85) exerted low-dose effects. No dose-response information was found for the remaining 26% (22/85). Our analysis suggests that the cumulative effects of individual (non-carcinogenic) chemicals acting on different pathways, and a variety of related systems, organs, tissues and cells could plausibly conspire to produce carcinogenic synergies. Additional basic research on carcinogenesis and research focused on low-dose effects of chemical mixtures needs to be rigorously pursued before the merits of this hypothesis can be further advanced. However, the structure of the World Health Organization International Programme on Chemical Safety 'Mode of Action' framework should be revisited as it has inherent weaknesses that are not fully aligned with our current understanding of cancer biology

Meta-analysis of genome-wide association studies of asthma in ethnically diverse North American populations.

Asthma is a common disease with a complex risk architecture including both genetic and environmental factors. We performed a meta-analysis of North American genome-wide association studies of asthma in 5,416 individuals with asthma (cases) including individuals of European American, African American or African Caribbean, and Latino ancestry, with replication in an additional 12,649 individuals from the same ethnic groups. We identified five susceptibility loci. Four were at previously reported loci on 17q21, near IL1RL1, TSLP and IL33, but we report for the first time, to our knowledge, that these loci are associated with asthma risk in three ethnic groups. In addition, we identified a new asthma susceptibility locus at PYHIN1, with the association being specific to individuals of African descent (P = 3.9 × 10(-9)). These results suggest that some asthma susceptibility loci are robust to differences in ancestry when sufficiently large samples sizes are investigated, and that ancestry-specific associations also contribute to the complex genetic architecture of asthma