A genomic portrait of the emergence, evolution, and global spread of a methicillin-resistant staphylococcus aureus pandemic

The widespread use of antibiotics in association with high-density clinical care has driven the emergence of drug-resistant bacteria that are adapted to thrive in hospitalized patients. Of particular concern are globally disseminated methicillin-resistant Staphylococcus aureus (MRSA) clones that cause outbreaks and epidemics associated with health care. The most rapidly spreading and tenacious health-care-associated clone in Europe currently is EMRSA-15, which was first detected in the UK in the early 1990s and subsequently spread throughout Europe and beyond. Using phylogenomic methods to analyze the genome sequences for 193 S. aureus isolates, we were able to show that the current pandemic population of EMRSA-15 descends from a health-care-associated MRSA epidemic that spread throughout England in the 1980s, which had itself previously emerged from a primarily community-associated methicillin-sensitive population. The emergence of fluoroquinolone resistance in this EMRSA-15 subclone in the English Midlands during the mid-1980s appears to have played a key role in triggering pandemic spread, and occurred shortly after the first clinical trials of this drug. Genome-based coalescence analysis estimated that the population of this subclone over the last 20 yr has grown four times faster than its progenitor. Using comparative genomic analysis we identified the molecular genetic basis of 99.8% of the antimicrobial resistance phenotypes of the isolates, highlighting the potential of pathogen genome sequencing as a diagnostic tool. We document the genetic changes associated with adaptation to the hospital environment and with increasing drug resistance over time, and how MRSA evolution likely has been influenced by country-specific drug use regimens

Can residuals of the Solar system foreground explain low multipole anomalies of the CMB ?

The low multipole anomalies of the Cosmic Microwave Background has received much attention during the last few years. It is still not ascertained whether these anomalies are indeed primordial or the result of systematics or foregrounds. An example of a foreground, which could generate some non-Gaussian and statistically anisotropic features at low multipole range, is the very symmetric Kuiper Belt in the outer solar system. In this paper, expanding upon the methods presented by Maris et al. (2011), we investigate the contributions from the Kuiper Belt objects (KBO) to the WMAP ILC 7 map, whereby we can minimize the contrast in power between even and odd multipoles in the CMB, discussed discussed by Kim & Naselsky (2010). We submit our KBO de-correlated CMB signal to several tests, to analyze its validity, and find that incorporation of the KBO emission can decrease the quadrupole-octupole alignment and parity asymmetry problems, provided that the KBO signals has a non-cosmological dipole modulation, associated with the statistical anisotropy of the ILC 7 map. Additionally, we show that the amplitude of the dipole modulation, within a 2 sigma interval, is in agreement with the corresponding amplitudes, discussed by Lew (2008).Comment: 24 pages, 9 figures, 5 tables. Matches version in JCA

The impact of COVID-19 critical illness on new disability, functional outcomes and return to work at 6 months: a prospective cohort study

Background: There are few reports of new functional impairment following critical illness from COVID-19. We aimed to describe the incidence of death or new disability, functional impairment and changes in health-related quality of life of patients after COVID-19 critical illness at 6 months. Methods: In a nationally representative, multicenter, prospective cohort study of COVID-19 critical illness, we determined the prevalence of death or new disability at 6 months, the primary outcome. We measured mortality, new disability and return to work with changes in the World Health Organization Disability Assessment Schedule 2.0 12L (WHODAS) and health status with the EQ5D-5LTM. Results: Of 274 eligible patients, 212 were enrolled from 30 hospitals. The median age was 61 (51–70) years, and 124 (58.5%) patients were male. At 6 months, 43/160 (26.9%) patients died and 42/108 (38.9%) responding survivors reported new disability. Compared to pre-illness, the WHODAS percentage score worsened (mean difference (MD), 10.40% [95% CI 7.06–13.77]; p < 0.001). Thirteen (11.4%) survivors had not returned to work due to poor health. There was a decrease in the EQ-5D-5LTM utility score (MD, − 0.19 [− 0.28 to − 0.10]; p < 0.001). At 6 months, 82 of 115 (71.3%) patients reported persistent symptoms. The independent predictors of death or new disability were higher severity of illness and increased frailty. Conclusions: At six months after COVID-19 critical illness, death and new disability was substantial. Over a third of survivors had new disability, which was widespread across all areas of functioning.Carol L. Hodgson, Alisa M. Higgins, Michael J. Bailey, Anne M. Mather, Lisa Beach, Rinaldo Bellomo, Bernie Bissett, Ianthe J. Boden, Scott Bradley, Aidan Burrell, D. James Cooper, Bentley J. Fulcher, Kimberley J. Haines, Jack Hopkins, Alice Y. M. Jones, Stuart Lane, Drew Lawrence, Lisa van der Lee, Jennifer Liacos, Natalie J. Linke, Lonni Marques Gomes, Marc Nickels, George Ntoumenopoulos, Paul S. Myles, Shane Patman, Michelle Paton, Gemma Pound, Sumeet Rai, Alana Rix, Thomas C. Rollinson, Janani Sivasuthan, Claire J. Tipping, Peter Thomas, Tony Trapani, Andrew A. Udy, Christina Whitehead, Isabelle T. Hodgson, Shannah Anderson, Ary Serpa Neto, and The COVID-Recovery Study Investigators and the ANZICS Clinical Trials Grou

Whole genome sequencing of Shigella sonnei through PulseNet Latin America and Caribbean: advancing global surveillance of foodborne illnesses

Objectives Shigella sonnei is a globally important diarrhoeal pathogen tracked through the surveillance network PulseNet Latin America and Caribbean (PNLA&C), which participates in PulseNet International. PNLA&C laboratories use common molecular techniques to track pathogens causing foodborne illness. We aimed to demonstrate the possibility and advantages of transitioning to whole genome sequencing (WGS) for surveillance within existing networks across a continent where S. sonnei is endemic. Methods We applied WGS to representative archive isolates of S. sonnei (n = 323) from laboratories in nine PNLA&C countries to generate a regional phylogenomic reference for S. sonnei and put this in the global context. We used this reference to contextualise 16 S. sonnei from three Argentinian outbreaks, using locally generated sequence data. Assembled genome sequences were used to predict antimicrobial resistance (AMR) phenotypes and identify AMR determinants. Results S. sonnei isolates clustered in five Latin American sublineages in the global phylogeny, with many (46%, 149 of 323) belonging to previously undescribed sublineages. Predicted multidrug resistance was common (77%, 249 of 323), and clinically relevant differences in AMR were found among sublineages. The regional overview showed that Argentinian outbreak isolates belonged to distinct sublineages and had different epidemiologic origins. Conclusions Latin America contains novel genetic diversity of S. sonnei that is relevant on a global scale and commonly exhibits multidrug resistance. Retrospective passive surveillance with WGS has utility for informing treatment, identifying regionally epidemic sublineages and providing a framework for interpretation of prospective, locally sequenced outbreaks

Constraints on the mass spectrum of primordial black holes and braneworld parameters from the high-energy diffuse photon background

We investigate the spectral shape of a high-energy diffuse photon emitted by evaporating primordial black holes (PBHs) in the Randall-Sundrum type II (RS2) braneworld. In their braneworld scenario, the nature of small PBHs is drastically modified from the ordinary four-dimensional case for the following two reasons. (i) dropping Hawking temperature, which equivalently lengthens the lifetime of the individual PBH due to the change of space-time topology and (ii) the effective increase of the total amount of PBHs caused by accretion during the earliest part of the radiation-dominated epoch, the brane high-energy phase. From studies of the expected spectral shape and its dependence on braneworld parameters, we obtain two qualitatively distinctive possibilities of constraints on the braneworld PBHs from the observations of diffuse high-energy photon background. If the efficiency of accretion in the high-energy phase exceeds a critical value, the existence of the extra dimension gives a more stringent upper bound on the abundance of PBHs than the 4D case and a small length scale for the extra dimension is favored. On the contrary, in the case below the critical accretion efficiency, we find that the constraint on the PBH abundance can be relaxed by a few orders of magnitude in exchange for the existence of the large extra dimension; its size may be even bounded in the region above 10^{19} times 4D Planck length scale provided the rest mass energy density of the PBHs relative to energy density of radiation is actually larger than 10^{-27} (4D upper bound) at their formation time. The above analytical studies are also confirmed numerically, and an allowed region for braneworld parameters and PBH abundance is clearly obtained.Comment: 16 pages, 8 figures, REVTeX4; version published in PR

A method to measure the resonance transitions between the gravitationally bound quantum states of neutrons in the GRANIT spectrometer

We present a method to measure the resonance transitions between the gravitationally bound quantum states of neutrons in the GRANIT spectrometer. The purpose of GRANIT is to improve the accuracy of measurement of the quantum states parameters by several orders of magnitude, taking advantage of long storage of Ultracold neutrons at specula trajectories. The transitions could be excited using a periodic spatial variation of a magnetic field gradient. If the frequency of such a perturbation (in the frame of a moving neutron) coincides with a resonance frequency defined by the energy difference of two quantum states, the transition probability will sharply increase. The GRANIT experiment is motivated by searches for short-range interactions (in particular spin-dependent interactions), by studying the interaction of a quantum system with a gravitational field, by searches for extensions of the Standard model, by the unique possibility to check the equivalence principle for an object in a quantum state and by studying various quantum optics phenomena

Big Bang Baryogenesis

An overview of baryogenesis in the early Universe is presented. The standard big bang model including big bang nucleosynthesis and inflation is breifly reviewed. Three basic models for baryogenesis will be developed: The ``standard" out-of-equilibrium decay model; the decay of scalar consensates along flat directions in supersymmetric models; and lepto-baryogenesis, which is the conversion of a lepton asymmetry into a baryon asymmetry via non-perturbative electroweak interactions.Comment: 36 pages, LaTeX, UMN-TH-1249, Lectures given at the 33rd International Winter School on Nuclear and Particle Physics, ``Matter Under Extreme Conditions", Feb. 27 - March 5 1994, Schladming Austri

Primordial Nucleosynthesis for the New Cosmology: Determining Uncertainties and Examining Concordance

Big bang nucleosynthesis (BBN) and the cosmic microwave background (CMB) have a long history together in the standard cosmology. The general concordance between the predicted and observed light element abundances provides a direct probe of the universal baryon density. Recent CMB anisotropy measurements, particularly the observations performed by the WMAP satellite, examine this concordance by independently measuring the cosmic baryon density. Key to this test of concordance is a quantitative understanding of the uncertainties in the BBN light element abundance predictions. These uncertainties are dominated by systematic errors in nuclear cross sections. We critically analyze the cross section data, producing representations that describe this data and its uncertainties, taking into account the correlations among data, and explicitly treating the systematic errors between data sets. Using these updated nuclear inputs, we compute the new BBN abundance predictions, and quantitatively examine their concordance with observations. Depending on what deuterium observations are adopted, one gets the following constraints on the baryon density: OmegaBh^2=0.0229\pm0.0013 or OmegaBh^2 = 0.0216^{+0.0020}_{-0.0021} at 68% confidence, fixing N_{\nu,eff}=3.0. Concerns over systematics in helium and lithium observations limit the confidence constraints based on this data provide. With new nuclear cross section data, light element abundance observations and the ever increasing resolution of the CMB anisotropy, tighter constraints can be placed on nuclear and particle astrophysics. ABRIDGEDComment: 54 pages, 20 figures, 5 tables v2: reflects PRD version minor changes to text and reference

Observations of the High Redshift Universe

(Abridged) In these lectures aimed for non-specialists, I review progress in understanding how galaxies form and evolve. Both the star formation history and assembly of stellar mass can be empirically traced from redshifts z~6 to the present, but how the various distant populations inter-relate and how stellar assembly is regulated by feedback and environmental processes remains unclear. I also discuss how these studies are being extended to locate and characterize the earlier sources beyond z~6. Did early star-forming galaxies contribute significantly to the reionization process and over what period did this occur? Neither theory nor observations are well-developed in this frontier topic but the first results presented here provide important guidance on how we will use more powerful future facilities.Comment: To appear in `First Light in Universe', Saas-Fee Advanced Course 36, Swiss Soc. Astrophys. Astron. in press. 115 pages, 64 figures (see http://www.astro.caltech.edu/~rse/saas-fee.pdf for hi-res figs.) For lecture ppt files see http://obswww.unige.ch/saas-fee/preannouncement/course_pres/overview_f.htm

Novel genetic loci associated with hippocampal volume

The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (rg =-0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness