Homologous Recombination within Large Chromosomal Regions Facilitates Acquisition of ?-Lactam and Vancomycin Resistance in Enterococcus faecium

The transfer of DNA between Enterococcus faecium strains has been characterized by both the movement of well-defined genetic elements and by the large-scale transfer of genomic DNA fragments. In this work we report on the whole genome analysis of transconjugants resulting from mating events between the vancomycin-resistant E. faecium C68 strain and vancomycin susceptible D344RRF to discern the mechanism by which the transferred regions enter the recipient chromosome. Vancomycin-resistant transconjugants from five independent matings were analysed by whole genome sequencing. In all cases but one, the penicillin binding protein 5 gene (pbp5) and the Tn5382-vancomycin resistance transposon were transferred together and replaced the corresponding pbp5 region of D344RRF. In one instance, Tn5382 inserted independently downstream of the D344RRF pbp5. Single nucleotide variants (SNV) analysis suggests that entry of donor DNA into the recipient chromosome occurred by recombination across regions of homology between donor and recipient chromosomes, rather than through insertion sequence-mediated transposition. Transfer of genomic DNA was also associated with transfer of C68 plasmid pLRM23 and another putative plasmid. Our data are consistent with transfer initiated by a cointegration of a transferable plasmid with the donor chromosome, with subsequent circularization of the plasmid/chromosome cointegrate in the donor prior to transfer. Entry into the recipient chromosome occurs most commonly across regions of homology between donor and recipient chromosomes

Circulating adrenomedullin estimates survival and reversibility of organ failure in sepsis: the prospective observational multinational Adrenomedullin and Outcome in Sepsis and Septic Shock-1 (AdrenOSS-1) study

Background: Adrenomedullin (ADM) regulates vascular tone and endothelial permeability during sepsis. Levels of circulating biologically active ADM (bio-ADM) show an inverse relationship with blood pressure and a direct relationship with vasopressor requirement. In the present prospective observational multinational Adrenomedullin and Outcome in Sepsis and Septic Shock 1 (, AdrenOSS-1) study, we assessed relationships between circulating bio-ADM during the initial intensive care unit (ICU) stay and short-term outcome in order to eventually design a biomarker-guided randomized controlled trial. Methods: AdrenOSS-1 was a prospective observational multinational study. The primary outcome was 28-day mortality. Secondary outcomes included organ failure as defined by Sequential Organ Failure Assessment (SOFA) score, organ support with focus on vasopressor/inotropic use, and need for renal replacement therapy. AdrenOSS-1 included 583 patients admitted to the ICU with sepsis or septic shock. Results: Circulating bio-ADM levels were measured upon admission and at day 2. Median bio-ADM concentration upon admission was 80.5 pg/ml [IQR 41.5-148.1 pg/ml]. Initial SOFA score was 7 [IQR 5-10], and 28-day mortality was 22%. We found marked associations between bio-ADM upon admission and 28-day mortality (unadjusted standardized HR 2.3 [CI 1.9-2.9]; adjusted HR 1.6 [CI 1.1-2.5]) and between bio-ADM levels and SOFA score (p < 0.0001). Need of vasopressor/inotrope, renal replacement therapy, and positive fluid balance were more prevalent in patients with a bio-ADM > 70 pg/ml upon admission than in those with bio-ADM ≤ 70 pg/ml. In patients with bio-ADM > 70 pg/ml upon admission, decrease in bio-ADM below 70 pg/ml at day 2 was associated with recovery of organ function at day 7 and better 28-day outcome (9.5% mortality). By contrast, persistently elevated bio-ADM at day 2 was associated with prolonged organ dysfunction and high 28-day mortality (38.1% mortality, HR 4.9, 95% CI 2.5-9.8). Conclusions: AdrenOSS-1 shows that early levels and rapid changes in bio-ADM estimate short-term outcome in sepsis and septic shock. These data are the backbone of the design of the biomarker-guided AdrenOSS-2 trial. Trial registration: ClinicalTrials.gov, NCT02393781. Registered on March 19, 2015

Emergence of Epidemic Multidrug-Resistant Enterococcus faecium from Animal and Commensal Strains

Peer reviewe

Global diversity of enterococci and description of 18 novel species

Bacteria of the genus Enterococcus colonize the guts of diverse animals. Some species have acquired multiple antibiotic resistances on top of a high level of intrinsic resistance and have emerged as leading causes of hospital-associated infection. Although clinical isolates of enterococcal species E. faecalis and E. faecium have been studied with respect to their antibiotic resistances and infection pathogenesis, comparatively little is known about the biology of enterococci in their natural context of the guts of humans and other land animals, including arthropods and other invertebrates. Importantly, little is also known about the global pool of genes already optimized for expression in an enterococcal background with the potential to be readily acquired by hospital adapted strains of E. faecalis and E. faecium , known facile exchangers of mobile genetic elements. We therefore undertook a global study designed to reach into maximally diverse habitats, to establish a first approximation of the genetic diversity of enterococci on Earth. Presumptive enterococci from over 900 diverse specimens were initially screened by PCR using a specific reporter gene that we found to accurately reflect genomic diversity. The genomes of isolates exceeding an operationally set threshold for diversity were then sequenced in their entirety and analyzed. This provided us with data on the global occurrence of many known enterococcal species and their association with various hosts and ecologies and identified 18 novel species expanding the diversity of the genus Enterococcus by over 25%. The 18 novel enterococcal species harbor a diverse array of genes associated with toxins, detoxification, and resource acquisition that highlight the capacity of the enterococci to acquire and adapt novel functions from diverse gut environments. In addition to the discovery and characterization of new species, this expanded diversity permitted a higher resolution analysis of the phylogenetic structure of the Enterococcus genus, including identification of distinguishing features of its 4 deeply rooted clades and genes associated with range expansion such as B-vitamin biosynthesis and flagellar motility. Collectively, this work provides an unprecedentedly broad and deep view of the genus Enterococcus , along with new insights into their potential threat to human health

Spectroscopic Survey of the Galaxy with Gaia II. The expected science yield from the Radial Velocity Spectrometer

The Gaia mission is designed as a Galaxy explorer, and will measure simultaneously, in a survey mode, the five or six phase space parameters of all stars brighter than 20th magnitude, as well as providing a description of their astrophysical characteristics. These measurements are obtained by combining an astrometric instrument with micro-arcsecond capabilities, a photometric system giving the magnitudes and colours in 15 bands and a medium resolution spectrograph named the Radial Velocity Spectrometer (RVS). The latter instrument will produce spectra in the 848 to 874 nm wavelength range, with a resolving power R = 11 500, from which radial velocities, rotational velocities, atmospheric parameters and abundances can be derived. A companion paper (Katz et al. 2004) presents the characteristics of the RVS and its performance. This paper details the outstanding scientific impact of this important part of the Gaia satellite on some key open questions in present day astrophysics. The unbiased and simultaneous acquisition of multi-epoch radial velocities and individual abundances of key elements in parallel with the astrometric parameters is essential for the determination of the dynamical state and formation history of our Galaxy. Moreover, for stars brighter than V=15, the resolving power of the RVS will give information about most of the effects which influence the position of a star in the Hertzsprung-Russell diagram, placing unprecedented constraints on the age, internal structure and evolution of stars of all types. Finally, the RVS multi-epoch observations are ideally suited to the identification, classification and characterisation of the many types of double, multiple and variable stars.Comment: 33 pages, 11 figures, in press at MNRAS. Figs 1, 3 and 9 included at reduced resolution; available in full resolution at http://www.blackwell-synergy.com/doi/pdf/10.1111/j.1365-2966.2005.09012.

ECMO for COVID-19 patients in Europe and Israel

Since March 15th, 2020, 177 centres from Europe and Israel have joined the study, routinely reporting on the ECMO support they provide to COVID-19 patients. The mean annual number of cases treated with ECMO in the participating centres before the pandemic (2019) was 55. The number of COVID-19 patients has increased rapidly each week reaching 1531 treated patients as of September 14th. The greatest number of cases has been reported from France (n = 385), UK (n = 193), Germany (n = 176), Spain (n = 166), and Italy (n = 136) .The mean age of treated patients was 52.6 years (range 16–80), 79% were male. The ECMO configuration used was VV in 91% of cases, VA in 5% and other in 4%. The mean PaO2 before ECMO implantation was 65 mmHg. The mean duration of ECMO support thus far has been 18 days and the mean ICU length of stay of these patients was 33 days. As of the 14th September, overall 841 patients have been weaned from ECMO support, 601 died during ECMO support, 71 died after withdrawal of ECMO, 79 are still receiving ECMO support and for 10 patients status n.a. . Our preliminary data suggest that patients placed on ECMO with severe refractory respiratory or cardiac failure secondary to COVID-19 have a reasonable (55%) chance of survival. Further extensive data analysis is expected to provide invaluable information on the demographics, severity of illness, indications and different ECMO management strategies in these patients

Toward the integrated marine debris observing system

Plastics and other artificial materials pose new risks to the health of the ocean. Anthropogenic debris travels across large distances and is ubiquitous in the water and on shorelines, yet, observations of its sources, composition, pathways, and distributions in the ocean are very sparse and inaccurate. Total amounts of plastics and other man-made debris in the ocean and on the shore, temporal trends in these amounts under exponentially increasing production, as well as degradation processes, vertical fluxes, and time scales are largely unknown. Present ocean circulation models are not able to accurately simulate drift of debris because of its complex hydrodynamics. In this paper we discuss the structure of the future integrated marine debris observing system (IMDOS) that is required to provide long-term monitoring of the state of this anthropogenic pollution and support operational activities to mitigate impacts on the ecosystem and on the safety of maritime activity. The proposed observing system integrates remote sensing and in situ observations. Also, models are used to optimize the design of the system and, in turn, they will be gradually improved using the products of the system. Remote sensing technologies will provide spatially coherent coverage and consistent surveying time series at local to global scale. Optical sensors, including high-resolution imaging, multi- and hyperspectral, fluorescence, and Raman technologies, as well as SAR will be used to measure different types of debris. They will be implemented in a variety of platforms, from hand-held tools to ship-, buoy-, aircraft-, and satellite-based sensors. A network of in situ observations, including reports from volunteers, citizen scientists and ships of opportunity, will be developed to provide data for calibration/validation of remote sensors and to monitor the spread of plastic pollution and other marine debris. IMDOS will interact with other observing systems monitoring physical, chemical, and biological processes in the ocean and on shorelines as well as the state of the ecosystem, maritime activities and safety, drift of sea ice, etc. The synthesized data will support innovative multi-disciplinary research and serve a diverse community of users

Extracorporeal Membrane Oxygenation for Severe Acute Respiratory Distress Syndrome associated with COVID-19: An Emulated Target Trial Analysis.

RATIONALE: Whether COVID patients may benefit from extracorporeal membrane oxygenation (ECMO) compared with conventional invasive mechanical ventilation (IMV) remains unknown. OBJECTIVES: To estimate the effect of ECMO on 90-Day mortality vs IMV only Methods: Among 4,244 critically ill adult patients with COVID-19 included in a multicenter cohort study, we emulated a target trial comparing the treatment strategies of initiating ECMO vs. no ECMO within 7 days of IMV in patients with severe acute respiratory distress syndrome (PaO2/FiO2 <80 or PaCO2 ≥60 mmHg). We controlled for confounding using a multivariable Cox model based on predefined variables. MAIN RESULTS: 1,235 patients met the full eligibility criteria for the emulated trial, among whom 164 patients initiated ECMO. The ECMO strategy had a higher survival probability at Day-7 from the onset of eligibility criteria (87% vs 83%, risk difference: 4%, 95% CI 0;9%) which decreased during follow-up (survival at Day-90: 63% vs 65%, risk difference: -2%, 95% CI -10;5%). However, ECMO was associated with higher survival when performed in high-volume ECMO centers or in regions where a specific ECMO network organization was set up to handle high demand, and when initiated within the first 4 days of MV and in profoundly hypoxemic patients. CONCLUSIONS: In an emulated trial based on a nationwide COVID-19 cohort, we found differential survival over time of an ECMO compared with a no-ECMO strategy. However, ECMO was consistently associated with better outcomes when performed in high-volume centers and in regions with ECMO capacities specifically organized to handle high demand. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/)

Genomic transition of enterococci from gut commensals to leading causes of multidrug-resistant hospital infection in the antibiotic era

The enterococci evolved over eons as highly adapted members of gastrointestinal consortia of a wide variety of hosts, but for reasons that are not entirely clear, emerged in the 1970s as leading causes of multidrug resistant hospital infection. Hospital-adapted pathogenic isolates are characterized by the presence of multiple mobile elements conferring antibiotic resistance, as well as pathogenicity islands, capsule loci and other variable traits. Enterococci may have been primed to emerge among the vanguard of antibiotic resistant strains because of their occurrence in the GI tracts of insects and simple organisms living and feeding on organic matter that is colonized by antibiotic resistant, antibiotic producing micro-organisms. In response to the opportunity to inhabit a new niche – the antibiotic treated hospital patient – the enterococcal genome is evolving in a pattern characteristic of other bacteria that have emerged as pathogens because of opportunities stemming from anthropogenic change