Diversity and dynamics of Escherichia coli ST131 causing bacteremia in a tertiary hospital in Madrid (1996-2016) using genomic tools and latest generation bioinformatics

Trabajo de fin de máster en Bioinformática y Biología ComputacionalMotivation: Extraintestinal pathogenic E. coli is the leading cause of urinary tract infections and of adult bacteremia. The clonal group STc131 has been identified as the primary cause of the global pandemic of multidrug resistance within these E. coli. Objective: To analyze the diversity of STc131 from a representative sample of isolates of phylogroup B2 E. coli that caused bacteremia in the hospital Ramón y Cajal in the last 20 years. Material and Methods: Eighty-three E. coli strains, primarily identified as STc131 from a representative sample of 528 B2-EC isolates associated with non-duplicated episodes of bacteremia in Hospital Ramón y Cajal from the years 1996-2016, were selected for next generation sequencing. Bioinformatic techniques were used to annotate the genomes and to identify epidemiological markers and mobile genetic elements that may contribute to the pathogenic success of particular STc131 clades. Results: The number of clade C subgroups of STc131 samples isolated from episodes of bacteremia in Hospital Ramón y Cajal has increased over the period of collection (1996-2016), while clade B maintained a stable frequency. Analysis of the accessory genomes of these isolates indicate a high degree of diversity between and within the different STc131 clades. Less than a quarter (23.7%) of the sample were ESBL positive. Conclusions. These data indicate the importance of the accessory genome, including the plasmid content of the isolates, in the dynamics of this STc131 population with each clade having a distinct plasmid, virulence, and antibiotic resistance signature. The results highlight diversification of the STc131 before and after the selection by first line antibiotics including fluoroquinolones and cephalosporins

Innovations in ex vivo light sheet fluorescence microscopy

Light Sheet Fluorescence Microscopy (LSFM) has revolutionized how optical imaging of biological specimens can be performed as this technique allows to produce 3D fluorescence images of entire samples with a high spatiotemporal resolution. In this manuscript, we aim to provide readers with an overview of the field of LSFM on ex vivo samples. Recent advances in LSFM architectures have made the technique widely accessible and have improved its acquisition speed and resolution, among other features. These developments are strongly supported by quantitative analysis of the huge image volumes produced thanks to the boost in computational capacities, the advent of Deep Learning techniques, and by the combination of LSFM with other imaging modalities. Namely, LSFM allows for the characterization of biological structures, disease manifestations and drug effectivity studies. This information can ultimately serve to develop novel diagnostic procedures, treatments and even to model the organs physiology in healthy and pathological conditions.This work was produced with the support of the Spanish Ministry of Science, Innovation and Universities (TEC2016-78052-R, RTC-2017-6600-1, PID2019-109820RB-100, FPU19/02854)

Multi-campaign Ship and Aircraft Observations of Marine Cloud Condensation Nuclei and Droplet Concentrations

In-situ marine cloud droplet number concentrations (CDNCs), cloud condensation nuclei (CCN), and CCN proxies, based on particle sizes and optical properties, are accumulated from seven field campaigns: ACTIVATE; NAAMES; CAMP2EX; ORACLES; SOCRATES; MARCUS; and CAPRICORN2. Each campaign involves aircraft measurements, ship-based measurements, or both. Measurements collected over the North and Central Atlantic, Indo-Pacific, and Southern Oceans, represent a range of clean to polluted conditions in various climate regimes. With the extensive range of environmental conditions sampled, this data collection is ideal for testing satellite remote detection methods of CDNC and CCN in marine environments. Remote measurement methods are vital to expanding the available data in these difficult-to-reach regions of the Earth and improving our understanding of aerosol-cloud interactions. The data collection includes particle composition and continental tracers to identify potential contributing CCN sources. Several of these campaigns include High Spectral Resolution Lidar (HSRL) and polarimetric imaging measurements and retrievals that will be the basis for the next generation of space-based remote sensors and, thus, can be utilized as satellite surrogates

Adjunctive rifampicin for Staphylococcus aureus bacteraemia (ARREST): a multicentre, randomised, double-blind, placebo-controlled trial.

BACKGROUND: Staphylococcus aureus bacteraemia is a common cause of severe community-acquired and hospital-acquired infection worldwide. We tested the hypothesis that adjunctive rifampicin would reduce bacteriologically confirmed treatment failure or disease recurrence, or death, by enhancing early S aureus killing, sterilising infected foci and blood faster, and reducing risks of dissemination and metastatic infection. METHODS: In this multicentre, randomised, double-blind, placebo-controlled trial, adults (≥18 years) with S aureus bacteraemia who had received ≤96 h of active antibiotic therapy were recruited from 29 UK hospitals. Patients were randomly assigned (1:1) via a computer-generated sequential randomisation list to receive 2 weeks of adjunctive rifampicin (600 mg or 900 mg per day according to weight, oral or intravenous) versus identical placebo, together with standard antibiotic therapy. Randomisation was stratified by centre. Patients, investigators, and those caring for the patients were masked to group allocation. The primary outcome was time to bacteriologically confirmed treatment failure or disease recurrence, or death (all-cause), from randomisation to 12 weeks, adjudicated by an independent review committee masked to the treatment. Analysis was intention to treat. This trial was registered, number ISRCTN37666216, and is closed to new participants. FINDINGS: Between Dec 10, 2012, and Oct 25, 2016, 758 eligible participants were randomly assigned: 370 to rifampicin and 388 to placebo. 485 (64%) participants had community-acquired S aureus infections, and 132 (17%) had nosocomial S aureus infections. 47 (6%) had meticillin-resistant infections. 301 (40%) participants had an initial deep infection focus. Standard antibiotics were given for 29 (IQR 18-45) days; 619 (82%) participants received flucloxacillin. By week 12, 62 (17%) of participants who received rifampicin versus 71 (18%) who received placebo experienced treatment failure or disease recurrence, or died (absolute risk difference -1·4%, 95% CI -7·0 to 4·3; hazard ratio 0·96, 0·68-1·35, p=0·81). From randomisation to 12 weeks, no evidence of differences in serious (p=0·17) or grade 3-4 (p=0·36) adverse events were observed; however, 63 (17%) participants in the rifampicin group versus 39 (10%) in the placebo group had antibiotic or trial drug-modifying adverse events (p=0·004), and 24 (6%) versus six (2%) had drug interactions (p=0·0005). INTERPRETATION: Adjunctive rifampicin provided no overall benefit over standard antibiotic therapy in adults with S aureus bacteraemia. FUNDING: UK National Institute for Health Research Health Technology Assessment

Multi-campaign ship and aircraft observations of marine cloud condensation nuclei and droplet concentrations

In-situ marine cloud droplet number concentrations (CDNCs), cloud condensation nuclei (CCN), and CCN proxies, based on particle sizes and optical properties, are accumulated from seven field campaigns: ACTIVATE; NAAMES; CAMP2EX; ORACLES; SOCRATES; MARCUS; and CAPRICORN2. Each campaign involves aircraft measurements, ship-based measurements, or both. Measurements collected over the North and Central Atlantic, Indo-Pacific, and Southern Oceans, represent a range of clean to polluted conditions in various climate regimes. With the extensive range of environmental conditions sampled, this data collection is ideal for testing satellite remote detection methods of CDNC and CCN in marine environments. Remote measurement methods are vital to expanding the available data in these difficult-to-reach regions of the Earth and improving our understanding of aerosol-cloud interactions. The data collection includes particle composition and continental tracers to identify potential contributing CCN sources. Several of these campaigns include High Spectral Resolution Lidar (HSRL) and polarimetric imaging measurements and retrievals that will be the basis for the next generation of space-based remote sensors and, thus, can be utilized as satellite surrogates

The Science Performance of JWST as Characterized in Commissioning

This paper characterizes the actual science performance of the James Webb Space Telescope (JWST), as determined from the six month commissioning period. We summarize the performance of the spacecraft, telescope, science instruments, and ground system, with an emphasis on differences from pre-launch expectations. Commissioning has made clear that JWST is fully capable of achieving the discoveries for which it was built. Moreover, almost across the board, the science performance of JWST is better than expected; in most cases, JWST will go deeper faster than expected. The telescope and instrument suite have demonstrated the sensitivity, stability, image quality, and spectral range that are necessary to transform our understanding of the cosmos through observations spanning from near-earth asteroids to the most distant galaxies.Comment: 5th version as accepted to PASP; 31 pages, 18 figures; https://iopscience.iop.org/article/10.1088/1538-3873/acb29

Evaluating the Effects of SARS-CoV-2 Spike Mutation D614G on Transmissibility and Pathogenicity.

Global dispersal and increasing frequency of the SARS-CoV-2 spike protein variant D614G are suggestive of a selective advantage but may also be due to a random founder effect. We investigate the hypothesis for positive selection of spike D614G in the United Kingdom using more than 25,000 whole genome SARS-CoV-2 sequences. Despite the availability of a large dataset, well represented by both spike 614 variants, not all approaches showed a conclusive signal of positive selection. Population genetic analysis indicates that 614G increases in frequency relative to 614D in a manner consistent with a selective advantage. We do not find any indication that patients infected with the spike 614G variant have higher COVID-19 mortality or clinical severity, but 614G is associated with higher viral load and younger age of patients. Significant differences in growth and size of 614G phylogenetic clusters indicate a need for continued study of this variant

Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Background Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. Methods We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. Results Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. Conclusions Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.Peer reviewe

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements

Post-intervention Status in Patients With Refractory Myasthenia Gravis Treated With Eculizumab During REGAIN and Its Open-Label Extension

OBJECTIVE: To evaluate whether eculizumab helps patients with anti-acetylcholine receptor-positive (AChR+) refractory generalized myasthenia gravis (gMG) achieve the Myasthenia Gravis Foundation of America (MGFA) post-intervention status of minimal manifestations (MM), we assessed patients' status throughout REGAIN (Safety and Efficacy of Eculizumab in AChR+ Refractory Generalized Myasthenia Gravis) and its open-label extension. METHODS: Patients who completed the REGAIN randomized controlled trial and continued into the open-label extension were included in this tertiary endpoint analysis. Patients were assessed for the MGFA post-intervention status of improved, unchanged, worse, MM, and pharmacologic remission at defined time points during REGAIN and through week 130 of the open-label study. RESULTS: A total of 117 patients completed REGAIN and continued into the open-label study (eculizumab/eculizumab: 56; placebo/eculizumab: 61). At week 26 of REGAIN, more eculizumab-treated patients than placebo-treated patients achieved a status of improved (60.7% vs 41.7%) or MM (25.0% vs 13.3%; common OR: 2.3; 95% CI: 1.1-4.5). After 130 weeks of eculizumab treatment, 88.0% of patients achieved improved status and 57.3% of patients achieved MM status. The safety profile of eculizumab was consistent with its known profile and no new safety signals were detected. CONCLUSION: Eculizumab led to rapid and sustained achievement of MM in patients with AChR+ refractory gMG. These findings support the use of eculizumab in this previously difficult-to-treat patient population. CLINICALTRIALSGOV IDENTIFIER: REGAIN, NCT01997229; REGAIN open-label extension, NCT02301624. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that, after 26 weeks of eculizumab treatment, 25.0% of adults with AChR+ refractory gMG achieved MM, compared with 13.3% who received placebo