Evolving Landscape of Carbapenem-Resistant

OBJECTIVES: The increased identification of carbapenem-resistant METHODS: A total of 169 CR-PA isolated from clinical specimens at a single centre in Houston, TX, USA were studied. Among them, 61 isolates collected between 1999 and 2005 were defined as historical strains, and 108 collected between 2017 and 2018 were defined as contemporary strains. Antimicrobial susceptibilities against selected β-lactams was determined. WGS data were used for the identification of antimicrobial resistance determinants and phylogenetic analysis. RESULTS: Non-susceptibility to ceftolozane/tazobactam and ceftazidime/avibactam increased from 2% (1/59) to 17% (18/108) and from 7% (4/59) to 17% (18/108) from the historical to the contemporary collection, respectively. Carbapenemase genes, which were not identified in the historical collection, were harboured by 4.6% (5/108) of the contemporary strains, and the prevalence of ESBL genes also increased from 3.3% (2/61) to 16% (17/108). Genes encoding acquired β-lactamases were largely confined to the high-risk clones. Among ceftolozane/tazobactam-resistant isolates, non-susceptibility to ceftazidime/avibactam, imipenem/relebactam and cefiderocol was observed in 94% (15/16), 56% (9/16) and 12.5% (2/16), respectively. Resistance to ceftolozane/tazobactam and imipenem/relebactam was primarily associated with the presence of exogenous β-lactamases. CONCLUSIONS: Acquisition of exogenous carbapenemases and ESBLs may be a worrisome trend i

Características clínicas, microbiología y resultados de una cohorte de pacientes tratados con ceftolozane/tazobactam en centros de hospitalización de cuidados agudos, Houston, Texas, EE.UU

Antecedentes Ceftolozane/tazobactam es una combinación de β-lactámico/β-inhibidor de lactamasa con actividad contra una variedad de bacterias Gram-negativas, incluyendo Pseudomonas aeruginosa MDR. Este agente está aprobado para la neumonía bacteriana adquirida en el hospital y asociada a la ventilación mecánica. Sin embargo, la mayoría de los datos de resultados en el mundo real proceden de pequeñas cohortes observacionales. Por lo tanto, se trató de evaluar la utilización de ceftolozane/tazobactam en múltiples hospitales terciarios en Houston, TX, EE.UU.. Métodos Realizamos un estudio retrospectivo multicéntrico de pacientes que recibieron al menos 48 h de terapia con ceftolozano/tazobactam desde enero de 2016 hasta septiembre de 2019 en dos sistemas hospitalarios en Houston. Se recopilaron datos demográficos, clínicos y microbiológicos, incluido el aislado bacteriano infectante, cuando estaba disponible. El resultado primario fue el éxito clínico compuesto al alta hospitalaria. Los resultados secundarios incluyeron la mortalidad intrahospitalaria y la disposición clínica a los 14 y 30 días después del inicio de ceftolozane/tazobactam. Se utilizó un análisis de regresión logística multivariable para identificar los factores predictivos del resultado primario y la mortalidad. Los aislados recuperados se sometieron a pruebas de sensibilidad a ceftolozano/tazobactam y a WGS. Resultados Se incluyó a un total de 263 pacientes, y se alcanzó el éxito clínico compuesto en 185 pacientes (70,3%). La gravedad de la enfermedad fue el factor predictivo más consistente del éxito clínico. El tratamiento combinado con ceftolozane/tazobactam y otro agente Gram negativo activo se asoció a una reducción de las probabilidades de éxito clínico (OR 0,32; IC del 95%: 0,16-0,63). Se observó resistencia a ceftolozano/tazobactam en el 15,4% de los aislados disponibles para WGS; las mutaciones en ampC y ftsI fueron frecuentes pero no se agruparon con una ST concreta. Conclusiones La tasa de éxito clínico entre esta cohorte de pacientes tratados con ceftolozane/tazobactam fue similar en comparación con experiencias anteriores. Ceftolozane/tazobactam sigue siendo un agente alternativo para el tratamiento de aislados susceptibles de P. aeruginosaBackground Ceftolozane/tazobactam is a β-lactam/β-lactamase inhibitor combination with activity against a variety of Gram-negative bacteria, including MDR Pseudomonas aeruginosa. This agent is approved for hospital-acquired and ventilator-associated bacterial pneumonia. However, most real-world outcome data come from small observational cohorts. Thus, we sought to evaluate the utilization of ceftolozane/tazobactam at multiple tertiary hospitals in Houston, TX, USA. Methods We conducted a multicentre retrospective study of patients receiving at least 48 h of ceftolozane/tazobactam therapy from January 2016 through to September 2019 at two hospital systems in Houston. Demographic, clinical and microbiological data were collected, including the infecting bacterial isolate, when available. The primary outcome was composite clinical success at hospital discharge. Secondary outcomes included in-hospital mortality and clinical disposition at 14 and 30 days post ceftolozane/tazobactam initiation. Multivariable logistic regression analysis was used to identify predictors of the primary outcome and mortality. Recovered isolates were tested for susceptibility to ceftolozane/tazobactam and underwent WGS. Results A total of 263 patients were enrolled, and composite clinical success was achieved in 185 patients (70.3%). Severity of illness was the most consistent predictor of clinical success. Combination therapy with ceftolozane/tazobactam and another Gram-negative-active agent was associated with reduced odds of clinical success (OR 0.32, 95% CI 0.16–0.63). Resistance to ceftolozane/tazobactam was noted in 15.4% of isolates available for WGS; mutations in ampC and ftsI were common but did not cluster with a particular ST. Conclusions Clinical success rate among this patient cohort treated with ceftolozane/tazobactam was similar compared with previous experiences. Ceftolozane/tazobactam remains an alternative agent for treatment of susceptible isolates of P. aeruginosa

Contemporary Clinical and Molecular Epidemiology of Vancomycin-Resistant Enterococcal Bacteremia: A Prospective Multicenter Cohort Study (VENOUS I)

Background Vancomycin-resistant enterococci (VRE) are major therapeutic challenges. Prospective contemporary data characterizing the clinical and molecular epidemiology of VRE bloodstream infections (BSIs) are lacking. Methods The Vancomycin-Resistant Enterococcal BSI Outcomes Study (VENOUS I) is a prospective observational cohort of adult patients with enterococcal BSI in 11 US hospitals. We included patients with Enterococcus faecalis or Enterococcus faecium BSI with >= 1 follow-up blood culture(s) within 7 days and availability of isolate(s) for further characterization. The primary study outcome was in-hospital mortality. Secondary outcomes were mortality at days 4, 7, 10, 12, and 15 after index blood culture. A desirability of outcome ranking was constructed to assess the association of vancomycin resistance with outcomes. All index isolates were subjected to whole genome sequencing. Results Forty-two of 232 (18%) patients died in hospital and 39 (17%) exhibited microbiological failure (lack of clearance in the first 4 days). Neutropenia (hazard ratio [HR], 3.13), microbiological failure (HR, 2.4), VRE BSI (HR, 2.13), use of urinary catheter (HR, 1.85), and Pitt BSI score >= 2 (HR, 1.83) were significant predictors of in-hospital mortality. Microbiological failure was the strongest predictor of in-hospital mortality in patients with E faecium bacteremia (HR, 5.03). The impact of vancomycin resistance on mortality in our cohort changed throughout the course of hospitalization. Enterococcus faecalis sequence type 6 was a predominant multidrug-resistant lineage, whereas a heterogeneous genomic population of E faecium was identified. Conclusions Failure of early eradication of VRE from the bloodstream is a major factor associated with poor outcomes. Failure to eradicate enterococci from the bloodstream in the first 4 days after the index blood culture was the most consistent factor associated with increased risk of mortality. The association of vancomycin resistance with mortality changed throughout the course of the hospitalization

The mu - e Conversion in Nuclei, mu --> e gamma, mu --> 3e Decays and TeV Scale See-Saw Scenarios of Neutrino Mass Generation

We perform a detailed analysis of lepton flavour violation (LFV) within minimal see-saw type extensions of the Standard Model (SM), which give a viable mechanism of neutrino mass generation and provide new particle content at the electroweak scale. We focus, mainly, on predictions and constraints set on each scenario from mu --> e gamma, mu --> 3e and mu - e conversion in the nuclei. In this class of models, the flavour structure of the Yukawa couplings between the additional scalar and fermion representations and the SM leptons is highly constrained by neutrino oscillation measurements. In particular, we show that in some regions of the parameters space of type I and type II see-saw models, the Dirac and Majorana phases of the neutrino mixing matrix, the ordering and hierarchy of the active neutrino mass spectrum as well as the value of the reactor mixing angle theta_{13} may considerably affect the size of the LFV observables. The interplay of the latter clearly allows to discriminate among the different low energy see-saw possibilities.Comment: Expressions for the factors |C_{me}|^2 and |C_{mu3e}|^2 in the mu-e conversion and mu-->3e decay rates, eqs. (36) and (49), respectively, corrected; results in subsections 2.2 and 2.3 quantitatively changed, qualitatively remain the same; figures 2, 3, 4 and 5 replace

Low HIV incidence in pregnant and postpartum women receiving a community-based combination HIV prevention intervention in a high HIV incidence setting in South Africa

BACKGROUND: Young Southern African women have the highest HIV incidence globally. Pregnancy doubles the risk of HIV acquisition further, and maternal HIV acquisition contributes significantly to the paediatric HIV burden. Little data on combination HIV prevention interventions during pregnancy and lactation are available. We measured HIV incidence amongst pregnant and postpartum women receiving a community-based combination HIV prevention intervention in a high HIV incidence setting in South Africa. METHODS: A cohort study that included HIV-uninfected pregnant women was performed. Lay community- based workers provided individualized HIV prevention counselling and performed three-monthly home and clinic-based individual and couples HIV testing. Male partners were referred for circumcision, sexually transmitted infections or HIV treatment as appropriate. Kaplan-Meier analyses and Cox's regression were used to estimate HIV incidence and factors associated with HIV acquisition. RESULTS The 1356 women included (median age 22.5 years) received 5289 HIV tests. Eleven new HIV infections were detected over 828.3 person-years (PY) of follow-up, with an HIV incidence rate of 1.33 infections/100 PY (95% CI: 0.74±2.40). Antenatally, the HIV incidence rate was 1.49 infections/100 PY (95% CI: 0.64±2.93) and postnatally the HIV incidence rate was 1.03 infections/100 PY (95% CI: 0.33±3.19). 53% of male partners received HIV testing and 66% of eligible partners received referral for circumcision. Women within known serodiscordant couples, and women with newly diagnosed HIV-infected partners, adjusted hazard ratio (aHR) = 32.7 (95% CI: 3.8±282.2) and aHR = 126.4 (95% CI: 33.8±472.2) had substantially increased HIV acquisition, respectively. Women with circumcised partners had a reduced risk of incident HIV infection, aHR = 0.22 (95% CI: 0.03±1.86). CONCLUSIONS: Maternal HIV incidence was substantially lower than previous regional studies. Community-based combination HIV prevention interventions may reduce high maternal HIV incidence in resource-poor settings. Expanded roll-out of home-based couples HIV testing and initiating pre-exposure prophylaxis for pregnant women within serodiscordant couples is needed in Southern Africa

The Microphenotron: a robotic miniaturized plant phenotyping platform with diverse applications in chemical biology

Background Chemical genetics provides a powerful alternative to conventional genetics for understanding gene function. However, its application to plants has been limited by the lack of a technology that allows detailed phenotyping of whole-seedling development in the context of a high-throughput chemical screen. We have therefore sought to develop an automated micro-phenotyping platform that would allow both root and shoot development to be monitored under conditions where the phenotypic effects of large numbers of small molecules can be assessed. Results The ‘Microphenotron’ platform uses 96-well microtitre plates to deliver chemical treatments to seedlings of Arabidopsis thaliana L. and is based around four components: (a) the ‘Phytostrip’, a novel seedling growth device that enables chemical treatments to be combined with the automated capture of images of developing roots and shoots; (b) an illuminated robotic platform that uses a commercially available robotic manipulator to capture images of developing shoots and roots; (c) software to control the sequence of robotic movements and integrate these with the image capture process; (d) purpose-made image analysis software for automated extraction of quantitative phenotypic data. Imaging of each plate (representing 80 separate assays) takes 4 min and can easily be performed daily for time-course studies. As currently configured, the Microphenotron has a capacity of 54 microtitre plates in a growth room footprint of 2.1 m², giving a potential throughput of up to 4320 chemical treatments in a typical 10 days experiment. The Microphenotron has been validated by using it to screen a collection of 800 natural compounds for qualitative effects on root development and to perform a quantitative analysis of the effects of a range of concentrations of nitrate and ammonium on seedling development. Conclusions The Microphenotron is an automated screening platform that for the first time is able to combine large numbers of individual chemical treatments with a detailed analysis of whole-seedling development, and particularly root system development. The Microphenotron should provide a powerful new tool for chemical genetics and for wider chemical biology applications, including the development of natural and synthetic chemical products for improved agricultural sustainability

A922 Sequential measurement of 1 hour creatinine clearance (1-CRCL) in critically ill patients at risk of acute kidney injury (AKI)

Meeting abstrac

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe

Multi-messenger observations of a binary neutron star merger

On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ~1.7 s with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of 40+8-8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 Mo. An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ~40 Mpc) less than 11 hours after the merger by the One- Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ~10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ~9 and ~16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta