Global dissemination of a multidrug resistant Escherichia coli clone.

Escherichia coli sequence type 131 (ST131) is a globally disseminated, multidrug resistant (MDR) clone responsible for a high proportion of urinary tract and bloodstream infections. The rapid emergence and successful spread of E. coli ST131 is strongly associated with several factors, including resistance to fluoroquinolones, high virulence gene content, the possession of the type 1 fimbriae FimH30 allele, and the production of the CTX-M-15 extended spectrum β-lactamase (ESBL). Here, we used genome sequencing to examine the molecular epidemiology of a collection of E. coli ST131 strains isolated from six distinct geographical locations across the world spanning 2000-2011. The global phylogeny of E. coli ST131, determined from whole-genome sequence data, revealed a single lineage of E. coli ST131 distinct from other extraintestinal E. coli strains within the B2 phylogroup. Three closely related E. coli ST131 sublineages were identified, with little association to geographic origin. The majority of single-nucleotide variants associated with each of the sublineages were due to recombination in regions adjacent to mobile genetic elements (MGEs). The most prevalent sublineage of ST131 strains was characterized by fluoroquinolone resistance, and a distinct virulence factor and MGE profile. Four different variants of the CTX-M ESBL-resistance gene were identified in our ST131 strains, with acquisition of CTX-M-15 representing a defining feature of a discrete but geographically dispersed ST131 sublineage. This study confirms the global dispersal of a single E. coli ST131 clone and demonstrates the role of MGEs and recombination in the evolution of this important MDR pathogen

Structure-function analyses of a pertussis-like toxin from pathogenic Escherichia coli reveal a distinct mechanism of inhibition of trimeric G-proteins

Pertussis-like toxins are secreted by several bacterial pathogens during infection. They belong to the AB virulence factors, which bind to glycans on host cell membranes for internalization. Host cell recognition and internalization are mediated by toxin B subunits sharing a unique pentameric ring-like assembly. Although the role of pertussis toxin in whooping cough is well-established, pertussis-like toxins produced by other bacteria are less studied, and their mechanisms of action are unclear. Here, we report that some extra-intestinal Escherichia coli pathogens (i.e. those that reside in the gut but can spread to other bodily locations) encode a pertussis-like toxin that inhibits mammalian cell growth in vitro. We found that this protein, EcPlt, is related to toxins produced by both nontyphoidal and typhoidal Salmonella serovars. Pertussis-like toxins are secreted as disulfide-bonded heterohexamers in which the catalytic ADP-ribosyltransferase subunit is activated when exposed to the reducing environment in mammalian cells. We found here that the reduced EcPlt exhibits large structural rearrangements associated with its activation. We noted that inhibitory residues tethered within the NAD-binding site by an intramolecular disulfide in the oxidized state dissociate upon the reduction and enable loop restructuring to form the nucleotide-binding site. Surprisingly, although pertussis toxin targets a cysteine residue within the α subunit of inhibitory trimeric G-proteins, we observed that activated EcPlt toxin modifies a proximal lysine/asparagine residue instead. In conclusion, our results reveal the molecular mechanism underpinning activation of pertussis-like toxins, and we also identified differences in host target specificity

Determinants of penetrance and variable expressivity in monogenic metabolic conditions across 77,184 exomes

Penetrance of variants in monogenic disease and clinical utility of common polygenic variation has not been well explored on a large-scale. Here, the authors use exome sequencing data from 77,184 individuals to generate penetrance estimates and assess the utility of polygenic variation in risk prediction of monogenic variants

Segurança do paciente no uso de medicamentos após a alta hospitalar: estudo exploratório1

No Brasil, são escassos os estudos sobre estratégias para a segurança do paciente no processo de uso de medicamentos após a alta hospitalar, o que dificulta o conhecimento sobre a atuação de hospitais brasileiros nessa área. Neste artigo, buscou-se compreender a dinâmica e os desafios do cuidado fornecido ao paciente pela equipe hospitalar, visando à segurança no processo de uso de medicamentos após a alta hospitalar. Realizou-se pesquisa exploratória por meio de entrevistas com médicos, enfermeiros, farmacêuticos e assistentes sociais do Hospital Universitário da Universidade de São Paulo. Foram pesquisadas as atividades de cuidado com a farmacoterapia durante e após a hospitalização, incluindo o acesso a medicamentos após alta, a existência de articulação do hospital com outros serviços de saúde, e barreiras para desenvolver essas atividades. A principal estratégia adotada é a orientação de alta, realizada de forma estruturada, principalmente para cuidadores de pacientes pediátricos. Em situações específicas, ocorre mobilização da equipe para viabilização do acesso a medicamentos prescritos na alta. Reconciliação medicamentosa está em fase de implantação, e visita domiciliar é realizada apenas para pacientes críticos com problemas de locomoção. As principais barreiras identificadas foram insuficiência de recursos humanos e falta de tecnologias de informação. Conclui-se que são desenvolvidas algumas estratégias, porém com limitações e sem articulação adequada com outros serviços de saúde para a continuidade do cuidado. Isto sugere a necessidade de concentração de esforços para transpor as barreiras identificadas, contribuindo para a segurança do paciente na interface entre hospital, atenção básica e domicílio