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

Inverting the model of genomics data sharing with the NHGRI Genomic Data Science Analysis, Visualization, and Informatics Lab-space

The NHGRI Genomic Data Science Analysis, Visualization, and Informatics Lab-space (AnVIL; https://anvilproject.org) was developed to address a widespread community need for a unified computing environment for genomics data storage, management, and analysis. In this perspective, we present AnVIL, describe its ecosystem and interoperability with other platforms, and highlight how this platform and associated initiatives contribute to improved genomic data sharing efforts. The AnVIL is a federated cloud platform designed to manage and store genomics and related data, enable population-scale analysis, and facilitate collaboration through the sharing of data, code, and analysis results. By inverting the traditional model of data sharing, the AnVIL eliminates the need for data movement while also adding security measures for active threat detection and monitoring and provides scalable, shared computing resources for any researcher. We describe the core data management and analysis components of the AnVIL, which currently consists of Terra, Gen3, Galaxy, RStudio/Bioconductor, Dockstore, and Jupyter, and describe several flagship genomics datasets available within the AnVIL. We continue to extend and innovate the AnVIL ecosystem by implementing new capabilities, including mechanisms for interoperability and responsible data sharing, while streamlining access management. The AnVIL opens many new opportunities for analysis, collaboration, and data sharing that are needed to drive research and to make discoveries through the joint analysis of hundreds of thousands to millions of genomes along with associated clinical and molecular data types

Effects of hydrodynamic culture on embryonic stem cell differentiation: cardiogenic modulation

Stem and progenitor cells are an attractive cell source for the treatment of degenerative diseases due to their potential to differentiate into multiple cell types and provide large cell yields. Thus far, however, clinical applications have been limited due to inefficient differentiation into desired cell types with sufficient yields for adequate tissue repair and regeneration. The ability to spontaneously aggregate in suspension makes embryonic stem cells (ESCs) amenable to large-scale culture techniques for the production of large yields of differentiating cell spheroids (termed embryoid bodies or EBs); however, the introduction of hydrodynamic conditions may alter differentiation profiles within EBs and should be methodically examined. The work presented here employs a novel, laboratory-scale hydrodynamic culture model to systematically interrogate the effects of ESC culture hydrodynamics on cardiomyocyte differentiation through the modulation of a developmentally-relevant signaling pathway. The fluidic environment was defined using computational fluid dynamic modeling, and the effects of hydrodynamic conditions on EB formation, morphology and structure were assessed. Additionally, EB differentiation was examined through gene and protein expression, and indicated that hydrodynamic conditions modulate differentiation patterns, particularly cardiogenic lineage development. This work illustrates that mixing conditions can modulate common signaling pathways active in ESC differentiation and suggests that differentiation may be regulated via bioprocessing parameters and bioreactor design.Ph.D.Committee Chair: McDevitt, Todd; Committee Member: Anderson, Leonard; Committee Member: Barabino, Gilda; Committee Member: Jo, Hanjoong; Committee Member: Yoganathan, Aji

Between death and shame: Dimensions of pain in Bariba culture

The Bariba of Benin idealize stoicism in response to pain. Analysis of the conceptualization of pain in Bariba thought indicates that an appropriate response to pain is considered intrinsic to Bariba identity. The Bariba example offers data illuminating the pain response and detailing the implications of urbanization and industrialization for this facet of ethnicity. The subject of pain elicits from informants a cognitive map of honor and shame, rather than discussion of pain per se. Features of the socialization process, particularly circumcision and clitoridectomy, signal courage and honour as crucial values and provide a basis for the Bariba perspective towards pain.

The implications of role expectations for birth assistance among Bariba women

Throughout the Third World, a notable trend has been the proliferation of parallel health care systems in which cosmopolitan medical services co-exist with a variety of indigenous health care services, and client populations must make decisions regarding the preferred choice among the existing alternatives. Correspondingly, Bariba women in People's Republic of Benin, West Africa, who seek obstetrical care have an increasing number of available options from which to select, including government hospitals, maternity clinics, private clinics, and a variety of indigenous practitioners. An examination of the factors influencing choices of birth assistance among Bariba women suggests that attributes of indigenous midwives such as status characteristics and type of training serve as significant considerations for clientele selecting obstetrical care. Characteristics discussed as salient features of the midwife include religion, age, marital status, education, apprenticeship, and certain personal qualities such as courage and lack of modesty. In addition, features of the midwifery role are delineated; for instance, the role of indigenous midwife involves a great deal of variability in contrast to that of the government nurse-midwife, which appears as a more narrow specialization. In order to fulfill role expectations, the indigenous midwife must demonstrate attributes which fall within an acceptable range to the client population, thus rendering her reasonably homophilous. Homophily is defined as 'the degree to which pairs of individuals who interact are similar in certain attributes such as beliefs, values, education, social status'. The data suggest that a healer, in this instance an indigenous midwife, is selected in order to accomplish a particular task. A client assumes certain characteristics of the role occupant are requisite for the healer to be effective and competent. Clients and midwives are found to be homophilous in that they share concepts of causation, beliefs, values and role expectations. Where the healer is not homophilous with the client, the absence of homophily operates to deter prospective clients from utilizing obstetrical services. Thus in the case of the rural client/government midwife relationship, the respective role occupants are shown not to be homophilous. In contrast to the indigenous midwife, the government midwife does not share significant attributes, values and expectations with her client and this lack of homophily deters prospective clients from selecting the government midwife as an option for birth assistance.