Meropenem versus piperacillin-tazobactam for definitive treatment of bloodstream infections due to ceftriaxone non-susceptible Escherichia coli and Klebsiella spp (the MERINO trial): study protocol for a randomised controlled trial

BACKGROUND: Gram-negative bacteria such as Escherichia coli or Klebsiella spp. frequently cause bloodstream infections. There has been a worldwide increase in resistance in these species to antibiotics such as third generation cephalosporins, largely driven by the acquisition of extended-spectrum beta-lactamase or plasmid-mediated AmpC enzymes. Carbapenems have been considered the most effective therapy for serious infections caused by such resistant bacteria; however, increased use creates selection pressure for carbapenem resistance, an emerging threat arising predominantly from the dissemination of genes encoding carbapenemases. Recent retrospective data suggest that beta-lactam/beta-lactamase inhibitor combinations, such as piperacillin-tazobactam, may be non-inferior to carbapenems for the treatment of bloodstream infection caused by extended-spectrum beta-lactamase-producers, if susceptible in vitro. This study aims to test this hypothesis in an effort to define carbapenem-sparing alternatives for these infections.

METHODS/DESIGN: The study will use a multicentre randomised controlled open-label non-inferiority trial design comparing two treatments, meropenem (standard arm) and piperacillin-tazobactam (carbapenem-sparing arm) in adult patients with bacteraemia caused by E. coli or Klebsiella spp. demonstrating non-susceptibility to third generation cephalosporins. Recruitment is planned to occur in sites across three countries (Australia, New Zealand and Singapore). A total sample size of 454 patients will be required to achieve 80% power to determine non-inferiority with a margin of 5%. Once randomised, definitive treatment will be for a minimum of 4 days, but up to 14 days with total duration determined by treating clinicians. Data describing demographic information, antibiotic use, co-morbid conditions, illness severity, source of infection and other risk factors will be collected. Vital signs, white cell count, use of vasopressors and days to bacteraemia clearance will be recorded up to day 7. The primary outcome measure will be mortality at 30 days, with secondary outcomes including days to clinical and microbiological resolution, microbiological failure or relapse, isolation of a multi-resistant organism or Clostridium difficile infection.

Testing the transferability of a coarse-grained model to intrinsically disordered proteins

The intermediate-resolution coarse-grained protein model PLUM [T. Bereau and M. Deserno, J. Chem. Phys., 2009, 130, 235106] is used to simulate small systems of intrinsically disordered proteins involved in biomineralisation. With minor adjustments to reduce bias toward stable secondary structure, the model generates conformational ensembles conforming to structural predictions from atomistic simulation. Without additional structural information as input, the model distinguishes regions of the chain by predicted degree of disorder, manifestation of structure, and involvement in chain dimerisation. The model is also able to distinguish dimerisation behaviour between one intrinsically disordered peptide and a closely related mutant. We contrast this against the poor ability of PLUM to model the S1 quartz-binding peptide.

Facet selectivity in gold binding peptides: exploiting interfacial water structure

Peptide sequences that can discriminate between gold facets under aqueous conditions offer a promising route to control the growth and organisation of biomimetically-synthesised gold nanoparticles. Knowledge of the interplay between sequence, conformations and interfacial properties is essential for predictable manipulation of these biointerfaces, but the structural connections between a given peptide sequence and its binding affinity remain unclear, impeding practical advances in the field. These structural insights, at atomic-scale resolution, are not easily accessed with experimental approaches, but can be delivered via molecular simulation. A current unmet challenge lies in forging links between predicted adsorption free energies derived from enhanced sampling simulations with the conformational ensemble of the peptide and the water structure at the surface. To meet this challenge, here we use an in situ combination of Replica Exchange with Solute Tempering with Metadynamics simulations to predict the adsorption free energy of a gold-binding peptide sequence, AuBP1, at the aqueous Au(111), Au(100)(1 × 1) and Au(100)(5 × 1) interfaces. We find adsorption to the Au(111) surface is stronger than to Au(100), irrespective of the reconstruction status of the latter. Our predicted free energies agree with experiment, and correlate with trends in interfacial water structuring. For gold, surface hydration is predicted as a chief determining factor in peptide-surface recognition. Our findings can be used to suggest how shaped seed-nanocrystals of Au, in partnership with AuBP1, could be used to control AuNP nanoparticle morphology.

Sequence-dependent structure/function relationships of catalytic peptide-enabled gold nanoparticles generated under ambient synthetic conditions

Peptide-enabled nanoparticle (NP) synthesis routes can create and/or assemble functional nanomaterials under environmentally friendly conditions, with properties dictated by complex interactions at the biotic/abiotic interface. Manipulation of this interface through sequence modification can provide the capability for material properties to be tailored to create enhanced materials for energy, catalysis, and sensing applications. Fully realizing the potential of these materials requires a comprehensive understanding of sequence-dependent structure/function relationships that is presently lacking. In this work, the atomic-scale structures of a series of peptide-capped Au NPs are determined using a combination of atomic pair distribution function analysis of high-energy X-ray diffraction data and advanced molecular dynamics (MD) simulations. The Au NPs produced with different peptide sequences exhibit varying degrees of catalytic activity for the exemplar reaction 4-nitrophenol reduction. The experimentally derived atomic-scale NP configurations reveal sequence-dependent differences in structural order at the NP surface. Replica exchange with solute-tempering MD simulations are then used to predict the morphology of the peptide overlayer on these Au NPs and identify factors determining the structure/catalytic properties relationship. We show that the amount of exposed Au surface, the underlying surface structural disorder, and the interaction strength of the peptide with the Au surface all influence catalytic performance. A simplified computational prediction of catalytic performance is developed that can potentially serve as a screening tool for future studies. Our approach provides a platform for broadening the analysis of catalytic peptide-enabled metallic NP systems, potentially allowing for the development of rational design rules for property enhancement.

Determination of Kamlet–Taft parameters for selected solvate ionic liquids

The normalised polarity E and Kamlet-Taft parameters of recently described solvate ionic liquids, composed of lithium bis(trifluoromethyl)sulfonimide (LiTFSI) in tri- () or tetraglyme () have been determined and compared to the parent glyme ( and ). We show that these solvate ionic liquids have a high polarity (, (E) = 1.03; , (E) = 1.03) and display very high electron pair accepting characteristics (, α = 1.32; , α = 1.35). Molecular dynamics simulations suggest that the chelated lithium cation is responsible for this observation. The relatively small hydrogen bond acceptor (β) values for these systems (, β = 0.41; , β = 0.37) are thought to be due primarily to the TFSI anion, which is supplemented slightly by the glyme oxygen atom. In addition, these solvate ionic liquids are found to have a high polarisability (, π* = 0.94; , π* = 0.90).

Complete structure of an epithelial keratin dimer: implications for intermediate filament assembly

Keratins are cytoskeletal proteins that hierarchically arrange into filaments, starting with the dimer sub-unit. They are integral to the structural support of cells, in skin, hair and nails. In skin, keratin is thought to play a critical role in conferring the barrier properties and elasticity of skin. In general, the keratin dimer is broadly described by a tri-domain structure: a head, a central rod and a tail. As yet, no atomistic-scale picture of the entire dimer structure exists; this information is pivotal for establishing molecular-level connections between structure and function in intermediate filament proteins. The roles of the head and tail domains in facilitating keratin filament assembly and function remain as open questions. To address these, we report results of molecular dynamics simulations of the entire epithelial human K1/K10 keratin dimer. Our findings comprise: (1) the first three-dimensional structural models of the complete dimer unit, comprising of the head, rod and tail domains; (2) new insights into the chirality of the rod-domain twist gained from analysis of the full domain structure; (3) evidence for tri-subdomain partitioning in the head and tail domains; and, (4) identification of the residue characteristics that mediate non-covalent contact between the chains in the dimer. Our findings are immediately applicable to other epithelial keratins, such as K8/K18 and K5/K14, and to intermediate filament proteins in general.

Indigenous intermediaries : new perspectives on exploration archives

This edited collection understands exploration as a collective effort and experience involving a variety of people in diverse kinds of relationships. It engages with the recent resurgence of interest in the history of exploration by focusing on the various indigenous intermediaries – Jacky Jacky, Bungaree, Moowattin, Tupaia, Mai, Cheealthluc and lesser-known individuals – who were the guides, translators, and hosts that assisted and facilitated European travellers in exploring different parts of the world.These intermediaries are rarely the authors of exploration narratives, or the main focus within exploration archives. Nonetheless the archives of exploration contain imprints of their presence, experience and contributions. The chapters present a range of ways of reading archives to bring them to the fore. The contributors ask new questions of existing materials, suggest new interpretive approaches, and present innovative ways to enhance sources so as to generate new stories.

Exploration archives and indigenous histories: an introduction

Since the 1990s, a number of scholars have sought to uncover ‘hidden histories’ of exploration, as Felix Driver and Lowri Jones have referred to it.1 Working against a conventional emphasis on the exploits and achievements of the singular heroic explorer, imperial and colonial exploration is recast as a collective enterprise involving a diverse labour force and upon which expeditions were dependent for their progress and success.2 Various approaches are pursued for writing a more representative history of exploration, such as recuperatingfrom the archives the stories of little- or lesser-known participants; rewriting histories of particular expeditions through the lens of their encounters and interactions with indigenous people; or giving greater prominence to the work of intermediaries of many kinds, including interpreters, brokers, guides, porters and other labourers.3 The result is a more complex and multivocal account of the practices and politics of European exploration, the social and historical contexts in which it occurred, and the relationships, networks and institutions it createdand on which it depended.

‘On my ground’: Indigenous farmers at New Norcia 1860s-1900s

These words were penned in 1867 by Father Venancio Garrido, a Benedictine monk at New Norcia Aboriginal mission in Western Australia (see Map 4.1). They form part of his lengthy report on the mission which was requested by the Colonial Secretary to be forwarded to the Aborigines Protection Society in London. In 1871 Father Garrido’s report was collated alongside other ‘information’ about Aborigines in Western Australia that had been collected by missionaries and government agents, and was printed by the government printer. The above statement suggests two issues which I will draw out in this chapter: the Aboriginal residents at New Norcia had a strong sense of right and wrong; and the Benedictine community at New Norcia considered them to be the original owners of the land which was, in 1867, increasingly occupied by pastoralists.

Enriching understanding of young adult voter decision-making in the Australian compulsory voting context

This thesis has provided insight into considering how the consumer behaviour theoretical concept of usage impacts on lower-involvement young adult voter decision-making within the Australian compulsory voting context. This differentiated replication of previous research extends the range of results under which decision-making factors hold in voter behaviour.

Problem gambling, familial violence and alcohol misuse: exploring the triad for treatment-seekers

Research into the co-occurrence of problem gambling, familial violence, and alcohol misuse is limited. While these issues have been considered in combination (i.e.violence and alcohol misuse, problem gambling and alcohol misuse, problem gambling and violence), within Australia, in particular, there has been an absence of exploration of this triad. The current research attempts to fill the gap in the literature, to establish whether there is any difference between problem gamblers with co-occurring violence and problem gamblers who had not experienced violence in terms of their alcohol misuse and gambling behaviours. Interviews were conducted with 81 treatment- seeking problem gamblers to explore how a history of victimization only, perpetration only, victimization and perpetration, or no history of family violence impacted on gambling behaviours (including baseline Victorian Gambling Screen), as well as alcohol misuse. Results indicated that in this treatment-seeking sample there were no significant differences for gambling behaviours or alcohol misuse between problem gamblers with issues of violence and those without. Males demonstrated (on average) a greater tendency toward hazardous drinking or disordered alcohol use. It would be prudent for treatment services to routinely examine problem gamblers’ history of violence and alcohol misuse until research verifies the nature of this triad

Experiences and perceptions of problem gamblers on cognitive and exposure therapies when taking part in a randomised controlled trial: a qualitative study

In South Australia (SA) problem gambling is mainly a result of the widespread availability of electronic gaming machines. A key treatment provider in SA offers free cognitive and behavioural therapy (CBT) to help-seeking problem gamblers. The CBT program focuses on the treatment of clients' urge to gamble using exposure therapy (ET) and cognitive therapy (CT) to restructure erroneous gambling beliefs. The aim of this study was to explore treatment specific and non-specific effects for CT alone and ET alone using qualitative interviews. Interviewees were a sub-sample of participants from a randomised trial that investigated the relative efficacy of CT versus ET. Findings revealed that all interviewees gained benefit from their respective therapies and their comments did not appear to favour one therapy over another. Both treatment specific and treatment non-specific effects were well supported as playing a therapeutic role to recovery. Participants' comments in both therapy groups suggested that symptom reduction was experienced on a gambling related urge-cognition continuum. In addition to symptom improvement from therapy-specific mechanisms, ET participants described a general acquisition of "rational thought" from their program of therapy and CT participants had "taken-over" their gambling urges. The findings also highlighted areas for further improvement including therapy drop-out.

How usage influences young adult voting decision-making: an SEM analysis

Political marketing is increasing in importance as a field of study, and despite decades of study, researchers suggest that still more focus needs to be on the voter as a consumer. This article addresses the need by analyzing consumer voting decision-making. Voting decision-making research by O’Cass (2002a) and O’Cass and Pecotich (2005) was replicated and extended specifically for young adult (ages 18–25) voters using quantitative data collected in Australia using a self-completion survey. This model was adapted to include an additional construct of commitment to voting, then tested across two groups of young adult voters: those who previously voted for the current political party in power and those who did not. Structural equation modeling was used to compare lower-involvement voting decisions of the two groups of young adults. The results showed that an influential factor on young voter decision-making was their previous behavior, or usage, of the political party. This was especially strong in voters who had previously voted for the current party in power. Those who did not vote for the current party in power required more steps in deciding whom to vote for. Implications for political marketing practice are also provided.