A Small Multidrug Resistance Transporter in Pseudomonas aeruginosa Confers Substrate-Specific Resistance or Susceptibility.

Small Multidrug Resistance (SMR) transporters are key players in the defense of multidrug-resistant pathogens to toxins and other homeostasis-perturbing compounds. However, recent evidence demonstrates that EmrE, an SMR from Escherichia coli and a model for understanding transport, can also induce susceptibility to some compounds by drug-gated proton leak. This runs down the ∆pH component of the Proton Motive Force (PMF), reducing viability of the affected bacteria. Proton leak may provide an unexplored drug target distinct from the targets of most known antibiotics. Activating proton leak requires an SMR to be merely present, rather than be the primary resistance mechanism, and dissipates the energy source for many other efflux pumps. PAsmr, an EmrE homolog from P. aeruginosa, transports many EmrE substrates in cells and purified systems. We hypothesized that PAsmr, like EmrE, may confer susceptibility to some compounds via drug-gated proton leak. Growth assays of E. coli expressing PAsmr displayed substrate-dependent resistance and susceptibility phenotypes, and in vitro solid-supported membrane electrophysiology experiments revealed that PAsmr performs both antiport and substrate-gated proton uniport, demonstrating the same functional promiscuity observed in EmrE. Growth assays of P. aeruginosa strain PA14 demonstrated that PAsmr contributes resistance to some antimicrobial compounds, but no growth defect is observed with susceptibility substrates, suggesting P. aeruginosa can compensate for the proton leak occurring through PAsmr. These phenotypic differences between P. aeruginosa and E. coli advance our understanding of underlying resistance mechanisms in P. aeruginosa and prompt further investigation into the role that SMRs play in antibiotic resistance in pathogens.

Contradictory coroners? Decision-making in death investigations.

AIM: National coroner data demonstrate differences in the rates at which coroners across England and Wales choose to investigate reported deaths and the frequency by which they record certain conclusions. This study sought to examine how decisions are made by coroners and whether they differed when faced with identical case information. METHODS: Three different clinical scenarios were circulated via a web link to all senior coroners. The case information was contained within a 'Decision Board' displayed on screen. Each scenario had nine consistent categories of information, such as the cause of death and the medical history. Participants were asked to indicate an inquest conclusion (verdict) using free text and to provide comments. The way in which participants accessed the case information (order, frequency, etc) was recorded by the computer software. RESULTS: 35 coroners responded. There was little consensus as to conclusion with scenarios 1 and 2 generating four different outcomes and scenario 3 generating an extraordinary eight different conclusions among respondents. Despite coming to widely different conclusions, coroners demonstrated very similar decision-making processes. Conclusions were robustly defended yet proffered alternatives were plentiful. The comments made indicated a difference in the personal attitudes of coroners towards case information. CONCLUSIONS: Different coroners faced with identical case information arrived at widely different case outcomes ranging from no further investigation to finding numerous alternative verdicts. Disparity appeared to be a product of differing personal attitudes among coroners. National coroner consensus to achieve a shared inference from available evidence is urgently needed.

Coroner consistency - The 10-jurisdiction, 10-year, postcode lottery?

The investigation and classification of deaths in England and Wales relies upon the application by medical practitioners of diverse reporting standards set locally by coroners and thereafter upon the effectively unconstrained decision process of those same coroners. The author has conducted extensive comparative analysis of Ministry of Justice data on reports to the coroner and their inquest and verdict returns alongside Office of National Statistics data pertaining to the numbers of registered deaths in equivalent local jurisdictions. Here, he analyses 10 jurisdictions characterised by almost identical inquest return numbers in 2011. Substantial variation was found in reporting rates to the coroner and in the profile of inquest verdicts. The range of deaths reported varied from 34% to 62% of all registered deaths. Likewise only 2 of the 10 jurisdictions shared the same ranking of proportions in which the six common verdicts were reached. Individual jurisdictions tended to be consistent over time in their use of verdicts. In all cases, proportionately more male deaths were reported to the coroner. Coroners generally seemed prima facie to be 'gendered' in their approach to verdicts; that is, they were consistently more likely to favour a particular verdict when dealing with a death, according to the sex of the deceased. The extent to which coroners seemed gendered varied widely. While similar services such as the criminal courts or the Crown Prosecution Service are subject to extensive national guidance in an attempt to constrain idiosyncratic decision making, there seems no reason why this should apply less to the process of death investigation and classification. Further analysis of coroners' local practices and their determinants seems necessary.

Local variations in reporting deaths to the coroner in England and Wales: a postcode lottery?

AIMS: In England and Wales, doctors are charged with a responsibility either to report a death to the coroner or issue a medical certificate specifying cause of death. A lack of formal prescriptive or presumptive oversight has resulted in the promulgation by individual coroners of local reporting regimes. The study reported here identified overall and gendered variations in local reporting rates to coroners across the jurisdictions of England and Wales, consistent over time. METHODS: Analysis was performed on Ministry of Justice (MOJ) data pertaining to the numbers and proportions of deaths reported to the coroner by jurisdiction over a 10-year period (2001-2010). Office of National Statistics (ONS) data provided the numbers of deaths registered in England and Wales over the same period to serve as a denominator for the calculation of proportions. Where coroner jurisdictions (and local authorities) had been amalgamated during this period, the combined reported and registered death figures have been included in line with the current jurisdiction areas. RESULTS: While reporting rates for individual jurisdictions were found to be stable over the 10-year period, wide local variations in reporting deaths to coroners were found with no obvious demographic explanation. The gender of the deceased was identified as a major factor in local variation. CONCLUSIONS: The decision to report a death to the coroner varies across jurisdictions. Implications for coronial investigations are discussed and the need for wider research into coroners' decision-making is proposed.