Heavy metal pollution and co-selection for antibiotic resistance: A microbial palaeontology approach

This is the final version. Available on open access from Elsevier via the DOI in this recordFrequent and persistent heavy metal pollution has profound effects on the composition and activity of microbial communities. Heavy metals select for metal resistance but can also co-select for resistance to antibiotics, which is a global health concern. We here document metal concentration, metal resistance and antibiotic resistance along a sediment archive from a pond in the North West of the United Kingdom covering over a century of anthropogenic pollution. We specifically focus on zinc, as it is a ubiquitous and toxic metal contaminant known to co-select for antibiotic resistance, to assess the impact of temporal variation in heavy metal pollution on microbial community diversity and to quantify the selection effects of differential heavy metal exposure on antibiotic resistance. Zinc concentration and bioavailability was found to vary over the core, likely reflecting increased industrialisation around the middle of the 20th century. Zinc concentration had a significant effect on bacterial community composition, as revealed by a positive correlation between the level of zinc tolerance in culturable bacteria and zinc concentration. The proportion of zinc resistant isolates was also positively correlated with resistance to three clinically relevant antibiotics (oxacillin, cefotaxime and trimethoprim). The abundance of the class 1 integron-integrase gene, intI1, marker for anthropogenic pollutants correlated with the prevalence of zinc- and cefotaxime resistance but not with oxacillin and trimethoprim resistance. Our microbial palaeontology approach reveals that metal-contaminated sediments from depths that pre-date the use of antibiotics were enriched in antibiotic resistant bacteria, demonstrating the pervasive effects of metal-antibiotic co-selection in the environment.University of Exete

Poor outcome of revised resurfacing hip arthroplasty: 397 cases from the Australian Joint Replacement Registry

BACKGROUND AND PURPOSE: Recent years have seen a rapid increase in the use of resurfacing hip arthroplasty despite the lack of literature on the long-term outcome. In particular, there is little evidence regarding the outcome of revisions of primary resurfacing. The purpose of this analysis was to examine the survivorship of primary resurfacing hip arthroplasties that have been revised. PATIENTS AND METHODS: Over 12,000 primary resurfacing hip arthroplasties were recorded by the Australian Orthopaedic Association National Joint Replacement Registry between September 1, 1999 and December 31, 2008. During this time, 397 revisions for reasons other than infection were reported for these primary resurfacings and classified as acetabular, femoral, or both acetabular and femoral revisions. The survivorship of the different types of revisions was estimated using the Kaplan-Meier method and compared using proportional hazard models. Additionally, the outcome of a femoral-only revision was compared to that of primary conventional total hip arthroplasty. RESULTS: Acetabular-only revision had a high risk of re-revision compared to femoral-only and both acetabular and femoral revision (5-year cumulative per cent revision of 20%, 7%, and 5% respectively). Femoral-only revision had a risk of re-revision similar to that of revision of both the acetabular and femoral components. Femoral-only revision had over twice the risk of revision of primary conventional total hip arthroplasty. INTERPRETATION: Revision of a primary resurfacing arthroplasty is associated with a major risk of re-revision. The best outcome is achieved when either the femoral-only or both the acetabular and femoral components are revised. Technically straightforward femoral-only revisions generally have a worse outcome than a primary conventional total hip arthroplasty

Computed tomographic pulmonary angiography and pulmonary embolism: predictive value of a d-dimer assay

<p>Abstract</p> <p>Background</p> <p>Computed tomographic pulmonary angiography (CTPA) is increasingly being used as first investigation for suspected pulmonary embolism (PE). The investigation has high predictive value, but is resource and time intensive and exposes patients to considerable radiation. Our aim was to assess the potential value of a negative d-dimer assay to exclude pulmonary emboli and reduce the number of performed CTPAs.</p> <p>Methods</p> <p>All CTPAs performed in a Scottish secondary care hospital for a fourteen month period were retrospectively reviewed. Collected data included the presence or absence of PE, d-dimer results and patient demographics. PE positive CTPAs were reviewed by a specialist panel.</p> <p>Results</p> <p>Pulmonary embolisms were reported for 66/405 (16.3%) CTPAs and d-dimer tests were performed for 216 (53%). 186/216 (86%) patients had a positive and 30 (14%) a negative d-dimer result. The panel agreed 5/66 (7.6%) false positive examinations. The d-dimer assay's negative predictive value was 93.3% (95% CI = 76.5%-98.8%) based on the original number of positive CTPAs and 100% (95% CI = 85.9%-100%) based on expert review. Significant non-PE intrapulmonary pathology was reported for 312/405 (77.0) CTPAs, including 13 new diagnoses of carcinoma.</p> <p>Conclusions</p> <p>We found that a low d-dimer score excluded all pulmonary embolisms, after a further specialist panel review identified initial false positive reports. However, current evidence-based guidelines still recommend that clinicians combine a d-dimer result with a validated clinical risk score when selecting suitable patients for CTPA. This may result in better use of limited resources, prevent patients being exposed to unnecessary irradiation and prevent potential complications as a result of iodinated contrast.</p

In-reach specialist nursing teams for residential care homes : uptake of services, impact on care provision and cost-effectiveness

Background: A joint NHS-Local Authority initiative in England designed to provide a dedicated nursing and physiotherapy in-reach team (IRT) to four residential care homes has been evaluated.The IRT supported 131 residents and maintained 15 'virtual' beds for specialist nursing in these care homes. Methods: Data captured prospectively (July 2005 to June 2007) included: numbers of referrals; reason for referral; outcome (e.g. admission to IRT bed, short-term IRT support); length of stay in IRT; prevented hospital admissions; early hospital discharges; avoided nursing home transfers; and detection of unrecognised illnesses. An economic analysis was undertaken. Results: 733 referrals were made during the 2 years (range 0.5 to 13.0 per resident per annum)resulting in a total of 6,528 visits. Two thirds of referrals aimed at maintaining the resident's independence in the care home. According to expert panel assessment, 197 hospital admissions were averted over the period; 20 early discharges facilitated; and 28 resident transfers to a nursing home prevented. Detection of previously unrecognised illnesses accounted for a high number of visits. Investment in IRT equalled £44.38 per resident per week. Savings through reduced hospital admissions, early discharges, delayed transfers to nursing homes, and identification of previously unrecognised illnesses are conservatively estimated to produce a final reduction in care cost of £6.33 per resident per week. A sensitivity analysis indicates this figure might range from a weekly overall saving of £36.90 per resident to a 'worst case' estimate of £2.70 extra expenditure per resident per week. Evaluation early in implementation may underestimate some cost-saving activities and greater savings may emerge over a longer time period. Similarly, IRT costs may reduce over time due to the potential for refinement of team without major loss in effectiveness. Conclusion: Introduction of a specialist nursing in-reach team for residential homes is at least cost neutral and, in all probability, cost saving. Further benefits include development of new skills in the care home workforce and enhanced quality of care. Residents are enabled to stay in familiar surroundings rather than unnecessarily spending time in hospital or being transferred to a higher dependency nursing home setting

Dcas Supports Cell Polarization and Cell-Cell Adhesion Complexes in Development

Mammalian Cas proteins regulate cell migration, division and survival, and are often deregulated in cancer. However, the presence of four paralogous Cas family members in mammals (BCAR1/p130Cas, EFS/Sin1, NEDD9/HEF1/Cas-L, and CASS4/HEPL) has limited their analysis in development. We deleted the single Drosophila Cas gene, Dcas, to probe the developmental function of Dcas. Loss of Dcas had limited effect on embryonal development. However, we found that Dcas is an important modulator of the severity of the developmental phenotypes of mutations affecting integrins (If and mew) and their downstream effectors Fak56D or Src42A. Strikingly, embryonic lethal Fak56D-Dcas double mutant embryos had extensive cell polarity defects, including mislocalization and reduced expression of E-cadherin. Further genetic analysis established that loss of Dcas modified the embryonal lethal phenotypes of embryos with mutations in E-cadherin (Shg) or its signaling partners p120- and β-catenin (Arm). These results support an important role for Cas proteins in cell-cell adhesion signaling in development

High-resolution measurements of face-to-face contact patterns in a primary school

Little quantitative information is available on the mixing patterns of children in school environments. Describing and understanding contacts between children at school would help quantify the transmission opportunities of respiratory infections and identify situations within schools where the risk of transmission is higher. We report on measurements carried out in a French school (6-12 years children), where we collected data on the time-resolved face-to-face proximity of children and teachers using a proximity-sensing infrastructure based on radio frequency identification devices. Data on face-to-face interactions were collected on October 1st and 2nd, 2009. We recorded 77,602 contact events between 242 individuals. Each child has on average 323 contacts per day with 47 other children, leading to an average daily interaction time of 176 minutes. Most contacts are brief, but long contacts are also observed. Contacts occur mostly within each class, and each child spends on average three times more time in contact with classmates than with children of other classes. We describe the temporal evolution of the contact network and the trajectories followed by the children in the school, which constrain the contact patterns. We determine an exposure matrix aimed at informing mathematical models. This matrix exhibits a class and age structure which is very different from the homogeneous mixing hypothesis. The observed properties of the contact patterns between school children are relevant for modeling the propagation of diseases and for evaluating control measures. We discuss public health implications related to the management of schools in case of epidemics and pandemics. Our results can help define a prioritization of control measures based on preventive measures, case isolation, classes and school closures, that could reduce the disruption to education during epidemics

Utilisation of an operative difficulty grading scale for laparoscopic cholecystectomy

Background A reliable system for grading operative difficulty of laparoscopic cholecystectomy would standardise description of findings and reporting of outcomes. The aim of this study was to validate a difficulty grading system (Nassar scale), testing its applicability and consistency in two large prospective datasets. Methods Patient and disease-related variables and 30-day outcomes were identified in two prospective cholecystectomy databases: the multi-centre prospective cohort of 8820 patients from the recent CholeS Study and the single-surgeon series containing 4089 patients. Operative data and patient outcomes were correlated with Nassar operative difficultly scale, using Kendall’s tau for dichotomous variables, or Jonckheere–Terpstra tests for continuous variables. A ROC curve analysis was performed, to quantify the predictive accuracy of the scale for each outcome, with continuous outcomes dichotomised, prior to analysis. Results A higher operative difficulty grade was consistently associated with worse outcomes for the patients in both the reference and CholeS cohorts. The median length of stay increased from 0 to 4 days, and the 30-day complication rate from 7.6 to 24.4% as the difficulty grade increased from 1 to 4/5 (both p < 0.001). In the CholeS cohort, a higher difficulty grade was found to be most strongly associated with conversion to open and 30-day mortality (AUROC = 0.903, 0.822, respectively). On multivariable analysis, the Nassar operative difficultly scale was found to be a significant independent predictor of operative duration, conversion to open surgery, 30-day complications and 30-day reintervention (all p < 0.001). Conclusion We have shown that an operative difficulty scale can standardise the description of operative findings by multiple grades of surgeons to facilitate audit, training assessment and research. It provides a tool for reporting operative findings, disease severity and technical difficulty and can be utilised in future research to reliably compare outcomes according to case mix and intra-operative difficulty

Search for new phenomena in final states with an energetic jet and large missing transverse momentum in pp collisions at √ s = 8 TeV with the ATLAS detector

Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses 20.3 fb−1 of √ s = 8 TeV data collected in 2012 with the ATLAS detector at the LHC. Events are required to have at least one jet with pT > 120 GeV and no leptons. Nine signal regions are considered with increasing missing transverse momentum requirements between Emiss T > 150 GeV and Emiss T > 700 GeV. Good agreement is observed between the number of events in data and Standard Model expectations. The results are translated into exclusion limits on models with either large extra spatial dimensions, pair production of weakly interacting dark matter candidates, or production of very light gravitinos in a gauge-mediated supersymmetric model. In addition, limits on the production of an invisibly decaying Higgs-like boson leading to similar topologies in the final state are presente

Importance of a C-Terminal Conserved Region of Chk1 for Checkpoint Function

BACKGROUND: The protein kinase Chk1 is an essential component of the DNA damage checkpoint pathway. Chk1 is phosphorylated and activated in the fission yeast Schizosaccharomyces pombe when cells are exposed to agents that damage DNA. Phosphorylation, kinase activation, and nuclear accumulation are events critical to the ability of Chk1 to induce a transient delay in cell cycle progression. The catalytic domain of Chk1 is well-conserved amongst all species, while there are only a few regions of homology within the C-terminus. A potential pseudosubstrate domain exists in the C-terminus of S. pombe Chk1, raising the possibility that the C-terminus acts to inhibit the catalytic domain through interaction of this domain with the substrate binding site. METHODOLOGY/PRINCIPAL FINDINGS: To evaluate this hypothesis, we characterized mutations in the pseudosubstrate region. Mutation of a conserved aspartic acid at position 469 to alanine or glycine compromises Chk1 function when the mutants are integrated as single copies, demonstrating that this domain of Chk1 is critical for function. Our data does not support, however, the hypothesis that the domain acts to inhibit Chk1 function as other mutations in the amino acids predicted to comprise the pseudosubstrate do not result in constitutive activation of the protein. When expressed in multi-copy, Chk1D469A remains non-functional. In contrast, multi-copy Chk1D469G confers cell survival and imposes a checkpoint delay in response to some, though not all forms of DNA damage. CONCLUSIONS/SIGNIFICANCE: Thus, we conclude that this C-terminal region of Chk1 is important for checkpoint function and predict that a limiting factor capable of associating with Chk1D469G, but not Chk1D469A, interacts with Chk1 to elicit checkpoint activation in response to a subset of DNA lesions

Observational Evidence of For-Profit Delivery and Inferior Nursing Home Care: When Is There Enough Evidence for Policy Change?

This research was financially supported by the Social Sciences and Humanities Research Council