Major role of pKpQIL-like plasmids in the early dissemination of KPC-type carbapenemases in the UK

Objectives: KPC-producing Enterobacteriaceae were first seen in the UK in 2003 and have been increasingly reported since 2010, largely owing to an ongoing outbreak in North-West England. We examined the role of clonal spread and plasmid transmission in their emergence. Methods: Isolates comprised KPC-positive Klebsiella pneumoniae (n=33), Escherichia coli (n=7) and Enterobacter spp. (n=4) referred to the national reference laboratory between 2008 and 2010 from 17 UK centres, including three in North-West England. Isolates were typed by MLST. Plasmids were transferred by electroporation and characterised by PCR or sequencing. PCR screening assays were developed to distinguish plasmid pKpQIL variants. Results: The K. pneumoniae isolates included 10 STs, of which three belonged to clonal group (CG) 258. CG258 (n=19) isolates were detected in 13 centres but accounted for only 7/19 (36.8%) of those from North-West England. Most KPC-producers (37/44, 84.1%), including 16/19 CG258 K. pneumoniae carried blaKPC on IncFIIK2 plasmids. Sequencing of a subset of these plasmids (n=11) revealed similarities with published pKpQIL. One variant, pKpQIL-UK - identified in K. pneumoniae CG258 (n=5) and ST468 (n=1) isolates from distinct centres - had only a few nucleotide changes from classical pKpQIL, whereas pKpQIL-D1 (n=1) and pKpQIL-D2 (n=4), from isolates of various species in the North-West, harboured large variations reflecting replacement of the partitioning and replication functions and potentially thereby facilitating spread. PCR revealed that 36/37 (97.3%) IncFIIK2-type plasmids in KPC-positive isolates had pKpQIL markers. Conclusions: pKpQIL-like plasmids played a major role in the early dissemination of KPC enzymes in the UK

Coupling Non-Gravitational Fields with Simplicial Spacetimes

The inclusion of source terms in discrete gravity is a long-standing problem. Providing a consistent coupling of source to the lattice in Regge Calculus (RC) yields a robust unstructured spacetime mesh applicable to both numerical relativity and quantum gravity. RC provides a particularly insightful approach to this problem with its purely geometric representation of spacetime. The simplicial building blocks of RC enable us to represent all matter and fields in a coordinate-free manner. We provide an interpretation of RC as a discrete exterior calculus framework into which non-gravitational fields naturally couple with the simplicial lattice. Using this approach we obtain a consistent mapping of the continuum action for non-gravitational fields to the Regge lattice. In this paper we apply this framework to scalar, vector and tensor fields. In particular we reconstruct the lattice action for (1) the scalar field, (2) Maxwell field tensor and (3) Dirac particles. The straightforward application of our discretization techniques to these three fields demonstrates a universal implementation of coupling source to the lattice in Regge calculus.Comment: 10 pages, no figures, Latex, fixed typos and minor corrections

Moving frames applied to shell elasticity

Exterior calculus and moving frames are used to describe curved elastic shells. The kinematics follow from the Lie-derivative on forms whereas the dynamics via stress-forms.Comment: 20 pages, 1 figur

Use of probiotics in preventing antibiotic associated diarrhoea and Clostridium difficile associated diarrhoea in spinal injury centres: An international survey of four western European countries

Probiotics may prevent antibiotic-associatedand Clostridium difficile-associated- diarrhoea (AAD/CDAD). Many spinal cord injury centres (SCICs) practitioners consider probiotics generically and may not realise that efficacy can be strain-, dose-, and disease-specific. One to four SCICs per country (depending on population size) were contacted (UK:4; the Netherlands:3; Belgium: I; Republic of Ireland: 1) to (a) determine if they stocked probiotics; (b) determine whether the use of those probiotics was evidence-based; and (c) document their C. difficile infection (CDI) practices. All nine SCICs responded to the survey (7 physicians, 3 microbiologists, 1 nurse and 2 dietitians). Five (55.5%) stocked probiotics; five different probiotics were identified. Four probiotics were preferred choice prevention o f AAD/CDAD were Lactobacillus casei Shirota (44.4%), L. casei D N -114001 (22.2%), L. acidophilus (22.2%) and a mixed-strains probiotic (Ecologic Pro-AD) (11.1%). Only one evidence base study was identified supporting the use of probiotic for prevention of AAD in SCI patients. Mean CDI cases per 10,000 patient-days were 0.307 (s.d: 0.486, range 0.00 to 1.08). Definitions of diarrhoea and CDI varied among SCICs. Stocking probiotics for the prevention of AAD / CDAD is not common. There is only one single study showing efficiency of a particular strain in SCI populations. The study highlighted the importance of using a standardised definition o f diarrhoea when conducting AAD/CDAD research

Lactobacillus casei Shirota probiotic drinks reduce antibiotic associated diarrhoea in patients with spinal cord injuries who regularly consume proton pump inhibitors: a subgroup analysis of the ECLISP multicentre RCT

Study design This was a sub-group analysis of a multicentre, randomised, placebo-controlled, double-blind trial (ECLISP trial) Objectives To assess the efficacy of a probiotic containing at least 6.5 x 109 live Lactobacillus casei Shirota (LcS) in preventing antibiotic associated diarrhoea (AAD) in patients with spinal cord injury (SCI) who consumed proton pump inhibitor (PPI) regularly. LcS or placebo was given once daily for the duration of an antibiotic course and continued for 7 days thereafter. The trial was registered with ISRCTN:13119162. Setting Three SCI centres (National Spinal Injuries Centre, Midland Centre for Spinal Injuries and Princess Royal Spinal Cord Injuries Centre) in the United Kingdom Methods Between November 2014, and November 2019, 95 eligible consenting SCI patients (median age: 57; IQ range: 43-69) were randomly allocated to receive LcS (n = 50) or placebo (n = 45). The primary outcome is the occurrence of AAD up to 30 days after finishing LcS/placebo. Results The LcS group had a significantly lower incidence of AAD at 30 days after finishing the antibiotic course (28.0 v 53.3%, RR: 95% CI:0.53, 0.31-0.89; z = 2.5, p = 0.01). Multivariate logistic regression analysis identified that LcS can reduce the risk of AAD at 30 days (OR: 0.36, 95% CI 0.13, 0.99,p < 0.05). No intervention-related adverse events were reported during the study. Conclusions LcS has the potential to prevent AAD in what could be considered a defined vulnerable group of SCI patients on regular PPL A confirmatory, randomised, placebo-controlled study is needed to confirm this apparent therapeutic success to translate it into appropriate clinical outcomes

Anterior-enriched filopodia create appearance of asymmetric membrane microdomains in polarizing C. elegans zygotes

The association of molecules within membrane microdomains is critical for the intracellular organization of cells. During polarization of the C. elegans zygote, both polarity proteins and actomyosin regulators associate within dynamic membrane-associated foci. Recently, a novel class of asymmetric PIP2 membrane-associated structures was described, suggesting that PIP2 domains could constitute signaling hubs to promote cell polarization and actin nucleation. Here we probe the nature of these domains using a variety of membrane- and actin cortex-associated probes. These data demonstrate that these domains are filopodia, which are stimulated transiently during polarity establishment and accumulate in the zygote anterior. The resulting membrane protrusions create local membrane topology that quantitatively accounts for observed local increases in fluorescence signal of membrane-associated molecules, suggesting molecules are not selectively enriched in these domains relative to bulk membrane and that the PIP2 pool as revealed by PHPLCδ1 simply reflects plasma membrane localization. Given the ubiquity of 3D membrane structures in cells, including filopodia, microvilli, and membrane folds, similar caveats are likely to apply to analysis of membrane-associated molecules in a broad range of systems

Use of antibiotics and the prevalence of antibiotic-associated diarrhoea in patients with spinal cord injuries: an international, multi-centre study

BACKGROUND: Little is known about the use of antibiotics and the extent of antibiotic-associated diarrhoea (AAD) in patients with spinal cord injuries (SCIs). AIMS: To record the use of antibiotics, establish the prevalence of AAD and Clostridium difficile infection (CDI), and assess if there was any seasonal variation in antibiotic use and incidence of AAD in patients with SCIs. METHODS: A retrospective study was conducted in six European SCI centres between October 2014 and June 2015. AAD was defined as two or more watery stools (Bristol Stool Scale type 5, 6 or 7) over 24 h. FINDINGS: In total, 1267 adults (median age 54 years, 30.7% female) with SCIs (52.7% tetraplegia, 59% complete SCI) were included in this study. Among the 215 (17%) patients on antibiotics, the top three indications for antibiotics were urinary tract infections (UTIs), infected pressure ulcers and other skin infections. Thirty-two of these 215 (14.9%) patients developed AAD and two patients out of the total study population (2/1267; 0.16%) developed CDI. AAD was more common in summer than in spring, autumn or winter (30.3% vs 3.8%, 7.4% and 16.9%, respectively; P<0.01). AAD was associated with age ≥65 years, tetraplegia, higher body mass index, hypoalbuminaemia, polypharmacy, multiple antibiotic use and high-risk antibiotic use. Summer and winter seasons and male sex were identified as independent predictors for the development of AAD. CONCLUSION: This survey found that AAD is common in patients with SCIs, and UTI is the most common cause of infection. Summer and winter seasons and male sex are unique predictors for AAD. Both AAD and UTIs are potentially preventable; therefore, further work should focus on preventing the over-use of antibiotics, and developing strategies to improve hospital infection control measures

Discrete Routh Reduction

This paper develops the theory of abelian Routh reduction for discrete mechanical systems and applies it to the variational integration of mechanical systems with abelian symmetry. The reduction of variational Runge-Kutta discretizations is considered, as well as the extent to which symmetry reduction and discretization commute. These reduced methods allow the direct simulation of dynamical features such as relative equilibria and relative periodic orbits that can be obscured or difficult to identify in the unreduced dynamics. The methods are demonstrated for the dynamics of an Earth orbiting satellite with a non-spherical $J_2$ correction, as well as the double spherical pendulum. The $J_2$ problem is interesting because in the unreduced picture, geometric phases inherent in the model and those due to numerical discretization can be hard to distinguish, but this issue does not appear in the reduced algorithm, where one can directly observe interesting dynamical structures in the reduced phase space (the cotangent bundle of shape space), in which the geometric phases have been removed. The main feature of the double spherical pendulum example is that it has a nontrivial magnetic term in its reduced symplectic form. Our method is still efficient as it can directly handle the essential non-canonical nature of the symplectic structure. In contrast, a traditional symplectic method for canonical systems could require repeated coordinate changes if one is evoking Darboux' theorem to transform the symplectic structure into canonical form, thereby incurring additional computational cost. Our method allows one to design reduced symplectic integrators in a natural way, despite the noncanonical nature of the symplectic structure.Comment: 24 pages, 7 figures, numerous minor improvements, references added, fixed typo

Downregulation of Mcl-1 has anti-inflammatory pro-resolution effects and enhances bacterial clearance from the lung

Phagocytes not only coordinate acute inflammation and host defense at mucosal sites, but also contribute to tissue damage. Respiratory infection causes a globally significant disease burden and frequently progresses to acute respiratory distress syndrome, a devastating inflammatory condition characterized by neutrophil recruitment and accumulation of protein-rich edema fluid causing impaired lung function. We hypothesized that targeting the intracellular protein myeloid cell leukemia 1 (Mcl-1) by a cyclin-dependent kinase inhibitor (AT7519) or a flavone (wogonin) would accelerate neutrophil apoptosis and resolution of established inflammation, but without detriment to bacterial clearance. Mcl-1 loss induced human neutrophil apoptosis, but did not induce macrophage apoptosis nor impair phagocytosis of apoptotic neutrophils. Neutrophil-dominant inflammation was modelled in mice by either endotoxin or bacteria (Escherichia coli). Downregulating inflammatory cell Mcl-1 had anti-inflammatory, pro-resolution effects, shortening the resolution interval (R(i)) from 19 to 7 h and improved organ dysfunction with enhanced alveolar–capillary barrier integrity. Conversely, attenuating drug-induced Mcl-1 downregulation inhibited neutrophil apoptosis and delayed resolution of endotoxin-mediated lung inflammation. Importantly, manipulating lung inflammatory cell Mcl-1 also accelerated resolution of bacterial infection (R(i); 50 to 16 h) concurrent with enhanced bacterial clearance. Therefore, manipulating inflammatory cell Mcl-1 accelerates inflammation resolution without detriment to host defense against bacteria, and represents a target for treating infection-associated inflammation