When the carnival is over : Peter Barnes\u27 Red Noses and the theories of Mikhail Bakhtin

Peter Barnes, acknowledged as one of Britain\u27s most important contemporary playwrights, writes plays that are of an enormous scale, both physically and intellectually. Red Noses is one such play. Like Barnes\u27 other works, Red Noses makes great technical demands on directors, designers, actors and audiences. As with all of Barnes\u27 plays, Red Noses is, moreover, informed by a wide variety of theatrical styles. As Bernard Dukore (1990, p. 65) states, actors may be required to quickly switch from intellectual discourse, to period argot, to poetry, to modern slang, to rhetoric, to musical comedy, to ritual, to dance, to opera, to slapstick. .. Furthermore, all of Barnes\u27 plays operate, as Stephen Weeks (1996, p.46) points out, as much through the boldness of their visual imagery as through the inventiveness of their language. All plays in performance are polysemic, with the various systems of signs in dialogical relation. Barnes\u27 play Red Noses foregrounds the polysemic process. The systems of signs that operate within any play in performance may be defined as discrete languages. Some of these languages are non-verbal, such as the use of theatrical space and the movement of bodies within that space, scale of settings and sound and visual effects. This project looks at the verbal and non-verbal polysenic texts in Red Noses in performance. Mikhail Bakhtin\u27s theories are usually applied to verbal and, in particular, printed texts. Indeed, Bakhtin (1981, p.266) himself has stated that the organisation of languages in drama does not allow for the dialogic interpenetration of one language by another. Nevertheless, this project will examine whether the non-verbal language systems of production and performance challenge or extend Bakhtin\u27 s theories of language. Barnes\u27 plays are often referred to as anarchic or carnivalesque. with his theatrical style working as an analogue to his stated aim of seeking to disrupt the social order of contemporary society (Barnes, 1996a, p. viii; Barnes, 1996b, p. x). Some critics have defined Barnes as an iconoclastic writer, but this begs the question as to whether Barnes\u27 iconoclasm is conservative or radical. Is there a reaffirming of the hierarchies of social and political power as a result of the upside-down world created in Red Noses, or is there the promise of a new and ongoing process of change? The object of this project is to explore these questions through the rehearsal and performance processes of a production of Barnes\u27 play Red Noses. The play will be reassessed through Bakhtin\u27s theories of carnival, polyphonic discourse and dialogics, taking particular account of rehearsal and performance processes. In addition to problems of interpretation this project enters the debate about problems of texts in performance. The project can also be expected to generate useful research into performance itself as research

Simulation of Shakedown Behavior in Pavement’s Granular Layer

While in the design of flexible pavement the significance of asphalt layers is understood, the role of granular layers supporting the asphalt layers should not be underestimated. The behavior of granular layers used in base, sub-base or subgrade layer of flexible pavement is complicated due to nonlinear elastoplastic response of materials subjected to dynamic load of traffic. Shakedown theory integrated with Mohr-Coulomb criterion is applied to simulate the response of granular layers to dynamic loading in a numerical analysis. The results of analysis are then compared to simple the results of modeling without considering shakedown effects and the conclusion is drawn

Risk factors for failure of outpatient parenteral antibiotic therapy (OPAT) in infective endocarditis

Objectives: To identify risk factors for failure of outpatient antibiotic therapy (OPAT) in infective endocarditis (IE). Patients and methods: We identified IE cases managed at a single centre over 12 years from a prospectively maintained database. ‘OPAT failure’ was defined as unplanned readmission or antibiotic switch due to adverse drug reaction or antibiotic resistance. We analysed patient and disease-related risk factors for OPAT failure by univariate and multivariate logistic regression. We also retrospectively collected follow-up data on adverse disease outcome (defined as IE-related death or relapse) and performed Kaplan–Meier survival analysis up to 36 months following OPAT. Results: We identified 80 episodes of OPAT in IE. Failure occurred in 25/80 episodes (31.3%). On multivariate analysis, cardiac or renal failure [pooled OR 7.39 (95% CI 1.84–29.66), P = 0.005] and teicoplanin therapy [OR 8.69 (95% CI 2.01–37.47), P = 0.004] were independently associated with increased OPAT failure. OPAT failure with teicoplanin occurred despite therapeutic plasma levels. OPAT failure predicted adverse disease outcome up to 36 months (P = 0.016 log-rank test). Conclusions: These data caution against selecting patients with endocarditis for OPAT in the presence of cardiac or renal failure and suggest teicoplanin therapy may be associated with suboptimal OPAT outcomes. Alternative regimens to teicoplanin in the OPAT setting should be further investigated

Bioactive scaffolds for potential bone regenerative medical applications

Fracture non-unions and bone defects represent a recalcitrant problem in the field of orthopaedic surgery. Although the current gold-standard treatment, autologous bone grafting, has a relatively high success rate, the technique is not without serious problems. The emerging field of regenerative medicine may have the potential to provide an alternative treatment. One promising strategy involves the delivery of both cells and multiple growth factors with different release profiles. A range of scaffolds was developed from Poly( -caprolactone) (PCL), Poly(lactideco- glycolide) (PLGA), and two blends of PCL (Mn 42,500) and PLGA. The scaffolds were manufactured utilising a novel modified fused deposition modelling system, using polymer/dichloromethane solutions. The scaffolds were found to have pore sizes suitable for bone regenerative medical applications (373±9.5 μm in the Ydirection and 460±13 μm in the X-direction). However, the scaffolds were found to be only 52±3 μm in height. This means that the two-layer scaffolds were relatively flat. This was undesirable, as direct control of the complete 3D geometry was the favoured strategy, though it may not be a necessary requirement. Five scaffold coatings were also developed from alginate, chitosan (crosslinked using sodium hydroxide or tripolyphosphate), Type-I collagen and Type-A gelatin. The scaffold coatings were screened in vitro for their cell-compatibility with human marrow stromal cells (hMSCs), human osteoblasts and MG63 cells. This was assessed using an assay for cell death, and assessing total cell counts. From these studies, Type-I collagen was found to be the optimum coating. For hMSCs, their death rates were found to be 19.1±6.3% for alginate, 5.3±3.6% and 2.9±1.4% for chitosan crosslinked with tripolyphosphate and sodium hydroxide respectively, compared to 0.11±0.07% for Type-I collagen, and 0.15±0.13% and 0.16±0.12% for 0.1% and 0.2% gelatin respectively. Type-I collagen was found to be the most cellcompatible coating, as it was consistently associated with higher cell counts than Type-A gelatin. Similarly, PCL scaffolds vacuum dried for 1 hr were found to be cell-compatible. No detectable clinically significant difference was found in either total cell counts, or the proportion of cell death in; hMSCs exposed to PCL scaffolds processed with dichloromethane, hMSCs either exposed to scaffolds known to be biocompatible, or hMSCs cultured in the absence of scaffolds. When cell morphology was compared, scaffolds vacuum dried for 1 hr or more were found to have a similar morphology to the cells cultured in the absence of scaffolds. It was therefore concluded that a vacuum drying time of 1 hr was sufficient for cell-compatibility. The scaffold materials were screened both for their encapsulation efficiencies and release characteristics using the model drug, methylene blue. The encapsulation efficiency was found to be both relatively high and consistent for both Mn 42,500 and 80,000 PCL as well as PCL:PLGA 66:33, at 71±6%, 71±5%, and 78±10% respectively, relative to the low efficiencies recorded for both PCL:PLGA 66:33 and PLGA: 57±5% and 38±10% respectively. The release rate of methylene blue from PCL (Mn 42,500), was found to be relatively slow, controlled, and consistent between batches (between 21±2% and 20±3% released in the first 24 hr). Despite the release rate being consistent for PCL (Mn 80,000), the release rate was thought to be too high, since between 29±3% and 39±5% of the test compound was released in the first 24 hr period. The release rate of methylene blue from the PCL/PLGA blends (between 17±2% – 30±7% and 18±4% – 31±6% in the first 24 hr) and PLGA (between 7.1±3.4% – 9.3±2.9% in the first 24 hr) were found to be inconsistent, and low in the case of PLGA, even taking the different loading efficiencies into account. Therefore, PCL (Mn 42,500) was selected as the favoured candidate scaffold material. The loading content and release profiles from methylene blue loaded collagen scaffold coatings were also evaluated. The drug loading capacity was found to be suitable for use as a drug delivery system (65±5 μg/g of methylene blue per unit scaffold mass). The release of methylene blue was observed to be rapid (between 54±10% – 70±17% in the first 24 hr), which was thought to be desirable for the coating delivery system. Recombinant human bone morphogenetic protein-7 (rhBMP-7) was used as a representative growth factor of interest for bone regenerative medical applications. It was loaded in collagen scaffold coatings (CoatBMP 1.25) and encapsulated within PCL (Mn 42,500) scaffolds (ScaffBMP 1.25). Control coatings and scaffolds were designated CoatPBS and ScaffPBS respectively. Both delivery systems were found to release detectable quantities of rhBMP-7 (releasing 2.8±0.2 μg/g and 87±7 ng/g respectively in the first 24 hr), even after 14 days. The release rate of the growth factor from the scaffold coating was higher than that from the encapsulating scaffolds. However, the cumulative release profiles were found to deviate from the desired ideal release profiles, and burst release was observed from both delivery systems. Although differences were observed for the two delivery systems, this difference may not be of clinical significance. Nevertheless, scaffolds with less than ideal delivery properties may still be of potential clinical use. The bioactivity of the rhBMP-7 released from the test scaffolds was therefore assessed by quantifying the area of normalised ALP staining of hMSCs. The release of rhBMP-7 from the collagen coating of the PCL (Mn 42,500) scaffolds (CoatBMP 1.25ScaffPBS) was capable of statistically significantly increasing hMSC normalised ALP expression, although the actual differences were often relatively small. Therefore, at least a proportion of the growth factor released is likely to have been bioactive. The release from scaffolds encapsulating rhBMP-7 (CoatPBSScaffBMP 1.25) did not have this effect on the hMSCs, indicating that either the concentration released was too low, or the growth factor released was no longer bioactive. However, when the cells were seeded directly onto the scaffolds, the activity of ALP, normalised by a DNA assay, was statistically significantly increased for the CoatPBSScaffBMP 1.25 scaffolds, in hMSCs from all three test patient donors (by 35±10% on the control). ALP activity was also significantly increased in hMSCs from two of the three patients seeded onto CoatBMP 1.25ScaffBMP 1.25 scaffolds (by 39±10% on the control). ALP activity was only statistically significantly increased for one of the hMSC patients when seeded onto CoatBMP 1.25ScaffPBS scaffolds (by 35±14% on the control). The functional osteoinductive capacity of Type-I collagen coated PCL (Mn 42,500) scaffolds loaded with rhBMP-7 was assessed using C2C12 cells seeded onto the scaffolds, and quantified using qRT-PCR. The genes of interest were; Type-I collagen (Col1), osteopontin (OP), ALP, osteocalcin (OC) and runt related transcription factor 2 (Runx2). The CoatBMP 1.25ScaffPBS scaffolds had an early osteoinductive effect on the C2C12 cells, as ALP, OC and Runx2 were elevated during the first 2 days only, compared to the control (e.g. by 44±12%, 128±42%, 60±25% and 46±25% respectively at the 24 hr mark). The CoatPBSScaffBMP 1.25 scaffolds also had an osteoinductive effect on the cells, which was more sustained than that observed for the CoatBMP 1.25ScaffPBS group. While OP, ALP and Runx2 were up-regulated in the first 24 hr compared to the control (by 38±10%, 208±82% and 72±31% respectively), statistically significant up-regulation of the late marker OC was delayed until the 48 hr mark (by 73±49%). The effect was found to be sustained until day 7, when OC and Runx2 were both statistically significantly up-regulated compared to the control (by 151±91% and 93±27% respectively). The CoatBMP 1.25ScaffBMP 1.25 scaffolds were found to combine the early effect of the CoatBMP 1.25ScaffPBS scaffolds, with the more sustained effect of the CoatPBSScaffBMP 1.25 scaffolds. ALP, OC and Runx2 were all up-regulated at the 24 hr mark (by 312±56%, 329±39% and 96±25% respectively). This osteoinductive effect was sustained until day 7 when Col1, ALP and Runx2 were still up-regulated compared to the control (by 174±78%, 72±24% and 178±78% respectively). These data suggest that the scaffolds containing rhBMP-7 have a weak osteoinductive effect on the cells seeded onto them. The different delivery systems were found to affect the cells differently. The clinical significance of this was not assessed in these studies. 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) was used as a model drug to assess the feasibility of releasing lipid-soluble active factors from the scaffolds. This was assessed by quantifying the area of normalised ALP staining of hMSCs. The release of 1,25(OH)2D3 from the loaded collagen scaffold coatings and the encapsulating scaffolds significantly increased ALP expression compared to the control scaffold groups (by 115±28% and 69±25% respectively). Furthermore, ALP expression was significantly increased when the two delivery systems were used together, when compared to either delivery system on its own. These data suggest that the delivery of lipid-soluble active factors is feasible from collagen coated PCL scaffolds, and that the coating and encapsulating delivery systems are mutually compatible

A rapid, chromatography-free route to substituted acridine–isoalloxazine conjugates under microwave irradiation

Microwave irradiation was applied to a sequence of condensation reactions from readily available 9-chloroacridines to provide a range of novel acridine–isoalloxazine conjugates. The combination of these two moieties, both of biological interest, was achieved by a chromatography free route

From information seekers to innovators : qualitative analysis describing experiences of the second generation of e-patients

Background: Current health care systems are rarely designed to meet the needs of people living with chronic conditions. However, some patients and informal caregivers are not waiting for the health care system to redesign itself. These individuals are sometimes referred to as e-patients. The first generation of e-patients used the internet for finding information and for communicating with peers. Compared with the first generation, the second generation of e-patients collects their own health data and appears to be more innovative. Objective: The aim of this study was to describe the second generation of e-patients through exploration of their active engagement in their self-care and health care. Methods: Semistructured interviews were conducted with 10 patients with chronic conditions and 5 informal caregivers. They were all recruited through a Web-based advertisement. Data were analyzed according to the framework analysis approach, using the 3 concepts of the self-determination theory-autonomy, relatedness, and competence-at the outset. Results: Study participants were actively engaged in influencing their self-care and the health care system to improve their own health, as well as the health of others. This occurred at different levels, such as using their own experience when giving presentations and lectures to health care professionals and medical students, working as professional peers in clinical settings, performing self-tracking, contributing with innovations, and being active on social media. When interaction with health care providers was perceived as being insufficient, the participants sought support through their peers, which showed strong relatedness. Competence increased through the use of technology and learning experiences with peers. Their autonomy was important but was sometimes described as involuntary and to give up was not an option for them. Conclusions: Like the first generation of e-patients, the participants frequently searched for Web-based information. However, the second generation of e-patients also produce their own health data, which they learn from and share. They also engage in the innovation of digital tools to meet health-related needs. Utilizing technological developments comes naturally to the second generation of e-patients, even if the health care system is not prepared to support them under these new circumstancesVinnova, the Swedish Governmental Agency for Innovation Systems (grant number 2017-01221)Publishe

Sex-independent senescence in a cooperatively breeding mammal.

Researchers studying mammals have frequently interpreted earlier or faster rates of ageing in males as resulting from polygyny and the associated higher costs of reproductive competition. Yet, few studies conducted on wild populations have compared sex-specific senescence trajectories outside of polygynous species, making it difficult to make generalized inferences on the role of reproductive competition in driving senescence, particularly when other differences between males and females might also contribute to sex-specific changes in performance across lifespan. Here, we examine age-related variation in body mass, reproductive output and survival in dominant male and female meerkats, Suricata suricatta. Meerkats are socially monogamous cooperative breeders where a single dominant pair virtually monopolizes reproduction in each group and subordinate group members help to rear offspring produced by breeders. In contrast to many polygynous societies, we find that neither the onset nor the rate of senescence in body mass or reproductive output shows clear differences between males and females. Both sexes also display similar patterns of age-related survival across lifespan, but unlike most wild vertebrates, survival senescence (increases in annual mortality with rising age) was absent in dominants of both sexes, and as a result, the fitness costs of senescence were entirely attributable to declines in reproductive output from mid- to late-life. We suggest that the potential for intrasexual competition to increase rates of senescence in females-who are hormonally masculinized and frequently aggressive-is offset by their ability to maintain longer tenures of dominance than males, and that these processes when combined lead to similar patterns of senescence in both sexes. Our results stress the need to consider the form and intensity of sexual competition as well as other sex-specific features of life history when investigating the operation of senescence in wild populations

Pad-printed Prussian blue doped carbon ink for real-time peroxide sensing in cell culture

Hydrogen peroxide has important roles within cellular functions, as a prevalent form of Reactive Oxygen Species, detection within mammalian cells is of metabolic importance; typically requiring cell lysis or fluorescence-based methods to quantify. Herein, we explore the novel use of Prussian blue mediated, pad printed carbon electrodes to allow the indirect detection of cellular peroxides in bulk culture media, which facilitates non-invasive, real-time detection. Electrodes demonstrated capacity to detect H2O2 with a linear range of 1-200 μM in CMEM (R2 = 0.9988), enabling detection of peroxides found in culture media and lysate. Developed electrodes had a Limit of Detection (LOD) of 0.41 μM H2O2 in Britton-Robinson Buffer (BRB), 0.38 μM in Eagle's Minimum Essential Medium (EMEM) and 9.19 μM in Dulbecco's Modified Eagles Medium (DMEM). Electrodes were tested in a conventional 5% serum supplemented EMEM (CMEM) and demonstrated an LOD of 0.5 μM and LOQ of 0.9 μM. The results demonstrate proof of concept for monitoring H2O2 in complex culture media with potential long-term use and reusability using simple, pad printed Prussian Blue / Carbon electrodes. The lack of further modification, and cost-effectiveness of these disposable electrodes could offer great advancement to monitoring of peroxides in complex media

Pain relief for women with cervical intraepithelial neoplasia undergoing colposcopy treatment

Treatment for CIN is usually undertaken in an outpatient colposcopy clinic to remove the pre-cancerous cells from the cervix. It commonly involves lifting the cells off the cervix with electrically heated wire (diathermy) or laser, or destroying the abnormal cells with freezing methods (cryotherapy). This is potentially a painful procedure. The purpose of this review is to determine which, if any, pain relief should be used during cervical colposcopy treatment. We identified 17 trials and these reported different forms of pain relief before, during and after colposcopy. Evidence from two small trials showed that women having a colposcopy treatment had less pain and blood loss if the cervix was injected with a combination of a local anaesthetic drug and a drug that causes blood vessels to constrict (narrow), compared with placebo. Although taking oral pain-relieving drugs (e.g. ibuprofen) before treatment on the cervix in the colposcopy clinic is recommended by most guidelines, evidence from two small trials did not show that this practice reduced pain during the procedure. Most of the evidence in this field is of a low to moderate quality and further research may change these findings. Additionally, we were unable to obtain evidence with regards to dosage of the local anaesthetic drug or method of administering local anaesthetic into the cervix. There is need for high-quality trials with sufficient numbers of participants in order to provide the data necessary to estimate these effects

Biopsy and selective recall compared with immediate large loop excision in management of women with low grade abnormal cervical cytology referred for colposcopy : multicentre randomised controlled trial

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