Large scale organisational intervention to improve patient safety in four UK hospitals:mixed method evaluation

Objectives: To conduct an independent evaluation of the first phase of the Health Foundation's Safer Patients Initiative (SPI), and to identify the net additional effect of SPI and any differences in changes in participating and non-participating NHS hospitals. Design: Mixed method evaluation involving five substudies, before and after design. Setting: NHS hospitals in United Kingdom. Participants: Four hospitals (one in each country in the UK) participating in the first phase of the SPI (SPI1); 18 control hospitals. Intervention: The SPI1 was a compound (multicomponent) organisational intervention delivered over 18 months that focused on improving the reliability of specific frontline care processes in designated clinical specialties and promoting organisational and cultural change. Results: Senior staff members were knowledgeable and enthusiastic about SPI1. There was a small (0.08 points on a 5 point scale) but significant (P<0.01) effect in favour of the SPI1 hospitals in one of 11 dimensions of the staff questionnaire (organisational climate). Qualitative evidence showed only modest penetration of SPI1 at medical ward level. Although SPI1 was designed to engage staff from the bottom up, it did not usually feel like this to those working on the wards, and questions about legitimacy of some aspects of SPI1 were raised. Of the five components to identify patients at risk of deterioration - monitoring of vital signs (14 items); routine tests (three items); evidence based standards specific to certain diseases (three items); prescribing errors (multiple items from the British National Formulary); and medical history taking (11 items) - there was little net difference between control and SPI1 hospitals, except in relation to quality of monitoring of acute medical patients, which improved on average over time across all hospitals. Recording of respiratory rate increased to a greater degree in SPI1 than in control hospitals; in the second six hours after admission recording increased from 40% (93) to 69% (165) in control hospitals and from 37% (141) to 78% (296) in SPI1 hospitals (odds ratio for "difference in difference" 2.1, 99% confidence interval 1.0 to 4.3; P=0.008). Use of a formal scoring system for patients with pneumonia also increased over time (from 2% (102) to 23% (111) in control hospitals and from 2% (170) to 9% (189) in SPI1 hospitals), which favoured controls and was not significant (0.3, 0.02 to 3.4; P=0.173). There were no improvements in the proportion of prescription errors and no effects that could be attributed to SPI1 in non-targeted generic areas (such as enhanced safety culture). On some measures, the lack of effect could be because compliance was already high at baseline (such as use of steroids in over 85% of cases where indicated), but even when there was more room for improvement (such as in quality of medical history taking), there was no significant additional net effect of SPI1. There were no changes over time or between control and SPI1 hospitals in errors or rates of adverse events in patients in medical wards. Mortality increased from 11% (27) to 16% (39) among controls and decreased from17%(63) to13%(49) among SPI1 hospitals, but the risk adjusted difference was not significant (0.5, 0.2 to 1.4; P=0.085). Poor care was a contributing factor in four of the 178 deaths identified by review of case notes. The survey of patients showed no significant differences apart from an increase in perception of cleanliness in favour of SPI1 hospitals. Conclusions The introduction of SPI1 was associated with improvements in one of the types of clinical process studied (monitoring of vital signs) and one measure of staff perceptions of organisational climate. There was no additional effect of SPI1 on other targeted issues nor on other measures of generic organisational strengthening.

Challenges of developing non-linear devices to achieve the linear Shannon limit

To achieve the Shannon Capacity Limit, we need to develop practical, effective and deployable non-linear devices to invert the non-linear effects of the transmission line. In this work, we will summarise the progress we are making to realise these, specifically looking at optical phase conjugation and phase regenerators as methods to improve non-linear tolerances. © 2014 IEEE.

Mutations of beta-arrestin 2 that limit self-association also interfere with interactions with the beta2-adrenoceptor and the ERK1/2 MAPKs:implications for beta2-adrenoceptor signalling via the ERK1/2 MAPKs

FRET (fluorescence resonance energy transfer) and co-immunoprecipitation studies confirmed the capacity of beta-arrestin 2 to self-associate. Amino acids potentially involved in direct protein-protein interaction were identified via combinations of spot-immobilized peptide arrays and mapping of surface exposure. Among potential key amino acids, Lys(285), Arg(286) and Lys(295) are part of a continuous surface epitope located in the polar core between the N- and C-terminal domains. Introduction of K285A/R286A mutations into beta-arrestin 2-eCFP (where eCFP is enhanced cyan fluorescent protein) and beta-arrestin 2-eYFP (where eYFP is enhanced yellow fluorescent protein) constructs substantially reduced FRET, whereas introduction of a K295A mutation had a more limited effect. Neither of these mutants was able to promote beta2-adrenoceptor-mediated phosphorylation of the ERK1/2 (extracellular-signal-regulated kinase 1/2) MAPKs (mitogen-activated protein kinases). Both beta-arrestin 2 mutants displayed limited capacity to co-immunoprecipitate ERK1/2 and further spot-immobilized peptide arrays indicated each of Lys(285), Arg(286) and particularly Lys(295) to be important for this interaction. Direct interactions between beta-arrestin 2 and the beta2-adrenoceptor were also compromised by both K285A/R286A and K295A mutations of beta-arrestin 2. These were not non-specific effects linked to improper folding of beta-arrestin 2 as limited proteolysis was unable to distinguish the K285A/R286A or K295A mutants from wild-type beta-arrestin 2, and the interaction of beta-arrestin 2 with JNK3 (c-Jun N-terminal kinase 3) was unaffected by the K285A/R286A or L295A mutations. These results suggest that amino acids important for self-association of beta-arrestin 2 also play an important role in the interaction with both the beta2-adrenoceptor and the ERK1/2 MAPKs. Regulation of beta-arrestin 2 self-association may therefore control beta-arrestin 2-mediated beta2-adrenoceptor-ERK1/2 MAPK signalling.

Ultra-long haul optical fibre transmission systems

This thesis examines experimentally options for optical fibre transmission over oceanic distances. Its format follows the chronological evolution of ultra-long haul optical systems, commencing with opto-electronic regenerators as repeaters, progressing to optically amplified NRZ systems and finally solitonic propagation. In each case recirculating loop techniques are deployed to simplify the transmission experiments. Advances in high speed electronics have allowed regenerators operating at 10 Gbit/s to become a practical reality. By augmenting such devices with optical amplifiers it is possible to greatly enhance the repeater spacing. Work detailed in this thesis has culminated in the propagation of 10 Gbit/s data over 400,000 km with a repeater spacing of 160 km. System reliability and robustness are enhanced by the use of a directly modulated DFB laser transmitter and total insensitivity of the system to the signal state of polarisation. Optically amplified ultra-long haul NRZ systems have taken on particular importance with the impending deployment of TAT 12/13 and TPC 5. The performance of these systems is demonstrated to be primarily limited by analogue impairments such as the accumulation of amplifier noise, polarisation effects and optical non-linearities. These degradations may be reduced by the use of appropriate dispersion maps and by scrambling the transmitted state of signal polarisation. A novel high speed optically passive polarisation scrambler is detailed for the first time. At bit rates in excess of 10 Gbit/s it is shown that these systems are severely limited and do not offer the advantages that might be expected over regenerated links. Propagation using solitons as the data bits appears particularly attractive since the dispersive and non-linear effects of the fibre allow distortion free transmission. However, the generation of pure solitons is difficult but must be achieved if the uncontrolled transmission distance is to be maximised. This thesis presents a new technique for the stabilisation of an erbium fibre ring laser that has aUowed propagation of 2.5 Gbit/s solitons to the theoretical limit of ~ 18,000 km. At higher bit rates temporal jitter becomes a significant impairment and to aUow an increase in the aggregate line rate multiplexing in both time and polarisation domains has been proposed. These techniques are shown to be of only limited benefit in practical systems and ultimately some form of soliton transmission control is required. The thesis demonstrates synchronous retiming by amplitude modulation that has allowed 20 Gbit/s data to propagate 125,000 km error free with an amplifier spacing approaching the soliton period. Ultimately the speed of operation of such systems is limited by the electronics used and, thus, a new form of soliton control is demonstrated using all optical techniques to achieve synchronous phase modulation.

Interaction of peptides, peptidomimetics and other drug candidates with the DI/tripeptide transport system in intestinal epithelial cells, using the in vitro caco-2 cell culture system

An uptake system was developed using Caco-2 cell monolayers and the dipeptide, glycyl-[3H]L-proline, as a probe compound. Glycyl-[3H]L-proline uptake was via the di-/tripeptide transport system (DTS) and, exhibited concentration-, pH- and temperature-dependency. Dipeptides inhibited uptake of the probe, and the design of the system allowed competitors to be ranked against one another with respect to affinity for the transporter. The structural features required to ensure or increase interaction with the DTS were defined by studying the effect of a series of glycyl-L-proline and angiotensin-converting enzyme (ACE)-inhibitor (SQ-29852) analogues on the uptake of the probe. The SQ-29852 structure was divided into six domains (A-F) and competitors were grouped into series depending on structural variations within specific regions. Domain A was found to prefer a hydrophobic function, such as a phenyl group, and was intolerant to positive charges and H+ -acceptors and donors. SQ-29852 analogues were more tolerant of substitutions in the C domain, compared to glycyl-L-proline analogues, suggesting that interactions along the length of the SQ-29852 molecule may override the effects of substitutions in the C domain. SQ-29852 analogues showed a preference for a positive function, such as an amine group in this region, but dipeptide structures favoured an uncharged substitution. Lipophilic substituents in domain D increased affinity of SQ-29852 analogues with the DTS. A similar effect was observed for ACE-NEP inhibitor analogues. Domain E, corresponding to the carboxyl group was found to be tolerant of esterification for SQ-29852 analogues but not for dipeptides. Structural features which may increase interaction for one series of compounds, may not have the same effect for another series, indicating that the presence of multiple recognition sites on a molecule may override the deleterious effect of anyone change. Modifying current, poorly absorbed peptidomimetic structures to fit the proposed hypothetical model may improve oral bioavailability by increasing affinity for the DTS. The stereochemical preference of the transporter was explored using four series of compounds (SQ-29852, lysylproline, alanylproline and alanylalanine enantiomers). The L, L stereochemistry was the preferred conformation for all four series, agreeing with previous studies. However, D, D enantiomers were shown in some cases to be substrates for the DTS, although exhibiting a lower affinity than their L, L counterparts. All the ACE-inhibitors and β-lactam antibiotics investigated, produced a degree of inhibition of the probe, and thus show some affinity for the DTS. This contrasts with previous reports that found several ACE inhibitors to be absorbed via a passive process, thus suggesting that compounds are capable of binding to the transporter site and inhibiting the probe without being translocated into the cell. This was also shown to be the case for oligodeoxynucleotide conjugated to a lipophilic group (vitamin E), and highlights the possibility that other orally administered drug candidates may exert non-specific effects on the DTS and possibly have a nutritional impact. Molecular modelling of selected ACE-NEP inhibitors revealed that the three carbonyl functions can be oriented in a similar direction, and this conformation was found to exist in a local energy-minimised state, indicating that the carbonyls may possibly be involved in hydrogen-bond formation with the binding site of the DTS.

The anti-inflammatory action of tetracyclines

For six decades tetracyclines have been successfully used for their broad spectrum antibiotic effects. However, non-antibiotic effects of tetracyclines have been reported. The anti-inflammatory effects of tetracycline drugs have been investigated in the context of a range of inflammatory diseases including sepsis and a number of neurodegenerative diseases. This thesis investigates the effects of a range of clinically important tetracyclines (oxytetracycline, doxycycline, minocycline and tigecycline) on the ability of the J774.2 cell line to produce nitric oxide when stimulated with the bacterial cell wall component, LPS. The proteome of J774.2 cells was analysed in response to LPS stimulation (1 µg/ml) with and without prior treatment with minocycline (50µg/ml), this allows the unbiased analysis of the cellular proteome in response to minocycline and LPS, protein spots of interest were excised and identified by nano-electrospray ionisation-linear ion trap mass spectroscopy. All of the tetracyclines that were investigated inhibited LPS-induced nitric oxide production in a dose dependent manner and this was due to the inhibition of inducible nitric oxide synthase expression. This is the first report to show that tigecycline inhibits inducible nitric oxide expression and nitric oxide production. Using two-dimensional gel electrophoresis and total protein staining eleven proteins were identified as being modulated by LPS. Of these eleven proteins; expression of some, but not all was modulated when the cells received a prior treatment with minocycline suggesting that minocycline does not completely block LPS-induced macrophage activation but probably specifically acts on particular inflammatory signaling pathways in macrophages. Three protein spots with a similar molecular weight but different pI values identified in this proteomic study were identified as ATP synthase ß chain. These different protein spots probably correspond to different phosphorylation states of the protein, suggesting that minocycline affects the balance of protein kinase and protein phosphatase activity in the immune response.

The spatial distribution of self-employment in India:evidence from semi-parametric geoadditive models

The spatial distribution of self-employment in India: evidence from semiparametric geoadditive models, Regional Studies. The entrepreneurship literature has rarely considered spatial location as a micro-determinant of occupational choice. It has also ignored self-employment in developing countries. Using Bayesian semiparametric geoadditive techniques, this paper models spatial location as a micro-determinant of self-employment choice in India. The empirical results suggest the presence of spatial occupational neighbourhoods and a clear north–south divide in self-employment when the entire sample is considered; however, spatial variation in the non-agriculture sector disappears to a large extent when individual factors that influence self-employment choice are explicitly controlled. The results further suggest non-linear effects of age, education and wealth on self-employment.

Increased salience of gains versus decreased associative learning differentiate bipolar disorder from schizophrenia during incentive decision making

Background Abnormalities in incentive decision making, typically assessed using the Iowa Gambling Task (IGT), have been reported in both schizophrenia (SZ) and bipolar disorder (BD). We applied the Expectancy-Valence (E-V) model to determine whether motivational, cognitive and response selection component processes of IGT performance are differentially affected in SZ and BD. Method Performance on the IGT was assessed in 280 individuals comprising 70 remitted patients with SZ, 70 remitted patients with BD and 140 age-, sex-and IQ-matched healthy individuals. Based on the E-V model, we extracted three parameters, 'attention to gains or loses', 'expectancy learning' and 'response consistency', that respectively reflect motivational, cognitive and response selection influences on IGT performance. Results Both patient groups underperformed in the IGT compared to healthy individuals. However, the source of these deficits was diagnosis specific. Associative learning underlying the representation of expectancies was disrupted in SZ whereas BD was associated with increased incentive salience of gains. These findings were not attributable to non-specific effects of sex, IQ, psychopathology or medication. Conclusions Our results point to dissociable processes underlying abnormal incentive decision making in BD and SZ that could potentially be mapped to different neural circuits. © 2012 Cambridge University Press.

The unequal segmentation of public preparedness for mass evacuation:a cross-national perspective

This thesis is concerned with understanding how Emergency Management Agencies (EMAs) influence public preparedness for mass evacuation across seven countries. Due to the lack of cross-national research (Tierney et al., 2001), there is a lack of knowledge on EMAs perspectives and approaches to the governance of public preparedness. This thesis seeks to address this gap through cross-national research that explores and contributes towards understanding the governance of public preparedness. The research draws upon the risk communication (Wood et al., 2011; Tierney et al., 2001) social marketing (Marshall et al., 2007; Kotler and Lee, 2008; Ramaprasad, 2005), risk governance (Walker et al., 2010, 2013; Kuhlicke et al., 2011; IRGC, 2005, 2007; Renn et al., 2011; Klinke and Renn, 2012), risk society (Beck, 1992, 1999, 2002) and governmentality (Foucault, 1978, 2003, 2009) literature to explain this governance and how EMAs responsibilize the public for their preparedness. EMAs from seven countries (Belgium, Denmark, Germany, Iceland, Japan, Sweden, the United Kingdom) explain how they prepare their public for mass evacuation in response to different types of risk. A cross-national (Hantrais, 1999) interpretive research approach, using qualitative methods including semi-structured interviews, documents and observation, was used to collect data. The data analysis process (Miles and Huberman, 1999) identified how the concepts of risk, knowledge and responsibility are critical for theorising how EMAs influence public preparedness for mass evacuation. The key findings grounded in these concepts include: - Theoretically, risk is multi-functional in the governance of public preparedness. It regulates behaviour, enables surveillance and acts as a technique of exclusion. - EMAs knowledge and how this influenced their assessment of risk, together with how they share the responsibility for public preparedness across institutions and the public, are key to the governance of public preparedness for mass evacuation. This resulted in a form of public segmentation common to all countries, whereby the public were prepared unequally.  - EMAs use their prior knowledge and assessments of risk to target public preparedness in response to particular known hazards. However, this strategy places the non-targeted public at greater risk in relation to unknown hazards, such as a man-made disaster. - A cross-national conceptual framework of four distinctive governance practices (exclusionary, informing, involving and influencing) are utilised to influence public preparedness. - The uncertainty associated with particular types of risk limits the application of social marketing as a strategy for influencing the public to take responsibility and can potentially increase the risk to the public.

Inhibitory effects of persistent apoptotic cells on monoclonal antibody production in vitro:simple removal of non-viable cells improves antibody productivity by hybridoma cells in culture

Cells undergoing apoptosis in vivo are rapidly detected and cleared by phagocytes. Swift recognition and removal of apoptotic cells is important for normal tissue homeostasis and failure in the underlying clearance mechanisms has pathological consequences associated with inflammatory and auto-immune diseases. Cell cultures in vitro usually lack the capacity for removal of non-viable cells because of the absence of phagocytes and, as such, fail to emulate the healthy in vivo micro-environment from which dead cells are absent. While a key objective in cell culture is to maintain viability at maximal levels, cell death is unavoidable and non-viable cells frequently contaminate cultures in significant numbers. Here we show that the presence of apoptotic cells in monoclonal antibody-producing hybridoma cultures has markedly detrimental effects on antibody productivity. Removal of apoptotic hybridoma cells by macrophages at the time of seeding resulted in 100% improved antibody productivity that was, surprisingly to us, most pronounced late on in the cultures. Furthermore, we were able to recapitulate this effect using novel super-paramagnetic Dead-Cert Nanoparticles to remove non-viable cells simply and effectively at culture seeding. These results (1) provide direct evidence that apoptotic cells have a profound influence on their non-phagocytic neighbors in culture and (2) demonstrate the effectiveness of a simple dead-cell removal strategy for improving antibody manufacture in vitro.

A study of magnetic non-linearity and finite length effects in solid iron subjected to a travelling MMF wave

This thesis describes an experimental and analytic study of the effects of magnetic non-linearity and finite length on the loss and field distribution in solid iron due to a travelling mmf wave. In the first half of the thesis, a two-dimensional solution is developed which accounts for the effects of both magnetic non-linearity and eddy-current reaction; this solution is extended, in the second half, to a three-dimensional model. In the two-dimensional solution, new equations for loss and flux/pole are given; these equations contain the primary excitation, the machine parameters and factors describing the shape of the normal B-H curve. The solution applies to machines of any air-gap length. The conditions for maximum loss are defined, and generalised torque/frequency curves are obtained. A relationship between the peripheral component of magnetic field on the surface of the iron and the primary excitation is given. The effects of magnetic non-linearity and finite length are combined analytically by introducing an equivalent constant permeability into a linear three-dimensional analysis. The equivalent constant permeability is defined from the non-linear solution for the two-dimensional magnetic field at the axial centre of the machine to avoid iterative solutions. In the linear three-dimensional analysis, the primary excitation in the passive end-regions of the machine is set equal to zero and the secondary end faces are developed onto the air-gap surface. The analyses, and the assumptions on which they are based, were verified on an experimental machine which consists of a three-phase rotor and alternative solid iron stators, one with copper end rings, and one without copper end rings j the main dimensions of the two stators are identical. Measurements of torque, flux /pole, surface current density and radial power flow were obtained for both stators over a range of frequencies and excitations. Comparison of the measurements on the two stators enabled the individual effects of finite length and saturation to be identified, and the definition of constant equivalent permeability to be verified. The penetration of the peripheral flux into the stator with copper end rings was measured and compared with theoretical penetration curves. Agreement between measured and theoretical results was generally good.

The effects of faking on non-cognitive predictors of academic performance in University students

This study examined the extent to which students could fake responses on personality and approaches to studying questionnaires, and the effects of such responding on the validity of non-cognitive measures for predicting academic performance (AP). University students produced a profile of an ‘ideal’ student using the Big-Five personality taxonomy, which yielded a stereotype with low scores for Neuroticism, and high scores for the other four traits. A sub-set of participants were allocated to a condition in which they were instructed to fake their responses as University applicants, portraying themselves as positively as possible. Scores for these participants revealed higher scores than those in a control condition on measures of deep and strategic approaches to studying, but lower scores on the surface approach variable. Conscientiousness was a significant predictor of AP in both groups, but the predictive effect of approaches to studying variables and Openness to Experience identified in the control group was lower in the group who faked their responses. Non-cognitive psychometric measures can be valid predictors of AP, but scores on these measures can be affected by instructional set. Further implications for psychometric measurement in educational settings are discussed.

Memory effects in a non-equilibrium growth model

We study memory effects in a kinetic roughening model. For d=1, a different dynamic scaling is uncovered in the memory dominated phases; the Kardar-Parisi-Zhang scaling is restored in the absence of noise. dc=2 represents the critical dimension where memory is shown to smoothen the roughening front (a=0). Studies on a discrete atomistic model in the same universality class reconfirm the analytical results in the large time limit, while a different scaling behavior shows up for t