Antibacterial dosing in intensive care: Pharmacokinetics, degree of disease and pharmacodynamics of sepsis

Treatment of sepsis remains a significant challenge with persisting high mortality and morbidity. Early and appropriate antibacterial therapy remains an important intervention for such patients. To optimise antibacterial therapy, the clinician must possess knowledge of the pharmacokinetic and pharmacodynamic properties of commonly used antibacterials and how these parameters may be affected by the constellation of pathophysiological changes occurring during sepsis. Sepsis, and the treatment thereof, increases renal preload and, via capillary permeability, leads to 'third-spacing', both resulting in higher antibacterial clearances. Alternatively, sepsis can induce multiple organ dysfunction, including renal and/or hepatic dysfunction, causing a decrease in antibacterial clearance. Aminoglycosides are concentration-dependent antibacterials and they display an increased volume of distribution (V-d) in sepsis, resulting in decreased peak serum concentrations. Reduced clearance from renal dysfunction would increase the likelihood of toxicity. Individualised dosing using extended interval dosing, which maximises the peak serum drug concentration (C-max)/minimum inhibitory concentration ratio is recommended. beta-Lactams and carbapenems are time-dependent antibacterials. An increase in Vd and renal clearance will require increased dosing or administration by continuous infusion. If renal impairment occurs a corresponding dose reduction may be required. Vancomycin displays predominantly time-dependent pharmacodynamic properties and probably requires higher than conventionally recommended doses because of an increased V-d and clearance during sepsis without organ dysfunction. However, optimal dosing regimens remain unresolved. The poor penetration of vancomycin into solid organs may require alternative therapies when sepsis involves solid organs (e.g. lung). Ciprofloxacin displays largely concentration-dependent kill characteristics, but also exerts some time-dependent effects. The V-d of ciprofloxacin is not altered with fluid shifts or over time, and thus no alterations of standard doses are required unless renal dysfunction occurs. In order to optimise antibacterial regimens in patients with sepsis, the pathophysiological effects of systemic inflammatory response syndrome need consideration, in conjunction with knowledge of the different kill characteristics of the various antibacterial classes. In conclusion, certain antibacterials can have a very high V-d, therefore leading to a low C-max and if a high peak is needed, then this would lead to underdosing. The Vd of certain antibacterials, namely aminoglycosides and vancomycin, changes over time, which means dosing may need to be altered over time. Some patients with serum creatinine values within the normal range can have very high drug clearances, thereby producing low serum drug levels and again leading to underdosing. Copyright © 2010 Elsevier Inc. All rights reserved.

Characterisation of the signalment, clinical and survival characteristics of 41 cats with mast cell neoplasia

Mast cell tumours (MCTs) are relatively common tumours of cats, and are the second most common cutaneous tumours in cats in the USA. While the primary splenic form of the disease is far less common, it is usually associated with more severe clinical signs. Signalment, clinical and survival characteristics of mast cell neoplasia were characterised in 41 cats. The most common tumour location was cutaneous/ subcutaneous head and trunk. Stage la was the most common tumour stage at first diagnosis (n = 20), followed by stage 4 (both stage 4a and stage 4b; n = 10). Of 22 cats that underwent excisional biopsy, mast cell neoplasia recurred in four cats during the study period. Three of the 41 cats presented with simultaneous cutaneous and either splenic or lymph node tumours. A comparison between cats with only cutaneous tumours (n = 30) and those with tumours involving the spleen or lymph nodes (n = 11) showed longer survival times for the cutaneous-only group (P = 0.031). Twelve of the 41 cats died of mast cell neoplasia during the study period. When a subgroup of cats with only cutaneous tumours (no lymph node or visceral involvement) were divided according to whether there were multiple (five or more) tumours (n = 6) or a single tumour (n = 19), cats with single tumours survived longer than those with multiple tumours (P = 0.001). Solitary cutaneous feline MCTs without spread to the lymph nodes usually manifest as benign disease with a relatively protracted course. However, multiple cutaneous tumours, recurrent tumours and primary splenic disease should receive a guarded prognosis due to the relatively short median survival times associated with these forms of the disease. (C) 2006 ESFM and AAFR Published by Elsevier Ltd. All rights reserved.

Identification of oxidized phospholipids by electrospray ionization mass spectrometry and LC-MS using a QQLIT instrument

Phospholipids are complex and varied biomolecules that are susceptible to lipid peroxidation after attack by free radicals or electrophilic oxidants and can yield a large number of different oxidation products. There are many available methods for detecting phospholipid oxidation products, but also various limitations and problems. Electrospray ionization mass spectrometry allows the simultaneous but specific analysis of multiple species with good sensitivity and has a further advantage that it can be coupled to liquid chromatography for separation of oxidation products. Here, we explain the principles of oxidized phospholipid analysis by electrospray mass spectrometry and describe fragmentation routines for surveying the structural properties of the analytes, in particular precursor ion and neutral loss scanning. These allow targeted detection of phospholipid headgroups and identification of phospholipids containing hydroperoxides and chlorine, as well as the detection of some individual oxidation products by their specific fragmentation patterns. We describe instrument protocols for carrying out these survey routines on a QTrap5500 mass spectrometer and also for interfacing with reverse-phase liquid chromatography. The article highlights critical aspects of the analysis as well as some limitations of the methodology.

Risk management in oil and gas construction projects in Vietnam

Purpose - The purpose of the paper is to the identify risk factors, which affect oil and gas construction projects in Vietnam and derive risk responses. Design/methodology/approach - Questionnaire survey was conducted with the involvement of project executives of PetroVietnam and statistical analysis was carried out in order to identify the major project risks. Subsequently, mitigating measures were derived using informal interviews with the various levels of management of PetroVietnam. Findings - Bureaucratic government system and long project approval procedures, poor design, incompetence of project team, inadequate tendering practices, and late internal approval processes from the owner were identified as major risks. The executives suggested various strategies to mitigate the identified risks. Reforming the government system, effective partnership with foreign collaborators, training project executives, implementing contractor evaluation using multiple criteria decision-making technique, and enhancing authorities of project people were suggested as viable approaches. Practical implications - The improvement measures as derived in this study would improve chances of project success in the oil and gas industry in Vietnam. Originality/value - There are several risk management studies on managing projects in developing countries. However, as risk factors vary considerably across industry and countries, the study of risk management for successful projects in the oil and gas industry in Vietnam is unique and has tremendous importance for effective project management.

Managing the quality, value and impact of academic libraries: the role of external standards

Purpose – The purpose of this paper is to explore the role and relevance of external standards in demonstrating the value and impact of academic library services to their stakeholders. Design/methodology/approach – Two UK standards, Charter Mark and Customer Service Excellence, are evaluated via an exploratory case study, employing multiple data collection techniques. Methods and results of phases 1-2 of a three phase research project are outlined. Findings – Despite some limitations, standards may assist the manager in demonstrating the value, impact and quality of academic libraries in a recessional environment. Active engagement and partnership with customers is imperative if academic libraries are to be viewed as vital to their parent organisations and thus survive. Originality/value – This paper provides a systematic evaluation of the role of external accreditation standards in measuring academic library service value and impact.

Vergence analysis reveals the influence of axial distances on accommodation with age and axial ametropia

Despite numerous investigations, the aetiology and mechanism of accommodation and presbyopia remains equivocal. Using Gaussian first-order ray tracing calculations, we examine the contribution that ocular axial distances make to the accommodation response. Further, the influence of age and ametropia are also considered. The data show that all changes in axial distances during accommodation reduce the accommodation response, with the reduction in anterior chamber depth contributing most to this overall attenuation. Although the total power loss due to the changes in axial distances remained constant with increasing age, hyperopes exhibited less accommodation than myopes. The study, therefore, enhances our understanding of biometric accommodative changes and demonstrates the utility of vergence analysis in the assessment of accommodation.

Meta-analysis of the population and phenotypic expression of CYP2C9/2C19 polymorphism on drug metabolism in different ethnicities

The term "pharmacogenetics" has been defined as the scientific study of inherited factors that affect the human drug response. Many pharmacogenetie studies have been published since 1995 and have focussed on the principal enzyme family involved in drug metabolism, the cytochrome P450 family, particularly cytochrome P4502C9 and 2C19. In order to investigate the pharmacogenetic aspect of pharmacotherapy, the relevant studies describing the association of pharmacogenetic factor(s) in drug responses must be retrieved from existing literature using a systematic review approach. In addition, the estimation of variant allele prevalence for the gene under study between different ethnic populations is important for pharmacogenetic studies. In this thesis, the prevalence of CYP2C9/2C19 alleles between different ethnicities has been estimated through meta-analysis and the population genetic principle. The clinical outcome of CYP2C9/2C19 allelic variation on the pharmacotherapy of epilepsy has been investigated; although many new antiepileptic drugs have been launched into the market, carbamazepine, phenobarbital and phenytoin are still the major agents in the pharmacotherapy of epilepsy. Therefore, phenytoin was chosen as a model AED and the effect of CYP2C9/2C19 genetic polymorphism on phenytoin metabolism was further examined.An estimation of the allele prevalence was undertaken for three CYP2C9/2C19 alleles respectively using a meta-analysis of studies that fit the Hardy-Weinberg equilibrium. The prevalence of CYP2C9*1 is approximately 81%, 96%, 97% and 94% in Caucasian, Chinese, Japanese, African populations respectively; the pooled prevalence of CYP2C19*1 is about 86%, 57%, 58% and 85% in these ethnic populations respectively. However, the studies of association between CYP2C9/2C19 polymorphism and phenytoin metabolism failed to achieve any qualitative or quantitative conclusion. Therefore, mephenytoin metabolism was examined as a probe drug for association between CYP2C19 polymorphism and mephenytoin metabolic ratio. Similarly, analysis of association between CYP2C9 polymorphism and warfarin dose requirement was undertaken.It was confirmed that subjects carrying two mutated CYP2C19 alleles have higher S/R mephenytoin ratio due to deficient CYP2C19 enzyme activity. The studies of warfarin and CYP2C9 polymorphism did not provide a conclusive result due to poor comparability between studies.The genetic polymorphism of drug metabolism enzymes has been studied extensively, however other genetic factors, such as multiple drug resistance genes (MDR) and genes encoding ion channels, which may contribute to variability in function of drug transporters and targets, require more attention in future pharmacogenetic studies of antiepileptic drugs.

Nations and organizations:a comparative study of English and Indian work-related attitudes and values in matched manufacturing firms

This thesis reports a cross-national study carried out in England and India in an attempt to clarify the association of certain cultural and non-cultural characteristics with people's work-related attitudes and values, and with the structure of their work organizations. Three perspectives are considered to be relevant to the objectives of the study. The contingency perspective suggests that a 'fit' between an organization's context and its structural arrangements will be fundamentally necessary for achieving success and survival. The political economy perspective argues for the determining role of the social and economic structures within which the organization operates. The culturalist perspective looks to cultural attitudes and values of organizational members for an explanation for their organization's structure. The empirical investigation was carried out in three stages in each of the two countries involved by means of surveys of cultural attitudes, work-related attitudes and organizational structures and systems. The cultural surveys suggested that Indian and English people were different from one another with regard to fear of, and respect and obedience to, their seniors, ability to cope with ambiguity, honesty, independence, expression of emotions, fatalism, reserve, and care for others; they were similar with regard to tolerance, friendliness, attitude to change, attitude to law, self-control and self-confidence, and attitude to social differentiation. The second stage of the study, involving the employees of fourteen organizations, found that the English ones perceived themselves to have more power at work, expressed more tolerance for ambiguity, and had different expectations from their job than did the Indian equivalents. The two samples were similar with respect to commitment to their company and trust in their colleagues. The findings also suggested that employees' occupations, education and age had some influences on their work-related attitudes. The final stage of the research was a study of structures, control systems, and reward and punishment policies of the same fourteen organizations which were matched almost completely on their contextual factors across the two countries. English and Indian organizations were found to be similar in terms of centralization, specialization, chief executive's span of control, height and management control strategies. English organizations, however, were far more formalized, spent more time on consultation and their managers delegated authority lower down the hierarchy than Indian organizations. The major finding of the study was the multiple association that cultural, national and contingency factors had with the structural characteristics of the organizations and with the work-related attitudes of their members. On the basis of this finding, a multi-perspective model for understanding organizational structures and systems is proposed in which the contributions made by contingency, political economy and cultural perspectives are recognized and incorporated.

Pharmacy and public health: examining the link between strategy and practice

Despite having been described by the then (2003) Chief Pharmaceutical Officer for England as ·probably the biggest untapped resource for health improvement", the development of the public health function of community pharmacists has been limited. However, devolution of healthcare budgets has led 10 differential rates of development of the public health function in each administration of the UK (England, Scotland, Wales and Northern Ireland). This is measured and reflected upon in this thesis. Two large-scale surveys were conducted, one of key strategic personnel (Directors of Public Health and Chief Pharmacists) in Primary Care Organisations (PCOs) and one of practicing community pharmacists. This research highlights the fact that community pharmacists have developed an individualistic, service-based approach to their engagement with public health that is contrary to the more collective approach adopted by the wider public health movement. The study measures the scope and level of health-improving services through community pharmacy across the UK and shows that the nature of the pharmacy contractor (independent, multiple etc.) may impact on the range and nature of services provided. Survey data also suggest that attitudes towards pharmacy involvement in the public health agenda vary markedly between Directors of Public Health, PCO Chief Pharmacists, and community pharmacists. Furthermore, within the community pharmacist population, attitudes are affected by a wide range of factors including the nature of employment (owner, employee, self-employed) and the type of employing pharmacy (independent, multiple etc.). Implications for policy and areas for further research aimed at maximising the public health function of community pharmacists are suggested.

Fibre Bragg grating sensor interrogation using an acousto-optic tunable filter and low-coherence interferometry

We describe how an acousto-optic tunable filter can be used to both demultiplex the signals from multiple fibre Bragg grating sensors and simultaneously provide wide bandwidth signal demodulation in a system using interferometric wavelength shift detection. In an experimental demonstration, the approach provided a noise limited strain resolution of 24.9 n epsilon Hz(-1/ 2) at 15 Hz.

Statnote 24: Multiple regression

In previous statnotes, the application of correlation and regression methods to the analysis of two variables (X,Y) was described. These methods can be used to determine whether there is a linear relationship between the two variables, whether the relationship is positive or negative, to test the degree of significance of the linear relationship, and to obtain an equation relating Y to X. This Statnote extends the methods of linear correlation and regression to situations where there are two or more X variables, i.e., 'multiple linear regression’.

Typical case behaviour of spin systems in random graph and composite ensembles

This thesis includes analysis of disordered spin ensembles corresponding to Exact Cover, a multi-access channel problem, and composite models combining sparse and dense interactions. The satisfiability problem in Exact Cover is addressed using a statistical analysis of a simple branch and bound algorithm. The algorithm can be formulated in the large system limit as a branching process, for which critical properties can be analysed. Far from the critical point a set of differential equations may be used to model the process, and these are solved by numerical integration and exact bounding methods. The multi-access channel problem is formulated as an equilibrium statistical physics problem for the case of bit transmission on a channel with power control and synchronisation. A sparse code division multiple access method is considered and the optimal detection properties are examined in typical case by use of the replica method, and compared to detection performance achieved by interactive decoding methods. These codes are found to have phenomena closely resembling the well-understood dense codes. The composite model is introduced as an abstraction of canonical sparse and dense disordered spin models. The model includes couplings due to both dense and sparse topologies simultaneously. The new type of codes are shown to outperform sparse and dense codes in some regimes both in optimal performance, and in performance achieved by iterative detection methods in finite systems.

Strategy as practice:recursiveness, adaptation, and practices-in-use

In this article, a social theory framework is developed to explain the common themes of recursive and adaptive practice underpinning the existing strategic management literature. In practice, there is a coexistent tension between recursive and adaptive forms of strategic action that spans multiple levels from macro-institutional and competitive contexts to within-firm levels of analysis to individual cognition. This tension may be better understood by examining how management practices are used to put strategy into practice. Such practices span multiple levels of context and are adaptable to their circumstances of use, serving to highlight both general characteristics and localized idiosyncrasies of strategy as practice. The article develops the concept of management practices-in-use into a research agenda and nine broad research questions that may be used to investigate empirically strategy as practice.

Activity and affect:repeated within-participant assessment in people after joint replacement surgery

Objective: Between-participant research has shown that high negative affectivity predicts greater activity limitations and vice versa. This study examined both between- and within-participant associations of negative and positive affectivity with activity levels using ecological momentary assessment. Method: Participants were 25 people who had undergone joint replacement surgery 12 months previously. Participants made multiple reports of their activity and positive and negative affectivity over a single day using, a computerized diary. Activity was also objectively recorded using an activity monitor. The following day, participants made a self-report of their activity over the measurement day and general positive and negative affectivity levels were recorded. Results: Higher self-reported walking time over the whole measurement day was associated with higher general positive affectivity but not negative affectivity. However, using ecological momentary assessment, higher diary reports of negative affectivity predicted increased activity levels while positive affectivity neither predicted nor was predicted by activity. Conclusion: These findings demonstrate the importance of within-participant methodology in detecting subtle and immediate effects of individuals' mood on behavior that may differ from findings investigating between-participant effects over longer time periods.