Group perceptions of knowledge management

This paper reports preliminary results of a project investigating how staff in UK organisations perceive knowledge management in their organisation as a group. The group setting appears to be effective in surfacing opinions and enabling progress in both understanding and action to be made. Among the findings thus far are the importance of the knowledge champion role and the state of the “knowledge management life cycle” in each organisation, and continuing confusion between knowledge, information and mechanisms.

Comparing knowledge management between organisations:searching for good practice

This paper reports ongoing work that is attempting to find out ‘what is good practice for knowledge management’. The data we have to analyse this issue is 109 maps of knowledge (on knowledge management) which were built during 18 group workshops with 152 people from 15 different organisations. The maps contain data on the aspirations and action plans which UK managers have to improve knowledge management practices in their organisation. So far we have attempted a number of approaches to analysing this data, both inductive and deductive, but we still feel there is more to be learned from the rich data set we have. The paper presents a flavour of the work we have done, have considered doing, and have resisted doing. The aim of the paper is to stimulate debate on the strengths of our analyses and, more importantly, on amassing views of how it can be further strengthened, and the difficulties and dilemmas which might need to be overcome.

Achieving closure through knowledge management strategy

Case studies of knowledge management practices are often conducted in organizations where the aim is to manage knowledge for future operational improvements. What about knowledge management for organizations with limited life-spans that are preparing for closure? Such organizations are not common but can benefit from knowledge management strategy. This case study concerns the knowledge management strategy of an organization that is preparing for its final phase of operations. We facilitated two group workshops with senior managers to scope a strategy, following which the organization initiated a set of projects to implement the resulting actions. This paper reviews their implemented actions against those designed in the workshop to shed light on knowledge management in this uncommon situation.

Using knowledge management to drive performance

Organisations are gathering ever more information, but are less good at analysing it and utilising the resultant knowledge for improved performance. Here Paul Collier, co-author of research on the subject, discusses how finance can help improve matters.

Communicating knowledge about police performance

This paper describes the organizational processes of knowledge acquisition, sharing, retention and utilisation as it affected the internal and external communication of knowledge about performance in an English police force. The research was gathered in three workshops for internal personnel, external stakeholders and chief officers, using Journey Making, a computer-assisted method of developing shared understanding. The research concluded that there are multiple audiences for the communication of knowledge about police performance, impeded by the requirement to publish performance data. However, the intelligence-led policing model could lead to a more focused means of communication with various stakeholder groups. Although technology investment was a preferred means of communicating knowledge about performance, without addressing cultural barriers, an investment in technology may not yield the appropriate changes in behaviour. Consequently, technology needs to be integrated with working practices in order to reduce organizational reliance on informal methods of communication.

Making a journey in knowledge management strategy

This paper reports results from an ongoing project examining what managers think about knowledge management in the context of their organisation. This was done in a facilitated computerassisted group workshop environment. Here we compare the outcomes of workshops held for two relatively large UK organisations, one public sector and the other private. Our conclusions are that there are relatively few differences between the perceptions of these two groups of managers, and that these differences stem more from the stage of the knowledge management life cycle that the two organisations have reached, rather than from the difference in context between public and private sector. © iKMS & World Scientific Publishing Co.

Knowledge management systems:finding a way with technology

Purpose - To consider the role of technology in knowledge management in organizations, both actual and desired. Design/methodology/approach - Facilitated, computer-supported group workshops were conducted with 78 people from ten different organizations. The objective of each workshop was to review the current state of knowledge management in that organization and develop an action plan for the future. Findings - Only three organizations had adopted a strongly technology-based "solution" to knowledge management problems, and these followed three substantially different routes. There was a clear emphasis on the use of general information technology tools to support knowledge management activities, rather than the use of tools specific to knowledge management. Research limitations/implications - Further research is needed to help organizations make best use of generally available software such as intranets and e-mail for knowledge management. Many issues, especially human, relate to the implementation of any technology. Participation was restricted to organizations that wished to produce an action plan for knowledge management. The findings may therefore represent only "average" organizations, not the very best practice. Practical implications - Each organization must resolve four tensions: Between the quantity and quality of information/knowledge, between centralized and decentralized organization, between head office and organizational knowledge, and between "push" and "pull" processes. Originality/value - Although it is the group rather than an individual that determines what counts as knowledge, hardly any previous studies of knowledge management have collected data in a group context.

The effects of perceived business uncertainty, external consultants and risk management on organisational outcomes

Purpose: The purpose of this paper is to investigate the relations between perceived business uncertainty (PBU), use of external risk management (RM) consultants, formalisation of RM, magnitude of RM methods and perceived organisational outcomes. Design/methodology/approach: This paper is based on a questionnaire survey of members of the Chartered Institute of Management Accountants in the UK. Using AMOS 17.0, the paper tests the strength of the direct and indirect effects among the variables and explores the fit of the overall path model. Findings: The results indicate significant and positive associations exist between the extent of PBU and the level ofRMformalisation, as well as between the level ofRMformalisation and the magnitude of RMmethods adopted. The use of externalRMconsultants is also found to have a significant and positive impact on the magnitude of RM methods adopted. Finally, both the extent of RM formalisation and the magnitude of RM methods adopted are seen to be significantly associated with overall improvement in organisational outcomes. Research limitations/implications: The study uses perceptual measures of the level of business uncertainty, usage of RM and organisational outcomes. Further, the respondents are members of a management accounting professional body and the views of other managers, such as risk managers, who are also important to the governance process are not incorporated. Originality/value: This study provides empirical evidence on the impact ofRMdesign and usage on improvements in organisational outcomes. It contributes to the RM literature where empirical research is needed in order to be comparable with the traditional management control system literature.

Prophylactic ranitidine treatment in critically ill children - a population pharmacokinetic study

Aims - To characterize the population pharmacokinetics of ranitidine in critically ill children and to determine the influence of various clinical and demographic factors on its disposition. Methods - Data were collected prospectively from 78 paediatric patients (n = 248 plasma samples) who received oral or intravenous ranitidine for prophylaxis against stress ulcers, gastrointestinal bleeding or the treatment of gastro-oesophageal reflux. Plasma samples were analysed using high-performance liquid chromatography, and the data were subjected to population pharmacokinetic analysis using nonlinear mixed-effects modelling. Results - A one-compartment model best described the plasma concentration profile, with an exponential structure for interindividual errors and a proportional structure for intra-individual error. After backward stepwise elimination, the final model showed a significant decrease in objective function value (−12.618; P < 0.001) compared with the weight-corrected base model. Final parameter estimates for the population were 32.1 l h−1 for total clearance and 285 l for volume of distribution, both allometrically modelled for a 70 kg adult. Final estimates for absorption rate constant and bioavailability were 1.31 h−1 and 27.5%, respectively. No significant relationship was found between age and weight-corrected ranitidine pharmacokinetic parameters in the final model, with the covariate for cardiac failure or surgery being shown to reduce clearance significantly by a factor of 0.46. Conclusions - Currently, ranitidine dose recommendations are based on children's weights. However, our findings suggest that a dosing scheme that takes into consideration both weight and cardiac failure/surgery would be more appropriate in order to avoid administration of higher or more frequent doses than necessary.

Population pharmacokinetic and pharmacogenetic analysis of 6-mercaptopurine in paediatric patients with acute lymphoblastic leukaemia

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • The cytotoxic effects of 6-mercaptopurine (6-MP) were found to be due to drug-derived intracellular metabolites (mainly 6-thioguanine nucleotides and to some extent 6-methylmercaptopurine nucleotides) rather than the drug itself. • Current empirical dosing methods for oral 6-MP result in highly variable drug and metabolite concentrations and hence variability in treatment outcome. WHAT THIS STUDY ADDS • The first population pharmacokinetic model has been developed for 6-MP active metabolites in paediatric patients with acute lymphoblastic leukaemia and the potential demographic and genetically controlled factors that could lead to interpatient pharmacokinetic variability among this population have been assessed. • The model shows a large reduction in interindividual variability of pharmacokinetic parameters when body surface area and thiopurine methyltransferase polymorphism are incorporated into the model as covariates. • The developed model offers a more rational dosing approach for 6-MP than the traditional empirical method (based on body surface area) through combining it with pharmacogenetically guided dosing based on thiopurine methyltransferase genotype. AIMS - To investigate the population pharmacokinetics of 6-mercaptopurine (6-MP) active metabolites in paediatric patients with acute lymphoblastic leukaemia (ALL) and examine the effects of various genetic polymorphisms on the disposition of these metabolites. METHODS - Data were collected prospectively from 19 paediatric patients with ALL (n = 75 samples, 150 concentrations) who received 6-MP maintenance chemotherapy (titrated to a target dose of 75 mg m−2 day−1). All patients were genotyped for polymorphisms in three enzymes involved in 6-MP metabolism. Population pharmacokinetic analysis was performed with the nonlinear mixed effects modelling program (nonmem) to determine the population mean parameter estimate of clearance for the active metabolites. RESULTS - The developed model revealed considerable interindividual variability (IIV) in the clearance of 6-MP active metabolites [6-thioguanine nucleotides (6-TGNs) and 6-methylmercaptopurine nucleotides (6-mMPNs)]. Body surface area explained a significant part of 6-TGNs clearance IIV when incorporated in the model (IIV reduced from 69.9 to 29.3%). The most influential covariate examined, however, was thiopurine methyltransferase (TPMT) genotype, which resulted in the greatest reduction in the model's objective function (P < 0.005) when incorporated as a covariate affecting the fractional metabolic transformation of 6-MP into 6-TGNs. The other genetic covariates tested were not statistically significant and therefore were not included in the final model. CONCLUSIONS - The developed pharmacokinetic model (if successful at external validation) would offer a more rational dosing approach for 6-MP than the traditional empirical method since it combines the current practice of using body surface area in 6-MP dosing with a pharmacogenetically guided dosing based on TPMT genotype.

Pharmacogenomic studies of the anticancer and immunosuppressive thiopurines mercaptopurine and azathioprine

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • 6-Mercaptopurine (6-MP) and azathioprine (AZA) are both inactive prodrugs that require intracellular activation into the active 6-thioguanine nucleotides (6-TGNs). • This metabolic process undergoes three different competitive pathways that are catalysed by three different enzymes; xanthine oxidase (XO), thiopurine methyltransferase (TPMT) and inosine triphosphatase (ITPA), all of which exhibit genetic polymorphisms. • Although the impact of genetic variation in the TPMT gene on treatment outcome and toxicity has been demonstrated, the role of other polymorphisms remains less well known. WHAT THIS STUDY ADDS • New information on the allelic variation of these three enzymes (XO, TPMT and ITPA) and their influence on 6-MP/AZA metabolism and toxicity. • Confirmation of the association of TPMT polymorphism with haematological toxicity. • Identified potential genetic characteristics that may contribute to higher risk of adverse events (such as ITPA IVS2+21A→C mutation). AIMS - To examine the allelic variation of three enzymes involved in 6-mercaptopurine/azathioprine (6-MP/AZA) metabolism and evaluate the influence of these polymorphisms on toxicity, haematological parameters and metabolite levels in patients with acute lymphoblastic leukaemia (ALL) or inflammatory bowel disease (IBD). METHODS - Clinical data and blood samples were collected from 19 ALL paediatric patients and 35 IBD patients who were receiving 6-MP/AZA therapy. All patients were screened for seven genetic polymorphisms in three enzymes involved in mercaptopurine metabolism [xanthine oxidase, inosine triphosphatase (C94→A and IVS2+21A→C) and thiopurine methyltransferase]. Erythrocyte and plasma metabolite concentrations were also determined. The associations between the various genotypes and myelotoxicity, haematological parameters and metabolite concentrations were determined. RESULTS - Thiopurine methyltransferase variant alleles were associated with a preferential metabolism away from 6-methylmercaptopurine nucleotides (P = 0.008 in ALL patients, P = 0.038 in IBD patients) favouring 6-thioguanine nucleotides (6-TGNs) (P = 0.021 in ALL patients). Interestingly, carriers of inosine triphosphatase IVS2+21A→C variants among ALL and IBD patients had significantly higher concentrations of the active cytotoxic metabolites, 6-TGNs (P = 0.008 in ALL patients, P = 0.047 in IBD patients). The study confirmed the association of thiopurine methyltransferase heterozygosity with leucopenia and neutropenia in ALL patients and reported a significant association between inosine triphosphatase IVS2+21A→C variants with thrombocytopenia (P = 0.012). CONCLUSIONS - Pharmacogenetic polymorphisms in the 6-MP pathway may help identify patients at risk for associated toxicities and may serve as a guide for dose individualization.

Influence of ABCB1 polymorphisms and haplotypes on tacrolimus nephrotoxicity and dosage requirements in children with liver transplant

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Currently tacrolimus is the mainstay of immunosuppression for most children undergoing liver transplantation (LT). • The clinical use of this agent, however, is complicated by its various adverse effects (mainly nephrotoxicity), its narrow therapeutic-index and considerable pharmacokinetic variability. • The low and variable oral bioavailability of tacrolimus is thought to result from the action of the multidrug efflux-pump P-glycoprotein, encoded by the ABCB1 gene. WHAT THIS STUDY ADDS • A significant association between ABCB1 genetic polymorphisms and tacrolimus-associated nephrotoxicity in paediatric patients following LT is reported for the first time. Genotyping such polymorphisms may have the potential to individualize better initial tacrolimus therapy and enhance drug safety. • The long-term effect of ABCB1 polymorphisms on tacrolimus trough concentrations were investigated up to 5 years post-transplantation. A significant effect of intestinal P-glycoprotein genotypes on tacrolimus pharmacokinetics was found at 3 and 4 years post-transplantation suggesting that the effect is maintained long term. AIMS - The aim of this study was to investigate the influence of genetic polymorphisms in ABCB1 on the incidence of nephrotoxicity and tacrolimus dosage-requirements in paediatric patients following liver transplantation. METHODS - Fifty-one paediatric liver transplant recipients receiving tacrolimus were genotyped for ABCB1 C1236>T, G2677>T and C3435>T polymorphisms. Dose-adjusted tacrolimus trough concentrations and estimated glomerular filtration rates (EGFR) indicative of renal toxicity were determined and correlated with the corresponding genotypes. RESULTS - The present study revealed a higher incidence of the ABCB1 variant-alleles examined among patients with renal dysfunction (≥30% reduction in EGFR) at 6 months post-transplantation (1236T allele: 63.3% vs 37.5% in controls, P= 0.019; 2677T allele: 63.3% vs. 35.9%, p = 0.012; 3435T allele: 60% vs. 39.1%, P= 0.057). Carriers of the G2677->T variant allele also had a significant reduction (%) in EGFR at 12 months post-transplant (mean difference = 22.6%; P= 0.031). Haplotype analysis showed a significant association between T-T-T haplotypes and an increased incidence of nephrotoxicity at 6 months post-transplantation (haplotype-frequency = 52.9% in nephrotoxic patients vs 29.4% in controls; P= 0.029). Furthermore, G2677->T and C3435->T polymorphisms and T-T-T haplotypes were significantly correlated with higher tacrolimus dose-adjusted pre-dose concentrations at various time points examined long after drug initiation. CONCLUSIONS - These findings suggest that ABCB1 polymorphisms in the native intestine significantly influence tacrolimus dosage-requirement in the stable phase after transplantation. In addition, ABCB1 polymorphisms in paediatric liver transplant recipients may predispose them to nephrotoxicity over the first year post-transplantation. Genotyping future transplant recipients for ABCB1 polymorphisms, therefore, could have the potential to individualize better tacrolimus immunosuppressive therapy and enhance drug safety.

Population pharmacokinetic model of canrenone after intravenous administration of potassium canrenoate to paediatric patients

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Little is known about the pharmacokinetics of potassium canrenoate/canrenone in paediatric patients WHAT THIS STUDY ADDS • A population pharmacokinetic model has been developed to evaluate the pharmacokinetics of canrenone in paediatric patients who received potassium canrenoate as part of their therapy in the intensive care unit. AIMS To characterize the population pharmacokinetics of canrenone following administration of potassium canrenoate to paediatric patients. METHODS Data were collected prospectively from 23 paediatric patients (2 days to 10 years of age; median weight 4 kg, range 2.16–28.0 kg) who received intravenous potassium canrenoate (K-canrenoate) as part of their intensive care therapy for removal of retained fluids, e.g. in pulmonary oedema due to chronic lung disease and for the management of congestive heart failure. Plasma samples were analyzed by HPLC for determination of canrenone (the major metabolite and pharmacologically active moiety) and the data subjected to pharmacokinetic analysis using NONMEM. RESULTS A one compartment model best described the data. The only significant covariate was weight (WT). The final population models for canrenone clearance (CL/F) and volume of distribution (V/F) were CL/F (l h−1) = 11.4 × (WT/70.0)0.75 and V/F (l) = 374.2 × (WT/70) where WT is in kg. The values of CL/F and V/F in a 4 kg child would be 1.33 l h−1 and 21.4 l, respectively, resulting in an elimination half-life of 11.2 h. CONCLUSIONS The range of estimated CL/F in the study population was 0.67–7.38 l h−1. The data suggest that adjustment of K-canrenoate dosage according to body weight is appropriate in paediatric patients.