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.

Fostering team creativity:perspective taking as key to unlocking diversity's potential

Despite the clear importance of team creativity for organizations, the conditions that foster it are not very well understood. Even though diversity, especially diversity of perspectives and knowledge, is frequently argued to stimulate higher creativity in teams, empirical findings on this relationship remain inconsistent. We have developed a theoretical model in which the effect of a team's diversity on its creativity is moderated by the degree to which team members engage in perspective taking. We propose that perspective taking helps realize the creative benefits of diversity of perspectives by fostering information elaboration. Results of a laboratory experiment support the hypothesized interaction between diversity and perspective taking on team creativity. Diverse teams performed more creatively than homogeneous teams when they engaged in perspective taking, but not when they were not instructed to take their team members' perspectives. Team information elaboration was found to mediate this moderated effect and was associated with a stronger indirect effect than mere information sharing or task conflict. Our results point to perspective taking as an important mechanism to unlock diversity's potential for team creativity. (PsycINFO Database Record (c) 2012 APA, all rights reserved)

An empirical examination of the strategic decision-making process:the relationship between context, process, and outcomes

Despite concerted academic interest in the strategic decision-making process (SDMP) since the 1980s, a coherent body of theory capable of guiding practice has not materialised. This is because many prior studies focus only on a single process characteristic, often rationality or comprehensiveness, and have paid insufficient attention to context. To further develop theory, research is required which examines: (i) the influence of context from multiple theoretical perspectives (e.g. upper echelons, environmental determinism); (ii) different process characteristics from both synoptic formal (e.g. rationality) and political incremental (e.g. politics) perspectives, and; (iii) the effects of context and process characteristics on a range of SDMP outcomes. Using data from 30 interviews and 357 questionnaires, this thesis addresses several opportunities for theory development by testing an integrative model which incorporates: (i) five SDMP characteristics representing both synoptic formal (procedural rationality, comprehensiveness, and behavioural integration) and political incremental (intuition, and political behaviour) perspectives; (ii) four SDMP outcome variables—strategic decision (SD) quality, implementation success, commitment, and SD speed, and; (iii) contextual variables from the four theoretical perspectives—upper echelons, SD-specific characteristics, environmental determinism, and firm characteristics. The present study makes several substantial and original contributions to knowledge. First, it provides empirical evidence of the contextual boundary conditions under which intuition and political behaviour positively influence SDMP outcomes. Second, it establishes the predominance of the upper echelons perspective; with TMT variables explaining significantly more variance in SDMP characteristics than SD specific characteristics, the external environment, and firm characteristics. A newly developed measure of top management team expertise also demonstrates highly significant direct and indirect effects on the SDMP. Finally, it is evident that SDMP characteristics and contextual variables influence a number of SDMP outcomes, not just overall SD quality, but also implementation success, commitment, and SD speed.

The need for wider supply chain management adoption:empirical results from Ireland

Purpose - This paper aims to provide empirical results which suggest that there is a need for more widespread adoption of supply chain management among Irish firms. Design/methodology/approach - The Republic of Ireland is a small, open, trade-dependent economy and is one of the fastest growing economies in the developed world. However, due to rising costs, there is an increasing trend in Ireland to outsource lower function manufacturing processes to lower-cost locations but to retain high-skill functions (such as R&D). This trend, together with other factors such as its peripheral location, suggests that supply chain management is critical from an Irish perspective. In order to gain unique insights of current levels of awareness/adoption of SCM and the potential impact SCM could have on competitiveness, a survey was conducted among 776 Irish firms. Findings - Overall, the findings suggest that many firms in Ireland pay lip-service to the importance of SCM elements and objectives but the majority of firms, about two thirds, have only a passing understanding of what constitutes SCM. Only 25 per cent adopt SCM programmes and only 9 per cent of Irish companies have a specialised SCM or logistics manager. The gaps in their understanding of SCM are matched by the gaps in their awareness of key costs (e.g. 59 per cent of companies do not know their total supply chain costs). While there are supply chain management adopters in Ireland that are already well up the s-curve of innovation transfer, it is the larger group of less aware companies that must become better at how they manage their supply chains. Originality/value - The paper offers a useful insight into supply chain management and its role in Irish industry. © Emerald Group Publishing Limited.

E-procurement in the aviation industry:value creation potential of B2B e-marketplaces

In academic literature, only limited research has been undertaken in exploring the value creation of B2B (Business-to-Business) e-Marketplace models in the aviation industry. The aim of this publication is a theoretical analysis to explore whether or not B2B e-Marketplaces can make a contribution to the achievement of competitive advantage in procurement in the aviation industry. The research focuses on the potential of B2B e-Marketplaces in terms of improving an airline’s competitiveness in its procurement value chain and discusses empirical results from a survey among international e-Marketplace / portal operators

Empirical prediction of peptide octanol-water partition coefficients

Peptides are of great therapeutic potential as vaccines and drugs. Knowledge of physicochemical descriptors, including the partition coefficient P (commonly expressed in logarithm form: logP), is useful for screening out unsuitable molecules and also for the development of predictive Quantitative Structure-Activity Relationships (QSARs). In this paper we develop a new approach to the prediction of LogP values for peptides based on an empirical relationship between global molecular properties and measured physical properties. Our method was successful in terms of peptide prediction (total r2 = 0.641). The final model consisted of 5 physicochemical descriptors (molecular weight, number of single bonds, 2D-VDW volume, 2D-VSA hydrophobic and 2D-VSA polar). The approach is peptide specific and its predictive accuracy was high. Overall, 67% of the peptides were able to be predicted within +/-0.5 log units from the experimental values. Our method thus represents a novel prediction method with proven predictive ability.

On the hydrophobicity of peptides:comparing empirical predictions of peptide log P values

Peptides are of great therapeutic potential as vaccines and drugs. Knowledge of physicochemical descriptors, including the partition coefficient logP, is useful for the development of predictive Quantitative Structure-Activity Relationships (QSARs). We have investigated the accuracy of available programs for the prediction of logP values for peptides with known experimental values obtained from the literature. Eight prediction programs were tested, of which seven programs were fragment-based methods: XLogP, LogKow, PLogP, ACDLogP, AlogP, Interactive Analysis's LogP and MlogP; and one program used a whole molecule approach: QikProp. The predictive accuracy of the programs was assessed using r(2) values, with ALogP being the most effective (r( 2) = 0.822) and MLogP the least (r(2) = 0.090). We also examined three distinct types of peptide structure: blocked, unblocked, and cyclic. For each study (all peptides, blocked, unblocked and cyclic peptides) the performance of programs rated from best to worse is as follows: all peptides - ALogP, QikProp, PLogP, XLogP, IALogP, LogKow, ACDLogP, and MlogP; blocked peptides - PLogP, XLogP, ACDLogP, IALogP, LogKow, QikProp, ALogP, and MLogP; unblocked peptides - QikProp, IALogP, ALogP, ACDLogP, MLogP, XLogP, LogKow and PLogP; cyclic peptides - LogKow, ALogP, XLogP, MLogP, QikProp, ACDLogP, IALogP. In summary, all programs gave better predictions for blocked peptides, while, in general, logP values for cyclic peptides were under-predicted and those of unblocked peptides were over-predicted.

N-dimensional electron in an anharmonic potential:the large-N limit

We show that the energy levels predicted by a frac(1, N)-expansion method for an N-dimensional electron in an anharmonic potential are always lower than the exact energy levels but monotonically converge toward their exact eigenstates for higher ordered corrections. The technique allows a systematic approach for quantum many body problems in a confined potential and explains the remarkable agreement of such approximate theories when compared with numerical results.

The implementation of supply chain management theory in practice:an empirical investigation

Purpose: The purpose of the research described in this paper is to disentangle the rhetoric from the reality in relation to supply chain management (SCM) adoption in practice. There is significant evidence of a divergence between theory and practice in the field of SCM. Design/methodology/approach: Based on a review of extant theory, the authors posit a new definitional construct for SCM – the Four Fundamentals – and investigated four research questions (RQs) that emerged from the theoretical review. The empirical work comprised three main phases: focussed interviews, focus groups and a questionnaire survey. Each phase used the authors’ definitional construct as its basis. While the context of the paper’s empirical work is Ireland, the insights and results are generalisable to other geographical contexts. Findings: The data collected during the various stages of the empirical research supported the essence of the definitional construct and allowed it to be further developed and refined. In addition, the findings suggest that, while levels of SCM understanding are generally quite high, there is room for improvement in relation to how this understanding is translated into practice. Research limitations/implications: Expansion of the research design to incorporate case studies, grounded theory and action research has the potential to generate new SCM theory that builds on the Four Fundamentals construct, thus facilitating a deeper and richer understanding of SCM phenomena. The use of longitudinal studies would enable a barometer of progress to be developed over time. Practical implications: The authors’ definitional construct supports improvement in the cohesion of SCM practices, thereby promoting the effective implementation of supply chain strategies. A number of critical success factors and/or barriers to implementation of SCM theory in practice are identified, as are a number of practical measures that could be implemented at policy/supply chain/firm level to improve the level of effective SCM adoption. Originality/value: The authors’ robust definitional construct supports a more cohesive approach to the development of a unified theory of SCM. In addition to a profile of SCM understanding and adoption by firms in Ireland, the related critical success factors and/or inhibitors to success, as well as possible interventions, are identified.

Public R&D policies and private R&D investment:a survey of the empirical evidence

The importance of R&D investment in explaining economic growth is well documented in the literature. Policies by modern governments increasingly recognise the benefits of supporting R&D investment. Government funding has, however, become an increasingly scarce resource in times of financial crisis and economic austerity. Hence, it is important that available funds are used and targeted effectively. This paper offers the first systematic review and critical discussion of what the R&D literature has to say currently about the effectiveness of major public R&D policies in increasing private R&D investment. Public policies are considered within three categories, R&D tax credits and direct subsidies, support of the university research system and the formation of high-skilled human capital, and support of formal R&D cooperations across a variety of institutions. Crucially, the large body of more recent literature observes a shift away from the earlier findings that public subsidies often crowd-out private R&D to finding that subsidies typically stimulate private R&D. Tax credits are also much more unanimously than previously found to have positive effects. University research, high-skilled human capital, and R&D cooperation also typically increase private R&D. Recent work indicates that accounting for non-linearities is one area of research that may refine existing results. © 2014 John Wiley & Sons Ltd.

An empirical investigation on firm-level performance of cross border mergers and acquisitions

This empirical study investigates the performance of cross border M&A. The first stage is to identify the determinants of making cross border M&A complete. One focus here is to extend the existing empirical evidence in the field of cross border M&A and exploit the likelihood of M&A from a different perspective. Given the determinants of cross border M&A completions, the second stage is to investigate the effects of cross border M&A on post-acquisition firm performance for both targets and acquirers. The thesis exploits a hitherto unused data base, which consists of those firms that are rumoured to be undertaking M&A, and then follow the deal to completion or abandonment. This approach highlights a number of limitations to the previous literature, which relies on statistical methodology to identify potential but non-existent mergers. This thesis changes some conventional understanding for M&A activity. Cross border M&A activity is underpinned by various motives such as synergy, management discipline, and acquisition of complementary resources. Traditionally, it is believed that these motives will boost the international M&A activity and improve firm performance after takeovers. However, this thesis shows that such factors based on these motives as acquirer’s profitability and liquidity and target’s intangible resource actually deter the completion of cross border M&A in the period of 2002-2011. The overall finding suggests that the cross border M&A is the efficiency-seeking activity rather than the resource-seeking activity. Furthermore, compared with firms in takeover rumours, the completion of M&A lowers firm performance. More specifically, the difficulties in transfer of competitive advantages and integration of strategic assets lead to low firm performance in terms of productivity. Besides, firms cannot realise the synergistic effect and managerial disciplinary effect once a cross border M&A is completed, which suggests a low post-acquisition profitability level.

GIS and optimisation:potential benefits for emergency facility location in humanitarian logistics

Floods are one of the most dangerous and common disasters worldwide, and these disasters are closely linked to the geography of the affected area. As a result, several papers in the academic field of humanitarian logistics have incorporated the use of Geographical Information Systems (GIS) for disaster management. However, most of the contributions in the literature are using these systems for network analysis and display, with just a few papers exploiting the capabilities of GIS to improve planning and preparedness. To show the capabilities of GIS for disaster management, this paper uses raster GIS to analyse potential flooding scenarios and provide input to an optimisation model. The combination is applied to two real-world floods in Mexico to evaluate the value of incorporating GIS for disaster planning. The results provide evidence that including GIS analysis for a decision-making tool in disaster management can improve the outcome of disaster operations by reducing the number of facilities used at risk of flooding. Empirical results imply the importance of the integration of advanced remote sensing images and GIS for future systems in humanitarian logistics.

Revisiting the lean agile paradigm:an empirical study in the aerospace industry

Much has been written about the potential impact of Lean Agile paradigm on firm's supply chain performance. However, most of the existing studies mainly pointed out Lean is for cost reduction, whereas Agility is for attaining flexibility. There are little empirical studies in literature that examined how Lean Agile paradigm impacts on supply chain performance. This paper aims to address this gap by studying the influence of Lean and Agility paradigms on a single commodity supply chain delivery performance in the aerospace industry. Data was collected from four separate 'Rigid pipes' supply chains to study how manufacturing alignment impacts on the delivery performance. Implications of the study to practitioners and academia are discussed and future research outlined.

Leader-member exchange and attitudes:a theoretical and empirical integration

The central proposition of this thesis is that there are key benefits to examining leadership perceptions as an attitude towards the leader. In particular, it is argued that doing so can provide an enhanced understanding of leadership perceptions and therefore advance theory in this area. To provide empirical support for this theoretcial integration, the current research focused on one of the most popular leadership theories, leader-member exchange (LMX), and demonstrated how the concept of attitude strength could advance understanding of how and when LMX influenced employee job performance. Although the measurement of LMX requires employees to provide a cognitive evaluation of their relationship with their leader, previous research has, to date, not considered this evaluation to be an attitude. This thesis provides a justification for doing so and develops two novel constructs: LMX importance and LMX ambivalence. Both of these variables are argued to represent previously unconsidered facets of the LMX relationship, which, according to attitude theory, provide a more multifaceted understanding of leadership perceptions than previously envisaged. Such an understanding can provide a more detailed understanding of how such perceptions influence outcomes. Two studies provided an empirical test of the above reasoning. Study 1, a longitudinal field study, demonstrated initial support for many of the hypotheses. LMX amivalence was shown to lead to poorer task performance and organisational citizenship behaviour, mediated by the experience of negative affect. Evidence was also found for the moderating effect of LMX importance, although felt obligations was not found to mediate this moderated effect. While Study 1 used project groups as its participants, Study 2 provided a first test of the construct in an organisational setting; with three companies proving data. Again, strong support was found for the negative effects of LMX ambivalence on employee outcomes, with evidence also found for the role of perceived organisational support in mitigating these negative effects. Support was also found for the moderated mediation hypothesis related to LMX importance, although this was only found in the largest organisation sample. Some of the main theoretical and methodological implications of viewing leadership perceptions as attitudes to the wider leadership area were discussed. The cross-fertilisation of research from the attitudes literature to understanding leadership perceptions provides new insights into leadership processes and potential avenues for further research.