Stochastic modelling of T cell homeostasis for two competing clonotypes via the master equation

Stochastic models for competing clonotypes of T cells by multivariate, continuous-time, discrete state, Markov processes have been proposed in the literature by Stirk, Molina-París and van den Berg (2008). A stochastic modelling framework is important because of rare events associated with small populations of some critical cell types. Usually, computational methods for these problems employ a trajectory-based approach, based on Monte Carlo simulation. This is partly because the complementary, probability density function (PDF) approaches can be expensive but here we describe some efficient PDF approaches by directly solving the governing equations, known as the Master Equation. These computations are made very efficient through an approximation of the state space by the Finite State Projection and through the use of Krylov subspace methods when evolving the matrix exponential. These computational methods allow us to explore the evolution of the PDFs associated with these stochastic models, and bimodal distributions arise in some parameter regimes. Time-dependent propensities naturally arise in immunological processes due to, for example, age-dependent effects. Incorporating time-dependent propensities into the framework of the Master Equation significantly complicates the corresponding computational methods but here we describe an efficient approach via Magnus formulas. Although this contribution focuses on the example of competing clonotypes, the general principles are relevant to multivariate Markov processes and provide fundamental techniques for computational immunology.

Stochastic chemical kinetics and the quasi-steady-state assumption : application to the stochastic simulation algorithm and chemical master equation

Recently the application of the quasi-steady-state approximation (QSSA) to the stochastic simulation algorithm (SSA) was suggested for the purpose of speeding up stochastic simulations of chemical systems that involve both relatively fast and slow chemical reactions [Rao and Arkin, J. Chem. Phys. 118, 4999 (2003)] and further work has led to the nested and slow-scale SSA. Improved numerical efficiency is obtained by respecting the vastly different time scales characterizing the system and then by advancing only the slow reactions exactly, based on a suitable approximation to the fast reactions. We considerably extend these works by applying the QSSA to numerical methods for the direct solution of the chemical master equation (CME) and, in particular, to the finite state projection algorithm [Munsky and Khammash, J. Chem. Phys. 124, 044104 (2006)], in conjunction with Krylov methods. In addition, we point out some important connections to the literature on the (deterministic) total QSSA (tQSSA) and place the stochastic analogue of the QSSA within the more general framework of aggregation of Markov processes. We demonstrate the new methods on four examples: Michaelis–Menten enzyme kinetics, double phosphorylation, the Goldbeter–Koshland switch, and the mitogen activated protein kinase cascade. Overall, we report dramatic improvements by applying the tQSSA to the CME solver.

A Krylov-based finite state projection algorithm for solving the chemical master equation arising in the discrete modelling of biological systems

Biochemical reactions underlying genetic regulation are often modelled as a continuous-time, discrete-state, Markov process, and the evolution of the associated probability density is described by the so-called chemical master equation (CME). However the CME is typically difficult to solve, since the state-space involved can be very large or even countably infinite. Recently a finite state projection method (FSP) that truncates the state-space was suggested and shown to be effective in an example of a model of the Pap-pili epigenetic switch. However in this example, both the model and the final time at which the solution was computed, were relatively small. Presented here is a Krylov FSP algorithm based on a combination of state-space truncation and inexact matrix-vector product routines. This allows larger-scale models to be studied and solutions for larger final times to be computed in a realistic execution time. Additionally the new method computes the solution at intermediate times at virtually no extra cost, since it is derived from Krylov-type methods for computing matrix exponentials. For the purpose of comparison the new algorithm is applied to the model of the Pap-pili epigenetic switch, where the original FSP was first demonstrated. Also the method is applied to a more sophisticated model of regulated transcription. Numerical results indicate that the new approach is significantly faster and extendable to larger biological models.

E-portfolios : developing nurse practitioner competence and capability

Objective: This paper aims to integrate nurse practitioner literature on competence and capability with post graduate and nursing literature on e‑portfolios in order to demonstrate the potential merits of e‑portfolios in nurse practitioner education for competence and capability development. Primary Argument In the Nurse Practitioner Standards Project, competence and capability were proposed as key criteria to assess candidates in nurse practitioner educational courses. Portfolios have traditionally been used to demonstrate competence in nursing and are integral to nursing education as well. An examination of the portfolio and electronic portfolio literature in postgraduate nursing education and professional practice indicates that these portfolios fall under two main structures, each with different purposes: 1) A spinal column structure, with evidence and reflective pieces aligned to competency standards or course objectives, for the purposes of meeting prescribed competencies, professional development planning and showcasing evidence for authorisation or potential employers; and 2) A cake mix structure, which consists of a reflective narrative tying evidence together, which enables a greater focus on personal learning journeys, reflection and the development of personal qualities. Finally, evidence from the general nursing literature suggests the complexity of e‑portfolios in assessment and evaluation can be overcome by using qualitative research methods. Conclusion: To meet the competence and capability needs of nurse practitioners, portfolios could be used, for competence and showcasing and for learning and capability. Further research would be useful to refine and explore the use of e‑portfolios to meet the needs of NP candidates and their educators, clinical mentors, authorisation personal and employers. The current evidence on nurse practitioner education, competence, capability and e‑portfolios points to the integration of the use of an e‑portfolio into current nurse practitioner curriculum models to meet the unique needs of nurse practitioner candidates.

Charting the system : the integrated master schedule as a multi-level and poly-temporal boundary object in complex projects

This paper investigates the use of visual artifacts to represent a complex adaptive system (CAS). The integrated master schedule (IMS) is one of those visuals widely used in complex projects for scheduling, budgeting, and project management. In this paper, we discuss how the IMS outperforms the traditional timelines and acts as a ‘multi-level and poly-temporal boundary object’ that visually represents the CAS. We report the findings of a case study project on the way the IMS mapped interactions, interdependencies, constraints and fractal patterns in a complex project. Finally, we discuss how the IMS was utilised as a complex boundary object by eliciting commitment and development of shared mental models, and facilitating negotiation through the layers of multiple interpretations from stakeholders.

Collaborative academic/practitioner research in project management : theory and models

Purpose – The purpose of this paper is to provide of a review of the theory and models underlying project management (PM) research degrees that encourage reflective learning. Design/methodology/approach – Review of the literature and reflection on the practice of being actively involved in conducting and supervising academic research and disseminating academic output. The paper argues the case for the potential usefulness of reflective academic research to PM practitioners. It also highlights theoretical drivers of and barriers to reflective academic research by PM practitioners. Findings – A reflective learning approach to research can drive practical results though it requires a great deal of commitment and support by both academic and industry partners. Practical implications – This paper suggests how PM practitioners can engage in academic research that has practical outcomes and how to be more effective at disseminating these research outcomes. Originality/value – Advanced academic degrees, in particular those completed by PM practitioners, can validate a valuable source of innovative ideas and approaches that should be more quickly absorbed into the PM profession’s sources of knowledge. The value of this paper is to critically review and facilitate a reduced adaptation time for implementation of useful reflective academic research to industry.

Collaborative academic/practitioner research in project management : examples and applications

Purpose – The purpose of this paper is to present a cost-benefit interpretation of academic-practitioner research by describing and analysing several recent relevant examples of academic-practitioner research with a focus on doctoral theses carried out at universities and business schools in clusters of research centred in North America, Australia and Europe. Design/methodology/approach – Using case study examples, a value proposition framework for undertaking collaborative research for higher degree level study is developed and presented. Findings – Value proposition benefits from this level of collaborative research can be summarised as enhancing competencies at the individual and organisational level as well as providing participating universities with high-quality candidates/students and opportunities for industry engagement. The project management (PM) professional bodies can also extend PM knowledge but they need to be prepared to provide active support. Practical implications – A model for better defining the value proposition of collaborative research from a range of stakeholder perspectives is offered that can be adapted for researchers and industry research sponsors. Originality/value – Few papers offer a value proposition framework for explaining collaborative research benefits. This paper addresses that need.

An examination of the psychologists' attitudes towards complementary and alternative therapies scale within a practitioner sample

This study assessed the validity of a scale measuring psychologists' attitudes towards complementary and alternative therapies and compared the attitudes of psychologists with a previous sample of psychology students. The scale, derived from existing measures for medical professionals and previously tested on a sample of psychology students, was completed by practising psychologists (N = 122). The data were factor analysed, and three correlated subscales were identified, assessing the perceived importance of knowledge about available therapies, attitudes towards integration with psychological practice, and concerns about associated risks of use. This structure was similar, but not identical, to that found in a previous sample of psychology students; however, psychologists expressed more concern for risks associated with integration and were less likely to hold a positive attitude towards integration. This scale will be useful in gauging changes in psychologists' attitudes towards integrative practice over time.

Small business entity tax concessions : through the eyes of the practitioner

The often competing imperatives of equity, simplicity and efficiency in the income tax regime, particularly the notion of simplicity, has been most evident within Australia’s small business sector over the last decade. In an attempt to provide tax simplification and reduce the tax compliance burden faced by Australian small businesses, provisions collectively referred to as the ‘simplified tax system’ or STS were introduced. The STS was designed to provide eligible small businesses with the option of adopting a range of ‘simplified’ tax measures designed to simplify their tax affairs whilst at the same time, reducing their tax compliance costs. Ultimately, a low take-up rate and accompanying criticisms led to a remodelled and rebadged concessionary regime known as the ‘Small Business Entity’ (SBE) regime which came into effect from 1 July 2007. This paper, through a pilot study, investigates the SBE regime though the eyes of the practitioner. In line the Australian Federal Government’s objective of simplification and reduced compliance costs, the purpose of the study was to (1) determine the extent to which the SBE concessions are being adopted by tax practitioners on behalf of their clients, (2) gain an understanding as to which individual SBE tax concessions are most favoured by practitioners, (3) determine the primary motivation as to why tax practitioners recommend particular SBE concessions to their clients, and (4) canvass the opinions of practitioners as to whether they believed that the introduction of the SBE concessions had met their stated objective of reducing tax compliance costs for small businesses. The findings of this research indicate that, while there is a perception that the SBE concessions are worth embracing, contrary to the policy intent, the reasons behind adopting the concessions was the opportunity to minimise a clients’ tax liability. It was revealed that adopting particular concessions had nothing to do with compliance costs savings and, in fact, the SBE concessions merely added another layer of complexity to an already cumbersome and complex tax code, which resulted in increased compliance costs for their small businesses clients. Further, the SBE concessions allowed tax practitioners the opportunity to engage in effective tax minimisation, thereby fulfilling the client advocacy role of the tax practitioner in maximising their clients’ tax preferences.

Reinvigorating the domestic violence sector : systemically addressing conflict, power and practitioner turnover

The purpose of this exploratory Australian study was to consider methods of retaining skilled and experienced staff within the domestic violence sector. The antecedents that might influence turnover of practitioners were investigated and analysed. Antecedents broadly included the work-related factors, organisational factors and professional factors. The changing nature of the domestic violence sector was also examined, in particular, feminist identity and feminist practice frameworks. It became evident, however, that the primary reasons for the turnover of study participants can be described as parallel power processes. The concept of parallel power processes as developed through this research aims to capture how workplace behaviours can strongly mirror, or parallel, behaviours used by domestic violence perpetrators. As such, it appears that some domestic violence practitioners are experiencing their own abusive relationship, not within the confines of their home, but within their workplace. Additionally, parallel power processes are compounded by ineffective conflict management processes within the workplace. These concepts directly contribute to practitioners leaving their workplace and, sometimes, the sector. This qualitative study utilised a feminist research epistemology and focused strongly on practitioners' stories. Interviews were undertaken with fifteen domestic violence practitioners from three services within South-East Queensland, Australia. Two sets of semi-structured interviews provided in-depth information based on practitioners‘ experiences of working within this specialised sector. Analysis was conducted using a thematic analytical frame, drawing attention to the key themes as mentioned above. From these findings, it is suggested that in order to retain practitioners, domestic violence services must identify and address parallel power processes through effective conflict management processes. In an operational sense, it is recommended that education and training be undertaken within all staffing levels, in particular management committees. Lastly, it is recommended that the sector itself places greater attention on the re-invigoration of the feminist principles and philosophy that has traditionally guided the sector.

Patient-practitioner relationships desired by overweight/obese adults

Objective: This study investigated the characteristics of the patient-practitioner relationship desired by overweight/obese individuals in weight management. The aim was to identify characteristics of the relationship which empower patients to make lifestyle changes. Methods: Grounded theory was used inductively to build a model of the patient-practitioner relationship based on the perspectives of 21 overweight/obese ¬adults. Results: Emerging from the match between patient and practitioner characteristics, collaboration was the key process explicitly occurring in the patient-practitioner relationship, and was characterised by two subcategories; perceived power dimensions and openness. Trust emerged implicitly from the collaborative process, being fostered by relational, informational, and credible aspects of the interaction. Patient trust in their practitioner consequently led to empowering outcomes including goal ownership and perceiving the utility of changes. Conclusion: An appropriate match between patient and practitioner characteristics facilitates collaboration which leads to trust, both of which appear to precede empowering outcomes for patients such as goal ownership and perceiving the utility of changes. Collaboration is an explicit process and precedes the patient trusting their practitioner. Practice implications: Practitioners should be sensitive to patient preferences for collaboration and the opportunity to develop trust with patients relationally, through information provision, and modelling a healthy lifestyle.

Temporal boundary objects in megaprojects : mapping the system with the integrated master schedule

Recently, a stream of project management research has recognized the critical role of boundary objects in the organization of projects. In this paper, we investigate how one advanced scheduling tool, the Integrated Master Schedule (IMS), is used as a temporal boundary object at various stages of complex projects. The IMS is critical to megaprojects which typically span long periods of time and face a high degree of complexity and uncertainty. In this paper, we conceptualize projects of this type as complex adaptive systems (CAS). We report the findings of four case projects on how the IMS mapped interactions, interdependencies, constraints, and fractal patterns of these emerging projects, and how the process of IMS visualization enabled communication and negotiation of project realities. This paper highlights that this advanced timeline tool acts as a boundary object and elicits shared understanding of complex projects from their stakeholders.

Vitronectin – master controller or micromanager?

The concept of the cellular glycoprotein vitronectin acts as a biological ‘glue’ and key controller of mammalian tissue repair and remodelling activity is emerging from nearly 50 years of experimental in vitro and in vivo data. Unexpectedly, the vitronectin-knock-out mouse was found to be viable and to have largely normal phenotype. However, diligent observation revealed that the VN-KO animal exhibits delayed coagulation and poor wound healing. This is interpreted to indicate that vitronectin occupies a role in the earliest events of thrombogenesis and tissue repair. That role is as a foundation upon which the thrombus grows in an organised structure. In addition to closing the wound, the thrombus also serves to protect the underlying tissue from oxidation, is a reservoir of mitogens and tissue repair mediators and provides a provisional scaffold for the repairing tissue. In the absence of vitronectin (e.g. VN-KO animal) this cascade is disrupted before it begins. Our data demonstrates that a wide variety of biologically active species associate with VN. While initial studies were focused on mitogens, other classes of bioactives (e.g. glycosaminoglycans, metalloproteinases) are now also known to specifically interact with VN. Many of these interactions are long-lived, often resulting in multi-protein complexes, while others are stable for prolonged periods. Multiprotein complexes provide several advantages: prolonging molecular interaction; sustaining local concentrations, facilitating co-stimulation of cell surface receptors and thereby enhancing cellular / biological responses. We contend that these, or equivalent, multi-protein complexes mediate vitronectin functionality in vivo. It is also likely that many of the species demonstrated to associate with vitronectin in vitro, also associate with vitronectin in vivo in similar multi-protein complexes. Thus the predominant biological function of vitronectin is that of a master controller of the extracellular environment; informing, and possibly instructing cells ‘where’ to behave, ‘when’ to behave, and ‘how’ to behave (i.e. appropriately for the current circumstance).