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.

Peer state assessment of TxDOT maintenance program and practices : workshop and road rally findings

In an effort to evaluate and improve their practices to ensure the future excellence of the Texas highway system, the Texas Department of Transportation (TxDOT) sought a forum in which experts from other state departments of transportation could share their expertise. Thus, the Peer State Review of TxDOT Maintenance Practices project was organized and conducted for TxDOT by the Center for Transportation Research (CTR) at The University of Texas at Austin. The goal of the project was to conduct a workshop at CTR and in the Austin District that would educate the visiting peers on TxDOT’s maintenance practices and invite their feedback. CTR and TxDOT arranged the participation of the following directors of maintenance: Steve Takigawa, CA; Roy Rissky, KS; Eric Pitts, GA; Jim Carney, MO; Jennifer Brandenburg, NC; and David Bierschbach, WA. One of the means used to capture the peer reviewers’ opinions was a carefully designed booklet of 15 questions. The peers provided TxDOT with written responses to these questions, and the oral comments made during the workshop were also captured. This information was then compiled and summarized in the following report. An examination of the peers’ comments suggests that TxDOT should use a more holistic, statewide approach to funding and planning rather than funding and planning for each district separately. Additionally, the peers stressed the importance of allocating funds based on the actual conditions of the roadways instead of on inventory. The visiting directors of maintenance also recommended continuing and proliferating programs that enhance communication, such as peer review workshops.

Under the carpet : the politics and trauma of patient harm

Few studies have investigated iatrogenic outcomes from the viewpoint of patient experience. To address this anomaly, the broad aim of this research is to explore the lived experience of patient harm. Patient harm is defined as major harm to the patient, either psychosocial or physical in nature, resulting from any aspect of health care. Utilising the method of Consensual Qualitative Research (CQR), in-depth interviews are conducted with twenty-four volunteer research participants who self-report having been severely harmed by an invasive medical procedure. A standardised measure of emotional distress, the Impact of Event Scale (IES), is additionally employed for purposes of triangulation. Thematic analysis of transcript data indicate numerous findings including: (i) difficulties regarding patients‘ prior understanding of risks involved with their medical procedure; (ii) the problematic response of the health system post-procedure; (iii) multiple adverse effects upon life functioning; (iv) limited recourse options for patients; and (v) the approach desired in terms of how patient harm should be systemically handled. In addition, IES results indicate a clinically significant level of distress in the sample as a whole. To discuss findings, a cross-disciplinary approach is adopted that draws upon sociology, medicine, medical anthropology, psychology, philosophy, history, ethics, law, and political theory. Furthermore, an overall explanatory framework is proposed in terms of the master themes of power and trauma. In terms of the theme of power, a postmodernist analysis explores the politics of patient harm, particularly the dynamics surrounding the politics of knowledge (e.g., notions of subjective versus objective knowledge, informed consent, and open disclosure). This analysis suggests that patient care is not the prime function of the health system, which appears more focussed upon serving the interests of those in the upper levels of its hierarchy. In terms of the master theme of trauma, current understandings of posttraumatic stress disorder (PTSD) are critiqued, and based on data from this research as well as the international literature, a new model of trauma is proposed. This model is based upon the principle of homeostasis observed in biology, whereby within every cell or organism a state of equilibrium is sought and maintained. The proposed model identifies several bio-psychosocial markers of trauma across its three main phases. These trauma markers include: (i) a profound sense of loss; (ii) a lack of perceived control; (iii) passive trauma processing responses; (iv) an identity crisis; (v) a quest to fully understand the trauma event; (vi) a need for social validation of the traumatic experience; and (vii) posttraumatic adaption with the possibility of positive change. To further explore the master themes of power and trauma, a natural group interview is carried out at a meeting of a patient support group for arachnoiditis. Observations at this meeting and members‘ stories in general support the homeostatic model of trauma, particularly the quest to find answers in the face of distressing experience, as well as the need for social recognition of that experience. In addition, the sociopolitical response to arachnoiditis highlights how public domains of knowledge are largely constructed and controlled by vested interests. Implications of the data overall are discussed in terms of a cultural revolution being needed in health care to position core values around a prime focus upon patients as human beings.

Defences in medical negligence : to what extent has tort law reform in Australia limited the liability of health professionals?

Tort law reform has resulted in legislation being passed by all Australian jurisdictions in the past decade implementing the recommendations contained in the Ipp Report. The report was in response to a perceived crisis in medical indemnity insurance. The objective was to restrict and limit liability in negligence actions. This paper will consider to what extent the reforms have impacted on the liability of health professionals in medical negligence actions. The reversal of the onus of proof through the obvious risk sections has attempted to extend the scope of the defence of voluntary assumption of risk. There is no liability for the materialisation of an inherent risk. Presumptions and mandatory reductions for contributory negligence have attempted to reduce the liability of defendants. It is now possible for reductions of 100% for contributory negligence. Apologies can be made with no admission of legal liability to encourage them being made and thereby reduce the number of actions being commenced. The peer acceptance defence has been introduced and enacted by legislation. There is protection for good samaritans even though the Ipp Report recommended against such protection. Limitation periods have been amended. Provisions relating to mental harm have been introduced re-instating the requirement of normal fortitude and direct perception. After an analysis of the legislation, it will be argued in this paper that while there has been some limitation and restriction, courts have generally interpreted the civil liability reforms in compliance with the common law. It has been the impact of statutory limits on the assessment of damages which has limited the liability of health professionals in medical negligence actions.

Loss of chance in medical negligence claims now a lost cause?

The question whether the loss of chance of a better medical outcome in cases of medical negligence should be recognised as actionable damage is ‘a question which has divided courts and commentators throughout the common law world.’ In April 2010, the High Court handed down its anticipated decision in the case of Tabet (by her Tutor Sheiban) v Gett (2010) 240 CLR 537. The issue considered by the court was whether the appellant could claim in negligence for the loss of a chance of a better medical outcome. This issue had not been considered by the High Court previously, the most relevant cases being Rufo v Hosking (2004) 61 NSWLR 678 and Gavalas v Singh (2001) 3 VLR 404. Claiming for a loss of chance in a personal injury action raises questions as to recognised damage and causation, and the members of the High Court considered both of these.

Insurance and the law of negligence : an influential or irrelevant persuader?

This article examines, from both within and outside the context of compulsory third party motor vehicle insurance, the different academic and judicial perspectives regarding the relevance of insurance to the imposition of negligence liability via the formulation of legal principle. In particular, the utility of insurance in setting the standard of care held owing by a learner driver to an instructor in Imbree v McNeilly is analysed and the implications of this High Court decision, in light of current jurisprudential argument and for other principles of negligence liability, namely claimant vulnerability, are considered. It concludes that ultimately one’s stance as to the relevance, or otherwise, of insurance to the development of the common law of negligence will be predominately influenced by normative views of torts’ function as an instrument of corrective or distributive justice.

Preventing injuries on a state-wide basis : researchers and parliamentary committees are partners in turning injury prevention and safety research into practice and policy

Context: Parliamentary committees established in Westminster parliaments, such as Queensland, provide a cross-party structure that enables them to recommend policy and legislative changes that may otherwise be difficult for one party to recommend. The overall parliamentary committee process tends to be more cooperative and less adversarial than the main chamber of parliament and, as a result, this process permits parliamentary committees to make recommendations more on the available research evidence and less on political or party considerations. Objectives: This paper considers the contributions that parliamentary committees in Queensland have made in the past in the areas of road safety, drug use as well as organ and tissue donation. The paper also discusses the importance of researchers actively engaging with parliamentary committees to ensure the best evidence based policy outcomes. Key messages: In the past, parliamentary committees have successfully facilitated important safety changes with many committee recommendations based on research results. In order to maximise the benefits of the parliamentary committee process it is essential that researchers inform committees about their work and become key stakeholders in the inquiry process. Researchers can keep committees informed by making submissions to their inquiries, responding to requests for information and appearing as witnesses at public hearings. Researchers should emphasise the key findings and implications of their research as well as considering the jurisdictional implications and political consequences. It is important that researchers understand the differences between lobbying and providing informed recommendations when interacting with committees. Discussion and conclusions: Parliamentary committees in Queensland have successfully assisted in the introduction of evidence based policy and legislation. In order to present best practice recommendations, committees rely on the evidence presented to them including the results of researchers. Actively engaging with parliamentary committees will help researchers to turn their results into practice with a corresponding decrease in injuries and fatalities. Developing an understanding of parliamentary committees, and the typical inquiry process used by these committees, will help researchers to present their research results in a manner that will encourage the adoption of their ideas by parliamentary committees, the presentation of these results as recommendations within the report and the subsequent enactment of the committee’s recommendations by the government.

State of the art and future challenges for information literacy research

This short paper focuses on strategic issues and important research questions.

Volatile properties of particles emitted by compressed natural gas and diesel buses during steady state and transient driving modes

Volatile properties of particle emissions from four compressed natural gas (CNG) and four diesel buses were investigated under steady state and transient driving modes on a chassis dynamometer. The exhaust was diluted utilising a full-flow continuous volume sampling system and passed through a thermodenuder at controlled temperature. Particle number concentration and size distribution were measured with a condensation particle counter and a scanning mobility particle sizer, respectively. We show that, while almost all the particles emitted by the CNG buses were in the nanoparticle size range, at least 85% and 98% were removed at 100ºC and 250ºC, respectively. Closer analysis of the volatility of particles emitted during transient cycles showed that volatilisation began at around 40°C with the majority occurring by 80°C. Particles produced during hard acceleration from rest exhibited lower volatility than that produced during other times of the cycle. Based on our results and the observation of ash deposits on the walls of the tailpipes, we suggest that these non-volatile particles were composed mostly of ash from lubricating oil. Heating the diesel bus emissions to 100ºC removed ultrafine particle numbers by 69% to 82% when a nucleation mode was present and just 18% when it was not.

Defences in medical negligence : to what extent has tort law reform in Australia limited the liability of health professionals?

Tort law reform has resulted in legislation being passed by all Australian jurisdictions in the past decade implementing the recommendations contained in the Ipp Report. The report was in response to a perceived crisis in medical indemnity insurance. The objective was to restrict and limit liability in negligence actions. This paper will consider to what extent the reforms have impacted on the liability of health professionals in medical negligence actions. After an analysis of the legislation, it will be argued in this paper that while there has been some limitation and restriction, courts have generally interpreted the civil liability reforms in compliance with the common law. It has been the impact of statutory limits on the assessment of damages through thresholds and caps which has limited the liability of health professionals in medical negligence actions.

State convergence and the effectiveness of time-memory-data tradeoffs

Various time-memory tradeoffs attacks for stream ciphers have been proposed over the years. However, the claimed success of these attacks assumes the initialisation process of the stream cipher is one-to-one. Some stream cipher proposals do not have a one-to-one initialisation process. In this paper, we examine the impact of this on the success of time-memory-data tradeoff attacks. Under the circumstances, some attacks are more successful than previously claimed while others are less. The conditions for both cases are established.