An Agent-Based Model of the IL-1 Stimulated Nuclear Factor-kappa B Signalling Pathway

The transcription factor NF-κB is a biological component that is central to the regulation of genes involved in the innate immune system. Dysregulation of the pathway is known to be involved in a large number of inflammatory diseases. Although considerable research has been performed since its discovery in 1986, we are still not in a position to control the signalling pathway, and thus limit the effects of NF-κB within promotion of inflammatory diseases. We believe that computational modelling and simulation of the NF-κB signalling pathway will complement wet-lab experimental approaches, and will facilitate a more comprehensive understanding of this example of a complex biological system. In this study, we have developed an agent-based model of the IL-1 stimulated NF-κB signalling pathway, which has been calibrated to wet- lab data at the single-cell level. Through rigorous software engineering, which followed a principled approach to design and development by adherence to the CoSMoS process, we believe our model provides an abstracted view of the underlying real-world system, and can be used in a predictive capacity through in silico experimentation. A novel approach to domain modelling has been presented, which uses linear and multivariate statistical techniques to complement the Unified Modelling Language. Furthermore, in silico experimentation with the newly developed agent-based model, has confirmed the robust yet fragile nature of the signalling pathway. We have discovered that the pathway is robust to perturbations of cell membrane receptor component number, intermediate component number, and the temporal lag between cell membrane receptor activation and subsequent activation of IKK. Conversely however, in silico experimentation predicts that the pathway is sensitive to changes in the ratio of free IκBα to NF-κB, and fragile to basal dissociation of NF-κB-IκBα outside of a narrow range of probabilities

Lessons learned on development and application of agent-based models of complex dynamical systems

The field of agent-based modelling (ABM) has gained a significant following in recent years, and it is often marketed as an excellent introduction to modelling for the novice modeller or non-programmer. The typical objective of developing an agent-based model is to either increase our mechanistic understanding of a real-world system, or to predict how the dynamics of the real-world system are likely to be affected by changes to internal or external factors. Although there are some excellent ABMs that have been used in a predictive capacity across a number of domains, we believe that the promotion of ABM as an ‘accessible to all’ approach, could potentially lead to models being published that are flawed and therefore generate inaccurate predictions of real-world systems. The purpose of this article is to use our experiences in modelling complex dynamical systems, to reinforce the view that agent-based models can be useful for answering questions of the real-world domain through predictive modelling, but also to emphasise that all modellers, expert and novice alike, must make a concerted effort to adopt robust methods and techniques for constructing, validating and analysing their models, if the result is to be meaningful and grounded in the system of interest

Rethinking gamete donor care:a satisfaction survey of egg and sperm donors in the UK

Objective Despite poor clinic communication and staff treatment being reported by donors, high rates of overall satisfaction are still reported in surveys. This study will evaluate the importance of communication and interaction between donors and fertility clinic staff in gamete donor care. Methods We report on 120 egg and sperm donors’ responses to a UK-wide online satisfaction survey. The survey focused on donors’ interactions with fertility clinic staff pre-, during, and post- donation. Basic cross-tabulation was performed on the data using online survey software. Textual data was read and extracts identified, which illustrated and expanded on the findings from the numerical data. Diagrammatic modeling was also utilised to analyse the textual data, with particular focus to relationships between the donors and clinic staff, the main activities within the gamete donation process, and how these activities may affect donor satisfaction with the gamete donation process. Results Donors expressed concern for the infertile couple and the resulting child; conveyed frustration at not receiving information on the expenses they could claim; felt lost in the system regarding the ease of making clinic appointments, and once made they were routinely not seen on time for these appointments. Donors also negatively commented on aftercare, the location and condition of the donation room, and information on contraception. In addition, Ovarian Hyperstimulation Syndrome was frequently reported, with these egg donors believing that clinic staff were not concerned with their physical or emotional well-being, but were instead disproportionately focused on extracting the eggs. Conclusions The multifaceted notion of donors highlights the complexity inherent to the gamete donation process, which comprises various aspects of uncertainty in the donation system, and ambiguity in the donation process. Categorising donors as Altruist, Customer, and Patient, conveys the particular importance of staff communication and treatment in donor care. These categories are not mutually exclusive however, in that an individual donor may experience more than one of these perspectives during the course of their gamete donation journey. Finally, there were a number of exemplar cases, where donors reported high satisfaction throughout, and these correlated with them being given a single point of contact at the clinic. Subject to resource constraints, we suggest that this practice should be implemented throughout clinics in the UK, so that donors have access to dedicated clinic staff who not only support them emotionally and physically throughout the gamete donation process, but also ensure that communication is open, clear, timely, and consistent

Interprofessional spanning and maintaining boundaries when supporting potential embryo donors to stem cell research

When patients undergo fertility treatment, it is likely that a surplus of embryos will be created. The existence of these surplus embryos creates responsibilities for the clinics where they are stored and for the people who own them. Since 2001, the owners of the surplus embryos in the UK have the option to donate them to be used in stem cell research (SCR). This development has generated a new population - potential embryo donors to SCR – who have unique support needs as they are neither fertility patients nor donors. However, little is known how lay and professional stakeholders associated with fertility treatment and SCR have conceptualised the support needs of potential embryo donors to SCR or have responded to the additional task once the option became available. In this paper, we draw on Gieryn’s concept of boundary-work to explore how the emergence of donating embryos to SCR has provided opportunities for embryologists, counsellors and scientists to shift, adapt or confirm their roles, knowledge base and areas of expertise. We present a thematic analysis of 21 in-depth, semi-structured interviews conducted between September 2006 and January 2007 with UK lay and professional stakeholders associated with fertility treatment, and SCR. We conclude with reflections on the implications this boundary-work has for those contemplating donating embryos to SCR, and the care they receive when making their decision. Such insights are pertinent given the current policy and practice discussions led by the National Donation Strategy Group to improve the care of donors in the UK

Towards a platform model of the IL-1 stimulated NF-kB signalling pathway using communicating stream X-machines

The Nuclear Factor-kappa B (NF-κB) signalling pathway is one of the key signalling pathways involved in the control and regulation of the immune system [3]. Activation of the NF-κB transcription factor is a tightly regulated event, with NF-κB normally sequestered in the cytosol of non-stimulated cells. Following activation of a cell membrane receptor and propagation of the signal via intracellular signalling to the IκB Kinase (IKK), phosphorylation-induced degradation of IκB inhibitors occurs to facilitate the release of NF-κB and its translocation to the nucleus. Dysregulation of the pathway is known to be involved in a large number of inflammatory diseases. Although considerable research has been performed since its discovery in 1986, we are still not in a position to control the signalling pathway, and thus limit the effects of NF-κB within promotion of inflammatory diseases. Through adherence to the CoSMoS framework, we are developing a computational model of the IL-1 stimulated NF-κB intracellular signalling pathway, to assist in promoting our understanding of the mechanistic behaviours within the signalling network, and therefore identify potential targets for therapeutic interventions. We have previously developed a separate domain model [4, 5] as advocated by the CoSMoS framework, which captures the essential processes and entities of the system under study using; in particular, the emergent behaviour, at an appropriate level of abstraction using a mixture of cartoon and UML diagrams, along with statistical techniques to define the temporal-spatial dynamics

Earlier cancer diagnosis in primary care: a feasibility economic analysis of ThinkCancer!

BackgroundUK cancer survival rates are much lower compared with other high-income countries. In primary care, there are opportunities for GPs and other healthcare professionals to act more quickly in response to presented symptoms that might represent cancer. ThinkCancer! is a complex behaviour change intervention aimed at primary care practice teams to improve the timely diagnosis of cancer.AimTo explore the costs of delivering the ThinkCancer! intervention to expedite cancer diagnosis in primary care.Design & settingFeasibility economic analysis using a micro-costing approach, which was undertaken in 19 general practices in Wales, UK.MethodFrom an NHS perspective, micro-costing methodology was used to determine whether it was feasible to gather sufficient economic data to cost the ThinkCancer!InterventionOwing to the COVID-19 pandemic, ThinkCancer! was mainly delivered remotely online in a digital format. Budget impact analysis (BIA) and sensitivity analysis were conducted to explore the costs of face-to-face delivery of the ThinkCancer! intervention as intended pre-COVID-19.ResultsThe total costs of delivering the ThinkCancer! intervention across 19 general practices in Wales was £25 030, with an average cost per practice of £1317 (standard deviation [SD]: 578.2). Findings from the BIA indicated a total cost of £34 630 for face-to-face delivery.ConclusionData collection methods were successful in gathering sufficient health economics data to cost the ThinkCancer!InterventionResults of this feasibility study will be used to inform a future definitive economic evaluation alongside a pragmatic randomised controlled trial (RCT)

Protocol for a feasibility study incorporating a randomised pilot trial with an embedded process evaluation and feasibility economic analysis of ThinkCancer!: a primary care intervention to expedite cancer diagnosis in Wales

Abstract Background Compared to the rest of Europe, the UK has relatively poor cancer outcomes, with late diagnosis and a slow referral process being major contributors. General practitioners (GPs) are often faced with patients presenting with a multitude of non-specific symptoms that could be cancer. Safety netting can be used to manage diagnostic uncertainty by ensuring patients with vague symptoms are appropriately monitored, which is now even more crucial due to the ongoing COVID-19 pandemic and its major impact on cancer referrals. The ThinkCancer! workshop is an educational behaviour change intervention aimed at the whole general practice team, designed to improve primary care approaches to ensure timely diagnosis of cancer. The workshop will consist of teaching and awareness sessions, the appointment of a Safety Netting Champion and the development of a bespoke Safety Netting Plan and has been adapted so it can be delivered remotely. This study aims to assess the feasibility of the ThinkCancer! intervention for a future definitive randomised controlled trial. Methods The ThinkCancer! study is a randomised, multisite feasibility trial, with an embedded process evaluation and feasibility economic analysis. Twenty-three to 30 general practices will be recruited across Wales, randomised in a ratio of 2:1 of intervention versus control who will follow usual care. The workshop will be delivered by a GP educator and will be adapted iteratively throughout the trial period. Baseline practice characteristics will be collected via questionnaire. We will also collect primary care intervals (PCI), 2-week wait (2WW) referral rates, conversion rates and detection rates at baseline and 6 months post-randomisation. Participant feedback, researcher reflections and economic costings will be collected following each workshop. A process evaluation will assess implementation using an adapted Normalisation Measure Development (NoMAD) questionnaire and qualitative interviews. An economic feasibility analysis will inform a future economic evaluation. Discussion This study will allow us to test and further develop a novel evidenced-based complex intervention aimed at general practice teams to expedite the diagnosis of cancer in primary care. The results from this study will inform the future design of a full-scale definitive phase III trial. Trial registration ClinicalTrials.gov NCT04823559. </jats:sec

Report Card grades on the physical activity of children and youth comparing 30 very high Human Development Index countries

Background: To better understand the childhood physical inactivity crisis, Report Cards on physical activity of children and youth were prepared concurrently in 30 very high Human Development Index countries. The aim of this article was to present, describe, and compare the findings from these Report Cards. Methods: The Report Cards were developed using a harmonized process for data gathering, assessing, and assigning grades to 10 common physical activity indicators. Descriptive statistics were calculated after converting letter grades to interval variables, and correlational analyses between the 10 common indicators were performed using Spearman's rank correlation coefficients. Results: A matrix of 300 grades was obtained with substantial variations within and between countries. Low grades were observed for behavioral indicators, and higher grades were observed for sources of influence indicators, indicating a disconnect between supports and desired behaviors. Conclusion: This analysis summarizes the level and context of the physical activity of children and youth among very high Human Development Index countries, and provides additional evidence that the situation regarding physical activity in children and youth is very concerning. Unless a major shift to a more active lifestyle happens soon, a high rate of noncommunicable diseases can be anticipated when this generation of children reaches adulthood.</p