An in silico modeling approach to understanding the dynamics of the post-burn immune response.

Introduction: Burns are characterized by a massive and prolonged acute inflammation, which persists for up to months after the initial trauma. Due to the complexity of the inflammatory process, Predicting the dynamics of wound healing process can be challenging for burn injuries. The aim of this study was to develop simulation models for the post-burn immune response based on (pre)clinical data. Methods: The simulation domain was separated into blood and tissue compartments. Each of these compartments contained solutes and cell agents. Solutes comprise pro-inflammatory cytokines, anti-inflammatory cytokines and inflammation triggering factors. The solutes diffuse around the domain based on their concentration profiles. The cells include mast cells, neutrophils, and macrophages, and were modeled as independent agents. The cells are motile and exhibit chemotaxis based on concentrations gradients of the solutes. In addition, the cells secrete various solutes that in turn alter the dynamics and responses of the burn wound system. Results: We developed an Glazier-Graner-Hogeweg method-based model (GGH) to capture the complexities associated with the dynamics of inflammation after burn injuries, including changes in cell counts and cytokine levels. Through simulations from day 0 - 4 post-burn, we successfully identified key factors influencing the acute inflammatory response, i.e., the initial number of endothelial cells, the chemotaxis threshold, and the level of chemoattractants. Conclusion: Our findings highlight the pivotal role of the initial endothelial cell count as a key parameter for intensity of inflammation and progression of acute inflammation, 0 - 4 days post-burn.

Protocol for analyzing emergence dynamics of diabetes with obesity using numerical continuation and bifurcation analysis.

Type 2 diabetes (T2D) is a multifactorial disease that slowly and inconspicuously progresses over years. Here, we present a protocol for analyzing slow progression dynamics of T2D with obesity. We describe steps for using software to exploit the differences between the timescales of the metabolic variables and using numerical continuation and bifurcation analysis. We detail procedures to analyze bi-stable system dynamics and identify the thresholds that separate healthy and diabetic states. For complete details on the use and execution of this protocol, please refer to Yildirim et al. (2023).1.

A data-driven computational model for obesity-driven diabetes onset and remission through weight loss.

Obesity is a major risk factor for the development of type 2 diabetes (T2D), where a sustained weight loss may result in T2D remission in individuals with obesity. To design effective and feasible intervention strategies to prevent or reverse T2D, it is imperative to study the progression of T2D and remission together. Unfortunately, this is not possible through experimental and observational studies. To address this issue, we introduce a data-driven computational model and use human data to investigate the progression of T2D with obesity and remission through weight loss on the same timeline. We identify thresholds for the emergence of T2D and necessary conditions for remission. We explain why remission is only possible within a window of opportunity and the way that window depends on the progression history of T2D, individual's metabolic state, and calorie restrictions. These findings can help to optimize therapeutic intervention strategies for T2D prevention or treatment.

Using network analysis to identify leverage points based on causal loop diagrams leads to false inference.

Network analysis is gaining momentum as an accepted practice to identify which factors in causal loop diagrams (CLDs)-mental models that graphically represent causal relationships between a system's factors-are most likely to shift system-level behaviour, known as leverage points. This application of network analysis, employed to quantitatively identify leverage points without having to use computational modelling approaches that translate CLDs into sets of mathematical equations, has however not been duly reflected upon. We evaluate whether using commonly applied network analysis metrics to identify leverage points is justified, focusing on betweenness- and closeness centrality. First, we assess whether the metrics identify the same leverage points based on CLDs that represent the same system but differ in inferred causal structure-finding that they provide unreliable results. Second, we consider conflicts between assumptions underlying the metrics and CLDs. We recognise six conflicts suggesting that the metrics are not equipped to take key information captured in CLDs into account. In conclusion, using betweenness- and closeness centrality to identify leverage points based on CLDs is at best premature and at worst incorrect-possibly causing erroneous identification of leverage points. This is problematic as, in current practice, the results can inform policy recommendations. Other quantitative or qualitative approaches that better correspond with the system dynamics perspective must be explored.

Embracing complexity in sepsis.

Sepsis involves the dynamic interplay between a pathogen, the host response, the failure of organ systems, medical interventions and a myriad of other factors. This together results in a complex, dynamic and dysregulated state that has remained ungovernable thus far. While it is generally accepted that sepsis is very complex indeed, the concepts, approaches and methods that are necessary to understand this complexity remain underappreciated. In this perspective we view sepsis through the lens of complexity theory. We describe the concepts that support viewing sepsis as a state of a highly complex, non-linear and spatio-dynamic system. We argue that methods from the field of complex systems are pivotal for a fuller understanding of sepsis, and we highlight the progress that has been made over the last decades in this respect. Still, despite these considerable advancements, methods like computational modelling and network-based analyses continue to fly under the general scientific radar. We discuss what barriers contribute to this disconnect, and what we can do to embrace complexity with regards to measurements, research approaches and clinical applications. Specifically, we advocate a focus on longitudinal, more continuous biological data collection in sepsis. Understanding the complexity of sepsis will require a huge multidisciplinary effort, in which computational approaches derived from complex systems science must be supported by, and integrated with, biological data. Such integration could finetune computational models, guide validation experiments, and identify key pathways that could be targeted to modulate the system to the benefit of the host. We offer an example for immunological predictive modelling, which may inform agile trials that could be adjusted throughout the trajectory of disease. Overall, we argue that we should expand our current mental frameworks of sepsis, and embrace nonlinear, system-based thinking in order to move the field forward.

New Approach to Privacy-Preserving Clinical Decision Support Systems for HIV Treatment.

BACKGROUND: HIV treatment prescription is a complex process. Clinical decision support systems (CDSS) are a category of health information technologies that can assist clinicians to choose optimal treatments based on clinical trials and expert knowledge. The usability of some CDSSs for HIV treatment would be significantly improved by using the knowledge obtained by treating other patients. This knowledge, however, is mainly contained in patient records, whose usage is restricted due to privacy and confidentiality constraints. METHODS: A treatment effectiveness measure, containing valuable information for HIV treatment prescription, was defined and a method to extract this measure from patient records was developed. This method uses an advanced cryptographic technology, known as secure Multiparty Computation (henceforth referred to as MPC), to preserve the privacy of the patient records and the confidentiality of the clinicians' decisions. FINDINGS: Our solution enables to compute an effectiveness measure of an HIV treatment, the average time-to-treatment-failure, while preserving privacy. Experimental results show that our solution, although at proof-of-concept stage, has good efficiency and provides a result to a query within 24 min for a dataset of realistic size. INTERPRETATION: This paper presents a novel and efficient approach HIV clinical decision support systems, that harnesses the potential and insights acquired from treatment data, while preserving the privacy of patient records and the confidentiality of clinician decisions.

Modelling the dynamic relationship between spread of infection and observed crowd movement patterns at large scale events.

Understanding how contact patterns arise from crowd movement is crucial for assessing the spread of infection at mass gathering events. Here we study contact patterns from Wi-Fi mobility data of large sports and entertainment events in the Johan Cruijff ArenA stadium in Amsterdam. We show that crowd movement behaviour at mass gathering events is not homogeneous in time, but naturally consists of alternating periods of movement and rest. As a result, contact duration distributions are heavy-tailed, an observation which is not explained by models assuming that pedestrian contacts are analogous to collisions in the kinetic gas model. We investigate the effect of heavy-tailed contact duration patterns on the spread of infection using various random walk models. We show how different types of intermittent movement behaviour interact with a time-dependent infection probability. Our results point to the existence of a crossover point where increased contact duration presents a higher level of transmission risk than increasing the number of contacts. In addition, we show that different types of intermittent movement behaviour give rise to different mass-action kinetics, but also show that neither one of two mass-action mechanisms uniquely describes events.

Refining the causal loop diagram: A tutorial for maximizing the contribution of domain expertise in computational system dynamics modeling.

Complexity science and systems thinking are increasingly recognized as relevant paradigms for studying systems where biology, psychology, and socioenvironmental factors interact. The application of systems thinking, however, often stops at developing a conceptual model that visualizes the mapping of causal links within a system, e.g., a causal loop diagram (CLD). While this is an important contribution in itself, it is imperative to subsequently formulate a computable version of a CLD in order to interpret the dynamics of the modeled system and simulate "what if" scenarios. We propose to realize this by deriving knowledge from experts' mental models in biopsychosocial domains. This article first describes the steps required for capturing expert knowledge in a CLD such that it may result in a computational system dynamics model (SDM). For this purpose, we introduce several annotations to the CLD that facilitate this intended conversion. This annotated CLD (aCLD) includes sources of evidence, intermediary variables, functional forms of causal links, and the distinction between uncertain and known-to-be-absent causal links. We propose an algorithm for developing an aCLD that includes these annotations. We then describe how to formulate an SDM based on the aCLD. The described steps for this conversion help identify, quantify, and potentially reduce sources of uncertainty and obtain confidence in the results of the SDM's simulations. We utilize a running example that illustrates each step of this conversion process. The systematic approach described in this article facilitates and advances the application of computational science methods to biopsychosocial systems. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

The Future of Burn Care From a Complexity Science Perspective.

Health care is undergoing a profound technological and digital transformation and has become increasingly complex. It is important for burns professionals and researchers to adapt to these developments which may require new ways of thinking and subsequent new strategies. As Einstein has put it: "We must learn to see the world anew." The relatively new scientific discipline "Complexity science" can give more direction to this and is the metaphorical open door that should not go unnoticed in view of the burn care of the future. Complexity science studies "why the whole is more than the sum of the parts." It studies how multiple separate components interact with each other and their environment and how these interactions lead to "behavior of the system." Biological systems are always part of smaller and larger systems and exhibit the behavior of adaptivity, hence the name complex adaptive systems. From the perspective of complexity science, a severe burn injury is an extreme disruption of the "human body system." But this disruption also applies to the systems at the organ and cellular levels. All these systems follow the principles of complex systems. Awareness of the scaling process at multilevel helps to understand and manage the complex situation when dealing with severe burn cases. This paper aims to create awareness of the concept of complexity and to demonstrate the value and possibilities of complexity science methods and tools for the future of burn care through examples from preclinical, clinical, and organizational perspectives in burn care.

Behavioural thermal regulation explains pedestrian path choices in hot urban environments.

Due to phenomena such as urban heat islands, outdoor thermal comfort of the cities' residents emerges as a growing concern. A major challenge for mega-cities in changing climate is the design of urban spaces that ensure and promote pedestrian thermal comfort. Understanding pedestrian behavioural adaptation to urban thermal environments is critically important to attain this goal. Current research in pedestrian behaviour lacks controlled experimentation, which limits the quantitative modelling of such complex behaviour. Combining well-controlled experiments with human participants and computational methods inspired by behavioural ecology and decision theory, we examine the effect of sun exposure on route choice in a tropical city. We find that the distance walked in the shade is discounted by a factor of 0.86 compared to the distance walked in the sun, and that shadows cast by buildings have a stronger effect than trees. The discounting effect is mathematically formalised and thus allows quantification of the behaviour that can be used in understanding pedestrian behaviour in changing urban climates. The results highlight the importance of assessment of climate through human responses to it and point the way forward to explore scenarios to mitigate pedestrian heat stress.

Scar formation from the perspective of complexity science: a new look at the biological system as a whole.

A burn wound is a complex systemic disease at multiple levels. Current knowledge of scar formation after burn injury has come from traditional biological and clinical studies. These are normally focused on just a small part of the entire process, which has limited our ability to sufficiently understand the underlying mechanisms and to predict systems behaviour. Scar formation after burn injury is a result of a complex biological system-wound healing. It is a part of a larger whole. In this self-organising system, many components form networks of interactions with each other. These networks of interactions are typically non-linear and change their states dynamically, responding to the environment and showing emergent long-term behaviour. How molecular and cellular data relate to clinical phenomena, especially regarding effective therapies of burn wounds to achieve minimal scarring, is difficult to unravel and comprehend. Complexity science can help bridge this gap by integrating small parts into a larger whole, such that relevant biological mechanisms and data are combined in a computational model to better understand the complexity of the entire biological system. A better understanding of the complex biological system of post-burn scar formation could bring research and treatment regimens to the next level. The aim of this review/position paper is to create more awareness of complexity in scar formation after burn injury by describing the basic principles of complexity science and its potential for burn care professionals.

How exposure to chronic stress contributes to the development of type 2 diabetes: A complexity science approach.

Chronic stress contributes to the onset of type 2 diabetes (T2D), yet the underlying etiological mechanisms are not fully understood. Responses to stress are influenced by earlier experiences, sex, emotions and cognition, and involve a complex network of neurotransmitters and hormones, that affect multiple biological systems. In addition, the systems activated by stress can be altered by behavioral, metabolic and environmental factors. The impact of stress on metabolic health can thus be considered an emergent process, involving different types of interactions between multiple variables, that are driven by non-linear dynamics at different spatiotemporal scales. To obtain a more comprehensive picture of the links between chronic stress and T2D, we followed a complexity science approach to build a causal loop diagram (CLD) connecting the various mediators and processes involved in stress responses relevant for T2D pathogenesis. This CLD could help develop novel computational models and formulate new hypotheses regarding disease etiology.

A review of mathematical modeling of addiction regarding both (neuro-) psychological processes and the social contagion perspectives.

Addiction is a complex biopsychosocial phenomenon, impacted by biological predispositions, psychological processes, and the social environment. Using mathematical and computational models that allow for surrogative reasoning may be a promising avenue for gaining a deeper understanding of this complex behavior. This paper reviews and classifies a selection of formal models of addiction focusing on the intra- and inter-individual dynamics, i.e., (neuro) psychological models and social models. We find that these modeling approaches to addiction are too disjoint and argue that in order to unravel the complexities of biopsychosocial processes of addiction, models should integrate intra- and inter-individual factors.

Inferring temporal dynamics from cross-sectional data using Langevin dynamics.

Cross-sectional studies are widely prevalent since they are more feasible to conduct compared with longitudinal studies. However, cross-sectional data lack the temporal information required to study the evolution of the underlying dynamics. This temporal information is essential to develop predictive computational models, which is the first step towards causal modelling. We propose a method for inferring computational models from cross-sectional data using Langevin dynamics. This method can be applied to any system where the data-points are influenced by equal forces and are in (local) equilibrium. The inferred model will be valid for the time span during which this set of forces remains unchanged. The result is a set of stochastic differential equations that capture the temporal dynamics, by assuming that groups of data-points are subject to the same free energy landscape and amount of noise. This is a 'baseline' method that initiates the development of computational models and can be iteratively enhanced through the inclusion of domain expert knowledge as demonstrated in our results. Our method shows significant predictive power when compared against two population-based longitudinal datasets. The proposed method can facilitate the use of cross-sectional datasets to obtain an initial estimate of the underlying dynamics of the respective systems.

Advancing urban mental health research: from complexity science to actionable targets for intervention.

Urbanisation and common mental disorders (CMDs; ie, depressive, anxiety, and substance use disorders) are increasing worldwide. In this Review, we discuss how urbanicity and risk of CMDs relate to each other and call for a complexity science approach to advance understanding of this interrelationship. We did an ecological analysis using data on urbanicity and CMD burden in 191 countries. We found a positive, non-linear relationship with a higher CMD prevalence in more urbanised countries, particularly for anxiety disorders. We also did a review of meta-analytic studies on the association between urban factors and CMD risk. We identified factors relating to the ambient, physical, and social urban environment and showed differences per diagnosis of CMDs. We argue that factors in the urban environment are likely to operate as a complex system and interact with each other and with individual city inhabitants (including their psychological and neurobiological characteristics) to shape mental health in an urban context. These interactions operate on various timescales and show feedback loop mechanisms, rendering system behaviour characterised by non-linearity that is hard to predict over time. We present a conceptual framework for future urban mental health research that uses a complexity science approach. We conclude by discussing how complexity science methodology (eg, network analyses, system-dynamic modelling, and agent-based modelling) could enable identification of actionable targets for treatment and policy, aimed at decreasing CMD burdens in an urban context.

A unifying model to estimate the effect of heat stress in the human innate immunity during physical activities.

Public health is threatened by climate change and extreme temperature events worldwide. Differences in health predispositions, access to cooling infrastructure and occupation raises an issue of heat-related health inequality in those vulnerable and disadvantaged demographic groups. To address these issues, a comprehensive understanding of the effect of elevated body temperatures on human biological systems and overall health is urgently needed. In this paper we look at the inner workings of the human innate immunity under exposure to heat stress induced through exposure to environment and physical exertion. We couple two experimentally validated computational models: the innate immune system and thermal regulation of the human body. We first study the dynamics of critical indicators of innate immunity as a function of human core temperature. Next, we identify environmental and physical activity regimes that lead to core temperature levels that can potentially compromise the performance of the human innate immunity. Finally, to take into account the response of innate immunity to various intensities of physical activities, we utilise the dynamic core temperatures generated by a thermal regulation model. We compare the dynamics of all key players of the innate immunity for a variety of stresses like running a marathon, doing construction work, and leisure walking at speed of 4 km/h, all in the setting of a hot and humid tropical climate such as present in Singapore. We find that exposure to moderate heat stress leading to core temperatures within the mild febrile range (37, 38][Formula: see text], nudges the innate immune system into activation and improves the efficiency of its response. Overheating corresponding to core temperatures beyond 38[Formula: see text], however, has detrimental effects on the performance of the innate immune system, as it further induces inflammation, which causes a series of reactions that may lead to the non-resolution of the ongoing inflammation. Among the three physical activities considered in our simulated scenarios (marathon, construction work, and walking), marathon induces the highest level of inflammation that challenges the innate immune response with its resolution. Our study advances the current state of research towards understanding the implications of heat exposure for such an essential physiological system as the innate immunity. Although we find that among considered physical activities, a marathon of 2 h and 46 min induces the highest level of inflammation, it must be noted that construction work done on a daily basis under the hot and humid tropical climate, can produce a continuous level of inflammation triggering moieties stretched at a longer timeline beating the negative effects of running a marathon. Our study demonstrates that the performance of the innate immune system can be severely compromised by the exposure to heat stress and physical exertion. This poses significant risks to health especially to those with limited access to cooling infrastructures. This is due in part to having low income, or having to work on outdoor settings, which is the case for construction workers. These risks to public health should be addressed through individual and population-level measures via behavioural adaptation and provision of the cooling infrastructure in outdoor environments.

Functional Structure in Production Networks.

Production networks are integral to economic dynamics, yet dis-aggregated network data on inter-firm trade is rarely collected and often proprietary. Here we situate company-level production networks within a wider space of networks that are different in nature, but similar in local connectivity structure. Through this lens, we study a regional and a national network of inferred trade relationships reconstructed from Dutch national economic statistics and re-interpret prior empirical findings. We find that company-level production networks have so-called functional structure, as previously identified in protein-protein interaction (PPI) networks. Functional networks are distinctive in their over-representation of closed squares, which we quantify using an existing measure called spectral bipartivity. Shared local connectivity structure lets us ferry insights between domains. PPI networks are shaped by complementarity, rather than homophily, and we use multi-layer directed configuration models to show that this principle explains the emergence of functional structure in production networks. Companies are especially similar to their close competitors, not to their trading partners. Our findings have practical implications for the analysis of production networks and give us precise terms for the local structural features that may be key to understanding their routine function, failure, and growth.

Social norms and obesity prevalence: From cohort to system dynamics models.

Group-level obesity can be seen as an emergent property of a complex system, consisting of feedback loops between individual body weight perception, individual weight-related behaviour and group-level social norms (a product of group-level 'normal' body mass index (BMI) and sociocultural 'ideal' BMI). As overweight becomes normal, the norm might be counteracting health awareness in shaping individual weight-related behaviour. System dynamics modelling facilitates understanding and simulating this system's emergent behaviour. We constructed six system dynamics models (SDMs) based on an expert-informed causal loop diagram and data from six sociocultural groups (Dutch, Moroccan and South-Asian Surinamese men and women). The SDMs served to explore the effect of three scenarios on group-level BMI: 'what if' weight-related behaviour were driven by (1) health awareness, (2) norms or (3) a combination of the two. Median BMI decreased approximately 50% and 30% less in scenarios 2 and 3, respectively, than in 1. In men, the drop in BMI was approximately two times larger in scenario 1 versus 3, whereas in women, the drop was approximately equal in these scenarios. This study indicates that the overweight norm in men holds group-level BMI close to overweight despite health awareness. Since norms are counteracting health awareness less strongly in women, other drivers of obesity must be more relevant.