Over the past 40 years, there has been a strong focus on the development of mathematical models of angiogenesis, while developmental remodelling has received little such attention from the ...mathematical community. Sprouting angiogenesis can be seen as a very crude way of laying out a primitive vessel network (the raw material), while remodelling (understood as pruning of redundant vessels, diameter control, and the establishment of vessel identity and hierarchy) is the key to turning that primitive network into a functional network. This multiscale problem is of prime importance in the development of a functional vasculature. In addition, defective remodelling (either during developmental remodelling or due to a reactivation of the remodelling programme caused by an injury) is associated with a significant number of diseases. In this review, we discuss existing mathematical models of developmental remodelling and explore the important contributions that these models have made to the field of vascular development. These mathematical models are effectively used to investigate and predict vascular development and are able to reproduce experimentally observable results. Moreover, these models provide a useful means of hypothesis generation and can explain the underlying mechanisms driving the observed structural and functional network development. However, developmental vascular remodelling is still a relatively new area in mathematical biology, and many biological questions remain unanswered. In this review, we present the existing modelling paradigms and define the key challenges for the field.
Simulations of tissue-specific effects of primary acute viral infections like COVID-19 are essential for understanding disease outcomes and optimizing therapies. Such simulations need to support ...continuous updating in response to rapid advances in understanding of infection mechanisms, and parallel development of components by multiple groups. We present an open-source platform for multiscale spatiotemporal simulation of an epithelial tissue, viral infection, cellular immune response and tissue damage, specifically designed to be modular and extensible to support continuous updating and parallel development. The base simulation of a simplified patch of epithelial tissue and immune response exhibits distinct patterns of infection dynamics from widespread infection, to recurrence, to clearance. Slower viral internalization and faster immune-cell recruitment slow infection and promote containment. Because antiviral drugs can have side effects and show reduced clinical effectiveness when given later during infection, we studied the effects on progression of treatment potency and time-of-first treatment after infection. In simulations, even a low potency therapy with a drug which reduces the replication rate of viral RNA greatly decreases the total tissue damage and virus burden when given near the beginning of infection. Many combinations of dosage and treatment time lead to stochastic outcomes, with some simulation replicas showing clearance or control (treatment success), while others show rapid infection of all epithelial cells (treatment failure). Thus, while a high potency therapy usually is less effective when given later, treatments at late times are occasionally effective. We illustrate how to extend the platform to model specific virus types (e.g., hepatitis C) and add additional cellular mechanisms (tissue recovery and variable cell susceptibility to infection), using our software modules and publicly-available software repository.
Angiogenesis occurs in distinct phases: initial spouting is followed by remodelling in which endothelial cells (ECs) composing blood vessels rearrange by migrating against the direction of flow. ...Abnormal remodelling can result in vascular malformation. Such is the case in mutation of the Alk1 receptor within the mouse retina which disrupts flow-migration coupling, creating mixed populations of ECs polarised with/against flow which aggregate into arteriovenous malformations (AVMs). The lack of live imaging options
means that the collective EC dynamics that drive AVM and the consequences of mixed populations of polarity remain a mystery. Therefore, our goal is to present a novel agent-based model to provide theoretical insight into EC force transmission and collective dynamics during angiogenic remodelling. Force transmission between neighbouring agents consists of extrusive forces which maintain spacing and cohesive forces which maintain the collective. We performed migration simulations within uniformly polarised populations (against flow) and mixed polarity (with/against flow). Within uniformly polarised populations, extrusive forces stabilised the plexus by facilitating EC intercalation which ensures that cells remained evenly distributed. Excess cohesion disrupts intercalation, resulting in aggregations of cells and functional shunting. Excess cohesion between ECs prevents them from resolving diameter balances within the plexus, leading to prolonged flow reversals which exert a critical behaviour change within the system as they switch the direction of cell migration and traffic patterns at bifurcations. Introducing mixtures of cell polarity dramatically changed the role of extrusive forces within the system. At low extrusion, opposing ECs were able to move past each other; however, at high extrusion the pushing between cells resulted in migration speeds close to zero, forming traffic jams and disrupting migration. In our study, we produced vascular malformations and functional shunting with either excess cohesion between ECs or mixtures of cell polarity. At the centre of both these mechanisms are cell-cell adherens junctions, which are involved in flow sensing/polarity and must remodelling dynamically to allow rearrangements of cells during vascular patterning. Thus, our findings implicate junctional dysfunction as a new target in the treatment and prevention of vascular disease and AVMs.
In this paper we present and validate a simple adaptive surface remeshing technique to transfer history dependent variables from an old distorting mesh to a new mesh during finite element simulations ...of elastic surface deformation. This technique allows us to reduce the error arising from excessive mesh distortion whilst preserving information about the initial configuration of the mesh and the history dependent variables. The transfer technique presented here constructs the initial configuration of the new mesh by considering the distortion incurred by the elements of the old mesh and projecting backwards in time. Using this new initial configuration, the stress and strain over the new mesh can be easily calculated. After presenting the necessary steps to reconstruct the initial configuration, we show that this relatively simple transfer technique adds stability to finite element simulations and reduces the spatial error and the strain error across the domain. The novel transfer technique presented in this paper is easy to implement, released under an open source licence, and provides a simple strategy to add stability to simulations undergoing large deformations.
•Excessive mesh distortion during finite element models corrupts simulation results.•Remeshing is essential, however it is difficult to transfer the history-dependent variables to to the new mesh.•Here we present the development of a novel history-dependent remeshing method in which we transfer the history-dependent variables between meshes through a mapping of the initial configuration to the new mesh.•Our variable transfer technique is easy to understand, and easy to implement.•This technique sucessfully avoids the error associated with excessive element distortion.
In this paper, we present and validate a simple adaptive surface remeshing technique to transfer history dependent variables from an old distorting mesh to a new mesh during finite element ...simulations of elastic surface deformation. This technique allows us to reduce the error arising from excessive mesh distortion whilst preserving information about the initial configuration of the mesh and the history dependent variables. The transfer technique presented here constructs the initial configuration of the new mesh by considering the distortion incurred by the elements of the old mesh and projecting backward in time. Using this new initial configuration, the stress and strain over the new mesh can be easily calculated. After presenting the necessary steps to reconstruct the initial configuration, we show that this relatively simple transfer technique adds stability to finite element simulations and reduces the spatial error and the strain error across the domain. The novel transfer technique presented in this paper is easy to implement and provides a simple strategy to add stability to simulations undergoing large deformations.
COVID-19 has led to big changes in UK primary care, including rapid digitalisation, with unknown impact on migrant groups.
To understand the pandemic's impact on recently-arrived migrants and their ...access to primary health care, and implications for vaccine roll-out.
Qualitative study involving semi-structured interviews with primary care professionals (PCPs) and migrants in urban, suburban, and rural settings across England.
Sixty-four PCPs and administrative staff, and 17 recently-arrived migrants were recruited using purposive, convenience, and snowball sampling. In-depth, semi-structured interviews were conducted by telephone. Data were analysed iteratively, informed by thematic analysis.
PCPs and migrants concurred that digitalisation and virtual consultations have amplified existing inequalities in access to health care for many migrants, due to a lack of digital literacy and access to technology, compounded by language barriers. PCPs were concerned that virtual consultations resulted in difficulties building trust and risked missing safeguarding cues. Both PCPs and migrants highlighted challenges around registering and accessing health care due to physical closure of surgeries, as well as indirect discrimination, language and communication barriers, and a lack of access to targeted and tailored COVID-19 information or interventions. Migrants reported a range of specific beliefs, from acceptance to mistrust, around COVID-19 and potential COVID-19 vaccines, often influenced by misinformation. Innovative opportunities were suggested, including translated digital health advice using text templates and YouTube; these merit further exploration.
Pandemic-related changes to primary care delivery may become permanent; some migrant groups are at risk of digital exclusion and may need targeted additional support to access services. Solutions are needed to address vaccine hesitancy in marginalised groups to ensure equitable COVID-19 vaccine uptake.
Understanding why some migrants in Europe are at risk of underimmunisation and show lower vaccination uptake for routine and COVID-19 vaccines is critical if we are to address vaccination inequities ...and meet the goals of WHO's new Immunisation Agenda 2030. We did a systematic review (PROSPERO: CRD42020219214) exploring barriers and facilitators of vaccine uptake (categorised using the 5As taxonomy: access, awareness, affordability, acceptance, activation) and sociodemographic determinants of undervaccination among migrants in the EU and European Economic Area, the UK, and Switzerland. We searched MEDLINE, CINAHL, and PsycINFO from 2000 to 2021 for primary research, with no restrictions on language. 5259 data sources were screened, with 67 studies included from 16 countries, representing 366 529 migrants. We identified multiple access barriers—including language, literacy, and communication barriers, practical and legal barriers to accessing and delivering vaccination services, and service barriers such as lack of specific guidelines and knowledge of health-care professionals—for key vaccines including measles-mumps-rubella, diphtheria-pertussis-tetanus, human papillomavirus, influenza, polio, and COVID-19 vaccines. Acceptance barriers were mostly reported in eastern European and Muslim migrants for human papillomavirus, measles, and influenza vaccines. We identified 23 significant determinants of undervaccination in migrants (p<0·05), including African origin, recent migration, and being a refugee or asylum seeker. We did not identify a strong overall association with gender or age. Tailored vaccination messaging, community outreach, and behavioural nudges facilitated uptake. Migrants' barriers to accessing health care are already well documented, and this Review confirms their role in limiting vaccine uptake. These findings hold immediate relevance to strengthening vaccination programmes in high-income countries, including for COVID-19, and suggest that tailored, culturally sensitive, and evidence-informed strategies, unambiguous public health messaging, and health system strengthening are needed to address access and acceptance barriers to vaccination in migrants and create opportunities and pathways for offering catch-up vaccinations to migrants.
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