Mathematical modelling of the potential determinants of foot-and-mouth disease virus-induced death of bovine epithelial cells

Foot-and-mouth disease virus (FMDV) is a highly infectious virus affecting cloven-hoofed animals. The most prominent of its clinical signs is the development of vesicular lesions on the feet and in or around the mouth, which are a consequence of extensive FMDV-induced epithelial cell death. Currently, there is no certain biological knowledge on why extensive epithelial cell death occurs in some FMDV-infected tissues, but not in others. Using the epithelial tissues of tongue and dorsal soft palate as examples of a tissue where lesions occur and one that does not visibly exhibit FMDV-induced cell death, this work aims to identify the potential drivers of epithelial cell death and survival. A partial differential equation (PDE) model informed by experimental data on epithelial structure, is used to test epithelium thickness and cell layer structure as potential determinants. A second PDE model investigates FMDV-interferon (IFN) dynamics and their impact on the levels of cell death and survival, while an experimental study is undertaken to provide data for model validation. The work carried out casts light on the important role of a variety of factors including FMDV replication, IFN production and release, and IFN antiviral action

Using Mathematical Modelling to Explore Hypotheses about the Role of Bovine Epithelium Structure in Foot-And-Mouth Disease Virus-Induced Cell Lysis.

Foot-and-mouth disease (FMD) is a highly contagious disease of cloven-hoofed animals. FMD virus (FMDV) shows a strong tropism for epithelial cells, and FMD is characterised by cell lysis and the development of vesicular lesions in certain epithelial tissues (for example, the tongue). By contrast, other epithelial tissues do not develop lesions, despite being sites of viral replication (for example, the dorsal soft palate). The reasons for this difference are poorly understood, but hypotheses are difficult to test experimentally. In order to identify the factors which drive cell lysis, and consequently determine the development of lesions, we developed a partial differential equation model of FMDV infection in bovine epithelial tissues and used it to explore a range of hypotheses about epithelium structure which could be driving differences in lytic behaviour observed in different tissues. Our results demonstrate that, based on current parameter estimates, epithelial tissue thickness and cell layer structure are unlikely to be determinants of FMDV-induced cell lysis. However, differences in receptor distribution or viral replication amongst cell layers could influence the development of lesions, but only if viral replication rates are much lower than current estimates.This work was funded by the Biotechnology and Biological Sciences Research Council (BBSRC) [grant code: BBS/E/I/00001397], http://www.bbsrc.ac.uk/home/home.aspx. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.This is the final version of the article. It first appeared from PLoS via http://dx.doi.org/10.1371/journal.pone.013857

COmparing Urolift and Standard Transurethral resection of prostate Ahead of Radiotherapy in men with urinary symptoms secondary to prostate enlargement in Southwest London and North Cumbria (CO-STAR): a study protocol for a randomised feasibility study

Introduction: Patients undergoing prostate radiotherapy with an enlarged prostate can have short-term and long-term urinary complications. Currently, transurethral resection of the prostate (TURP) is the mainstay surgical intervention for men with urinary symptoms due to an enlarged prostate prior to radiotherapy. UroLift (NeoTract, Pleasanton, CA, USA) is a recent minimally invasive alternative, widely used in benign disease but is untested in men with prostate cancer. // Methods and analysis: A multicentre, two-arm study designed in collaboration with a Patient Reference Group to assess the feasibility of randomising men with prostate cancer and coexisting urinary symptoms due to prostate enlargement to TURP or UroLift ahead of radiotherapy. 45 patients will be enrolled and randomised (1:1) using a computer-generated programme to TURP or UroLift. Recruitment and retention will be assessed over a 12 month period. Information on clinical outcomes, adverse events and costs will be collected. Clinical outcomes and patient reported outcome measures will be measured at baseline, 6 weeks postintervention and 3 months following radiotherapy. A further 12 in-depth interviews will be conducted with a subset of patients to assess acceptability using the Theoretical Framework of Acceptability. Descriptive analysis on all outcomes will be performed using Stata (StataCorp V.2021). // Ethics and dissemination: The trial has been approved by the Research Ethics Committee (REC) NHS Health Research Authority (HRA) and Health and Care Research Wales (HCRW). The results will be published in peer-reviewed journals, presented at national meetings and disseminated to patients via social media, charity and hospital websites. // Trial registration number: NCT05840549

Neurodevelopmental Impairment in Children After Group B Streptococcal Disease Worldwide: Systematic Review and Meta-analyses.

BACKGROUND: Survivors of infant group B streptococcal (GBS) disease are at risk of neurodevelopmental impairment (NDI), a burden not previously systematically quantified. This is the 10th of 11 articles estimating the burden of GBS disease. Here we aimed to estimate NDI in survivors of infant GBS disease. METHODS: We conducted systematic literature reviews (PubMed/Medline, Embase, Latin American and Caribbean Health Sciences Literature [LILACS], World Health Organization Library Information System [WHOLIS], and Scopus) and sought unpublished data on the risk of NDI after invasive GBS disease in infants <90 days of age. We did meta-analyses to derive pooled estimates of the percentage of infants with NDI following GBS meningitis. RESULTS: We identified 6127 studies, of which 18 met eligibility criteria, all from middle- or high-income contexts. All 18 studies followed up survivors of GBS meningitis; only 5 of these studies also followed up survivors of GBS sepsis and were too few to pool in a meta-analysis. Of meningitis survivors, 32% (95% CI, 25%-38%) had NDI at 18 months of follow-up, including 18% (95% CI, 13%-22%) with moderate to severe NDI. CONCLUSIONS: GBS meningitis is an important risk factor for moderate to severe NDI, affecting around 1 in 5 survivors. However, data are limited, and we were unable to estimate NDI after GBS sepsis. Comparability of studies is difficult due to methodological differences including variability in timing of clinical reviews and assessment tools. Follow-up of clinical cases and standardization of methods are essential to fully quantify the total burden of NDI associated with GBS disease, and inform program priorities

The role of Type I interferons in the pathogenesis of foot-and-mouth disease virus in cattle: A mathematical modelling analysis

Type I interferons (IFN) are the first line of immune response against infection. In this study, we explore the interaction between Type I IFN and foot-and-mouth disease virus (FMDV), focusing on the effect of this interaction on epithelial cell death. While several mathematical models have explored the interaction between interferon and viruses at a systemic level, with most of the work undertaken on influenza and hepatitis C, these cannot investigate why a virus such as FMDV causes extensive cell death in some epithelial tissues leading to the development of lesions, while other infected epithelial tissues exhibit negligible cell death. Our study shows how a model that includes epithelial tissue structure can explain the development of lesions in some tissues and their absence in others. Furthermore, we show how the site of viral entry in an epithelial tissue, the viral replication rate, IFN production, suppression of viral replication by IFN and IFN release by live cells, all have a major impact on results. </p

Simulation results for DSP and tongue over a 48 hour timescale.

<p>Epithelium surface used as the viral entry point for DSP and basement membrane as the viral entry point for tongue. (a), (b) Cellular space fraction, <i>S</i>_<i>c</i>, of DSP and tongue respectively. (c), (d) Intracellular viral load, <i>V</i>_<i>c</i><i>S</i>_<i>c</i>, of DSP and tongue respectively measured in PFU/cm. (e), (f) Extracellular viral load, <i>V</i>_<i>e</i><i>S</i>_<i>e</i>, of DSP and tongue respectively measured in PFU/cm. Green area at the bottom right hand corner of (e) indicates viral entry in DSP. Due to different scaling of (f), viral entry in tongue is not visible (bottom left hand corner). (g), (h) Intracellular resource, <i>K</i>, of DSP and tongue respectively, measured in cm⁻¹. (i), (j) Activator concentration, <i>E</i>, of DSP and tongue respectively.</p

Model parameters, their interpretation and ‘standard’ values used in the simulations.

<p>The values are either taken from the indicated source, measured as part of the study or estimated (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0138571#pone.0138571.s003" target="_blank">S3 Supplementary Information</a>).</p><p>Model parameters, their interpretation and ‘standard’ values used in the simulations.</p

Model variables.

<p>Model variables.</p

Extensive sensitivity analysis.

<p>LHS applied to the model with tested parameters ranging from 0.1 to 10 times their estimated values shows the consistency of results in predicting destruction of the cellular column. As parameters are varied, <i>S</i>_<i>c</i> in graph (a) of the DSP remains bounded below 1 × 10⁻⁶ and <i>V</i>_<i>c</i><i>S</i>_<i>c</i> in graph (c) below 4 × 10⁻⁷ PFU/cm, apart from at surface where <i>S</i>_<i>c</i> < 6 × 10⁻⁶ and <i>V</i>_<i>c</i><i>S</i>_<i>c</i> < 15 × 10⁻⁷ PFU/cm. In graph (b) of the tongue, <i>S</i>_<i>c</i> is bounded below 10⁻⁵ for most of the tissue, but closer to the granular layer <i>S</i>_<i>c</i> < 3 × 10⁻³. Similarly, in graph (d) <i>V</i>_<i>c</i><i>S</i>_<i>c</i> is bounded below 10⁻⁵ PFU/cm for most of the tissue, but closer to the granular layer <i>V</i>_<i>c</i><i>S</i>_<i>c</i> < 5 × 10⁻⁴ PFU/cm. The range of possible results is plotted in 5 percentile steps (shaded), from 100 replicates. Parameters tested: <i>K</i>_1/2, <i>μ</i>, <i>D</i>_<i>V</i>, <i>Q</i>_<i>V</i>, <i>V</i>₀, <i>m</i>₁, <i>m</i>₂, <i>m</i>₃.</p

Diagram of cattle head.

<p>Location of DSP (green arrow) and tongue (yellow arrows) bovine tissues. Lesions in tongue usually occur close to the tip (left-most yellow arrow).</p