Mathematical modelling of angiogenesis and vascular adaptation

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Mathematical modelling of vascular tumour growth and implications for therapy

In this chapter we briefly discuss the results of a mathematical model formulated in [22] that incorporates many processes associated with tumour growth. The deterministic model, a system of coupled non-linear partial differential equations, is a combination of two previous models that describe the tumour-host interactions in the initial stages of growth [11] and the tumour angiogenic process [6]. Combining these models enables us to investigate combination therapies that target different aspects of tumour growth. Numerical simulations show that the model captures both the avascular and vascular growth phases. Furthermore, we recover a number of characteristic features of vascular tumour growth such as the rate of growth of the tumour and invasion speed. We also show how our model can be used to investigate the effect of different anti-cancer therapies

Rule-based epidemic models

Rule-based models generalise reaction-based models with reagents that have internal state and may be bound together to form complexes, as in chemistry. An important class of system that would be intractable if expressed as reactions or ordinary differential equations can be efficiently simulated when expressed as rules. In this paper we demonstrate the utility of the rule-based approach for epidemiological modelling presenting a suite of seven models illustrating the spread of infectious disease under different scenarios: wearing masks, infection via fomites and prevention by hand-washing, the concept of vector-borne diseases, testing and contact tracing interventions, disease propagation within motif-structured populations with shared environments such as schools, and superspreading events. Rule-based models allow to combine transparent modelling approach with scalability and compositionality and therefore can facilitate the study of aspects of infectious disease propagation in a richer context than would otherwise be feasible

Evaluating the next generation of RSV intervention strategies: a mathematical modelling study and cost-effectiveness analysis

© 2020, The Author(s). Background: With a suite of promising new RSV prophylactics on the horizon, including long-acting monoclonal antibodies and new vaccines, it is likely that one or more of these will replace the current monoclonal Palivizumab programme. However, choosing the optimal intervention programme will require balancing the costs of the programmes with the health benefits accrued. Methods: To compare the next generation of RSV prophylactics, we integrated a novel transmission model with an economic analysis. We estimated key epidemiological parameters by calibrating the model to 7 years of historical epidemiological data using a Bayesian approach. We determined the cost-effective and affordable maximum purchase price for a comprehensive suite of intervention programmes. Findings: Our transmission model suggests that maternal protection of infants is seasonal, with 38–62% of infants born with protection against RSV. Our economic analysis found that to cost-effectively and affordably replace the current monoclonal antibody Palivizumab programme with long-acting monoclonal antibodies, the purchase price per dose would have to be less than around £4350 but dropping to £200 for vaccinated heightened risk infants or £90 for all infants. A seasonal maternal vaccine would have to be priced less than £85 to be cost-effective and affordable. While vaccinating pre-school and school-age children is likely not cost-effective relative to elderly vaccination programmes, vaccinating the elderly is not likely to be affordable. Conversely, vaccinating infants at 2 months seasonally would be cost-effective and affordable if priced less than £80. Conclusions: In a setting with seasonal RSV epidemiology, maternal protection conferred to newborns is also seasonal, an assumption not previously incorporated in transmission models of RSV. For a country with seasonal RSV dynamics like England, seasonal programmes rather than year-round intervention programmes are always optimal

Exploring overcrowding trends in an inner city emergence department in the UK before and during COVID-19 epidemic

BACKGROUND: The COVID-19 pandemic and the associated lockdowns have caused significant disruptions across society, including changes in the number of emergency department (ED) visits. This study aims to investigate the impact of three pre-COVID-19 interventions and of the COVID-19 UK-epidemic and the first UK national lockdown on overcrowding within University College London Hospital Emergency Department (UCLH ED). The three interventions: target the influx of patients at ED (A), reduce the pressure on in-patients' beds (B) and improve ED processes to improve the flow of patents out from ED (C). METHODS: We collected overcrowding metrics (daily attendances, the proportion of people leaving within 4 h of arrival (four-hours target) and the reduction in overall waiting time) during 01/04/2017-31/05/2020. We then performed three different analyses, considering three different timeframes. The first analysis used data 01/04/2017-31/12-2019 to calculate changes over a period of 6 months before and after the start of interventions A-C. The second and third analyses focused on evaluating the impact of the COVID-19 epidemic, comparing the first 10 months in 2020 and 2019, and of the first national lockdown (23/03/2020-31/05/2020). RESULTS: Pre-COVID-19 all interventions led to small reductions in waiting time (17%, p < 0.001 for A and C; an 9%, p = 0.322 for B) but also to a small decrease in the number of patients leaving within 4 h of arrival (6.6,7.4,6.2% respectively A-C,p < 0.001). In presence of the COVID-19 pandemic, attendance and waiting time were reduced (40% and 8%; p < 0.001), and the number of people leaving within 4 h of arrival was increased (6%,p < 0.001). During the first lockdown, there was 65% reduction in attendance, 22% reduction in waiting time and 8% increase in number of people leaving within 4 h of arrival (p < 0.001). Crucially, when the lockdown was lifted, there was an increase (6.5%,p < 0.001) in the percentage of people leaving within 4 h, together with a larger (12.5%,p < 0.001) decrease in waiting time. This occurred despite the increase of 49.6%(p < 0.001) in attendance after lockdown ended. CONCLUSIONS: The mixed results pre-COVID-19 (significant improvements in waiting time with some interventions but not improvement in the four-hours target), may be due to indirect impacts of these interventions, where increasing pressure on one part of the ED system affected other parts. This underlines the need for multifaceted interventions and a system-wide approach to improve the pathway of flow through the ED system is necessary. During 2020 and in presence of the COVID-19 epidemic, a shift in public behaviour with anxiety over attending hospitals and higher use of virtual consultations, led to notable drop in UCLH ED attendance and consequential curbing of overcrowding. Importantly, once the lockdown was lifted, although there was an increase in arrivals at UCLH ED, overcrowding metrics were reduced. Thus, the combination of shifted public behaviour and the restructuring changes during COVID-19 epidemic, maybe be able to curb future ED overcrowding, but longer timeframe analysis is required to confirm this

Repeatability of perfusion measurements in adult gliomas using pulsed and pseudo-continuous arterial spin labelling MRI

Objectives: To investigate the repeatability of perfusion measures in gliomas using pulsed- and pseudo-continuous-arterial spin labelling (PASL, PCASL) techniques, and evaluate different regions-of-interest (ROIs) for relative tumour blood flow (rTBF) normalisation. / Materials and methods: Repeatability of cerebral blood flow (CBF) was measured in the Contralateral Normal Appearing Hemisphere (CNAH) and in brain tumours (aTBF). rTBF was normalised using both large/small ROIs from the CNAH. Repeatability was evaluated with intra-class-correlation-coefficient (ICC), Within-Coefficient-of-Variation (WCoV) and Coefficient-of-Repeatability (CR). / Results: PASL and PCASL demonstrated high reliability (ICC > 0.9) for CNAH-CBF, aTBF and rTBF. PCASL demonstrated a more stable signal-to-noise ratio (SNR) with a lower WCoV of the SNR than that of PASL (10.9–42.5% vs. 12.3–29.2%). PASL and PCASL showed higher WCoV in aTBF and rTBF than in CNAH CBF in WM and GM but not in the caudate, and higher WCoV for rTBF than for aTBF when normalised using a small ROI (PASL 8.1% vs. 4.7%, PCASL 10.9% vs. 7.9%, respectively). The lowest CR was observed for rTBF normalised with a large ROI. / Discussion: PASL and PCASL showed similar repeatability for the assessment of perfusion parameters in patients with primary brain tumours as previous studies based on volunteers. Both methods displayed reasonable WCoV in the tumour area and CNAH. PCASL’s more stable SNR in small areas (caudate) is likely to be due to the longer post-labelling delays

Systematic review: Investigating the prognostic performance of four non‐invasive tests in alcohol‐related liver disease

BACKGROUND/AIMS: Mortality of Alcohol-related-Liver-Disease (ArLD) is increasing, and liver fibrosis stage is the best mortality predictor. Non-invasive-tests (NIT) are increasingly used to detect fibrosis, but their value as prognostic tests in chronic liver disease (CLD), and in particular in ArLD is less well recognized. We aimed to describe the prognostic performance of four widely used NITs (FIB4, ELF test, FibroScan and FibroTest) in ArLD. METHODS: Applying systematic-review methodology, four databases were searched from inception to May 2020. Inclusion/exclusion criteria were applied to search using MeSH terms and keywords. First and second reviewers independently screened results, extracted data and performed risk-of-bias assessment using Quality-In-Prognostic-Studies (QUIPS) tool. RESULTS: Searches produced 25,088 articles. After initial screening, 1,020 articles were reviewed independently by both reviewers. Eleven articles remained after screening for eligibility: one on ELF, four on FibroScan, four on FIB4, one on FIB4+FibroScan and one on FibroTest+FIB4. Area-Under-Receiving-Operator-Characteristics-curves (AUROCS) for outcome-prediction ranged from: 0.65-0.76 for FibroScan, 0.64-0.83 for FIB4, 0.69-0.79 for FibroTest and 0.72-0.85 for ELF. Studies scored low-moderate risk of bias for most domains, but high-risk in confounding/statistical reporting domains. The results were heterogeneous for outcomes and reporting, making pooling of data unfeasible. CONCLUSIONS: This systematic-review returned eleven papers, six of which were conference-abstracts and one unpublished manuscript. Whilst the heterogeneity of studies precluded direct comparisons of NITs, each NIT performed well in individual studies in predicting prognosis in ArLD (AUROCs >0.7 in each NIT category), and may add value to prognostication in clinical practice

The role of preoperative diffusion tensor imaging in predicting and improving functional outcome in pediatric patients undergoing epilepsy surgery: a systematic review

Objective: Diffusion tensor imaging (DTI) is a useful neuroimaging technique for surgical planning in adult patients. However, no systematic review has been conducted to determine its utility for pre-operative analysis and planning of Pediatric Epilepsy surgery. We sought to determine the benefit of pre-operative DTI in predicting and improving neurological functional outcome after epilepsy surgery in children with intractable epilepsy. Methods: A systematic review of articles in English using PubMed, EMBASE and Scopus databases, from inception to January 10, 2020 was conducted. All studies that used DTI as either predictor or direct influencer of functional neurological outcome (motor, sensory, language and/or visual) in pediatric epilepsy surgical candidates were included. Data extraction was performed by two blinded reviewers. Risk of bias of each study was determined using the QUADAS 2 Scoring System. Results: 13 studies were included (6 case reports/series, 5 retrospective cohorts, and 2 prospective cohorts) with a total of 229 patients. Seven studies reported motor outcome; three reported motor outcome prediction with a sensitivity and specificity ranging from 80 to 85.7 and 69.6 to 100%, respectively; four studies reported visual outcome. In general, the use of DTI was associated with a high degree of favorable neurological outcomes after epilepsy surgery. Conclusion: Multiple studies show that DTI helps to create a tailored plan that results in improved functional outcome. However, more studies are required in order to fully assess its utility in pediatric patients. This is a desirable field of study because DTI offers a non-invasive technique more suitable for children. Advances in knowledge: This systematic review analyses, exclusively, studies of pediatric patients with drug-resistant epilepsy and provides an update of the evidence regarding the role of DTI, as part of the pre-operative armamentarium, in improving post-surgical neurological sequels and its potential for outcome prediction

Uncovering unsuspected advanced liver fibrosis in patients referred to alcohol nurse specialists using the ELF test

BBackground and aims: Alcohol use disorders (AUD) cause 7.2% of UK hospital admissions/year. Most are not managed by hepatologists and liver disease may be missed. We used the Enhanced Liver Fibrosis (ELF) test to investigate prevalence and associations of occult advanced liver fibrosis in AUD patients not known to have liver fibrosis. / Methods: Liver fibrosis was assessed using ELF in prospective patients referred to the Royal Free Hospital Alcohol Specialist Nurse (November 2018–December 2019). Known cases of liver disease were excluded. Patient demographics, blood tests, imaging data and alcohol histories recorded. Advanced fibrosis was categorised as ELF ≥ 10.5. / Results: The study included 99 patients (69% male, mean age 53.1 ± 14.4) with median alcohol intake 140 units/week (IQR 80.9–280), and a mean duration of harmful drinking of 15 years (IQR 10–27.5). The commonest reason for admission was symptomatic alcohol withdrawal (36%). The median ELF score was 9.62, range 6.87–13.78. An ELF score ≥ 10.5 was recorded in 28/99 (29%) patients, of whom 28.6% had normal liver tests. Within previous 5-years, 76% had attended A&E without assessment of liver disease. The ELF score was not associated with recent alcohol intake (p = 0.081), or inflammation (p = 0.574). / Conclusion: Over a quarter of patients with AUD had previously undetected advanced liver fibrosis assessed by ELF testing. ELF was not associated with liver inflammation or recent alcohol intake. The majority had recent missed opportunities for investigating liver disease. We recommend clinicians use non-invasive tests to assess liver fibrosis in patients admitted to hospital with AUD