Long-Term Spatiotemporal Changes in Endemic Threshold Populations in England and Wales – A Multi-Disease Study

Metapopulation dynamics play a critical role in driving endemic persistence and transmission of childhood infections. The endemic threshold is defined as the minimum population size required to sustain a continuous chain of infection transmission. The concept is fundamental to the implementation of effective vaccine-based disease control programmes. Vaccination serves to increase endemic threshold population size, promoting disease fadeout and eventual elimination of infection. To date, empirical geographical investigations of endemic threshold populations have tended to focus on isolated populations in island communities. Few studies have examined endemic threshold dynamics in ‘mainland’ regional populations with divergent spatial structures and varying levels of connectivity between subpopulations. This thesis presents a geographical analysis of spatiotemporal changes in endemic threshold populations for three childhood infections (measles, pertussis and scarlet fever) in two regional metapopulations of England and Wales: Lancashire and South Wales. Drawing upon weekly disease records of the Registrar-General of England and Wales over a 30-year period (January 1940–December 1969), empirical regression techniques were used to estimate the endemic threshold populations for childhood infections in the two study regions. Hotspot and survival analyses were performed to compare disease fadeout duration and probability for both regions in the pre-vaccine and vaccine eras, respectively. Endemic-epidemic modelling was undertaken to identify and analyse potential drivers of disease persistence. The findings reveal strong regional differences in estimates of endemic threshold populations over time and space for all three childhood infections. Regional differences in endemic threshold populations reflect significant regional variations in spatial connectivity, population dispersion and level of geographical isolation. Significant growth in fadeout duration was observed in the vaccine era for pertussis non-hotspots in both regions, consistent with geographical synchronisation of epidemic activity

Long-Term Spatiotemporal Changes in Endemic Threshold Populations in England and Wales – A Multi-Disease Study

Metapopulation dynamics play a critical role in driving endemic persistence and transmission of childhood infections. The endemic threshold is defined as the minimum population size required to sustain a continuous chain of infection transmission. The concept is fundamental to the implementation of effective vaccine-based disease control programmes. Vaccination serves to increase endemic threshold population size, promoting disease fadeout and eventual elimination of infection. To date, empirical geographical investigations of endemic threshold populations have tended to focus on isolated populations in island communities. Few studies have examined endemic threshold dynamics in ‘mainland’ regional populations with divergent spatial structures and varying levels of connectivity between subpopulations. This thesis presents a geographical analysis of spatiotemporal changes in endemic threshold populations for three childhood infections (measles, pertussis and scarlet fever) in two regional metapopulations of England and Wales: Lancashire and South Wales. Drawing upon weekly disease records of the Registrar-General of England and Wales over a 30-year period (January 1940–December 1969), empirical regression techniques were used to estimate the endemic threshold populations for childhood infections in the two study regions. Hotspot and survival analyses were performed to compare disease fadeout duration and probability for both regions in the pre-vaccine and vaccine eras, respectively. Endemic-epidemic modelling was undertaken to identify and analyse potential drivers of disease persistence. The findings reveal strong regional differences in estimates of endemic threshold populations over time and space for all three childhood infections. Regional differences in endemic threshold populations reflect significant regional variations in spatial connectivity, population dispersion and level of geographical isolation. Significant growth in fadeout duration was observed in the vaccine era for pertussis non-hotspots in both regions, consistent with geographical synchronisation of epidemic activity

Bystander effects and their implications for clinical radiation therapy : insights from multiscale in silico experiments

GGP and MAJC thank University of Dundee, where this research was carried out. The authors gratefully acknowledge the support of the ERC Advanced Investigator Grant 227619, M5CGS - From Mutations to Metastases: Multiscale Mathematical Modelling of Cancer Growth and Spread. AJM Acknowledges support from EU BIOMICS Project DG-CNECT Contract 318202.Radiotherapy is a commonly used treatment for cancer and is usually given in varying doses. At low radiation doses relatively few cells die as a direct response to radiation but secondary radiation effects, such as DNA mutation or bystander phenomena, may affect many cells. Consequently it is at low radiation levels where an understanding of bystander effects is essential in designing novel therapies with superior clinical outcomes. In this article, we use a hybrid multiscale mathematical model to study the direct effects of radiation as well as radiation-induced bystander effects on both tumour cells and normal cells. We show that bystander responses play a major role in mediating radiation damage to cells at low-doses of radiotherapy, doing more damage than that due to direct radiation. The survival curves derived from our computational simulations showed an area of hyper-radiosensitivity at low-doses that are not obtained using a traditional radiobiological model.PostprintPeer reviewe

Long-Term Changes in Endemic Threshold Populations for Pertussis in England and Wales: A Spatiotemporal Analysis of Lancashire and South Wales, 1940-69

Metapopulation dynamics play a critical role in driving endemic persistence and transmission of childhood infections. The endemic threshold concept, also referred to as critical community size (CCS), is a key example and is defined as the minimumpopulation size required to sustain a continuous chain of infection transmission. The concept is fundamental to the implementation of effective vaccine-based disease control programmes. Vaccination serves to increase endemic threshold population size, promoting disease fadeout and eventual elimination of infection. To date, empirical investigations of the relationship between vaccination and endemic threshold population size have tended to focus on isolated populations in island communities. Very few studies have examined endemic threshold dynamics in ‘mainland’ regional populations with complex hierarchical spatial structures and varying levels of connectivity between subpopulations. The present paper provides the first spatially explicit analysis of the temporal changes in endemic threshold populations for one vaccine-preventable childhood infection (pertussis) in two dynamic regions of England and Wales: Lancashire and South Wales. Drawing upon weekly disease records of the Registrar-General of England and Wales over a 30-year period (January 1940–December 1969) regression techniques were used to estimate the endemic threshold size for pertussis in the two study regions. Survival analyses were performed to compare disease fadeout duration and probability for both regions in the pre-vaccine and vaccine eras, respectively. Our findings reveal the introduction of mass vaccination led to a considerable increase in threshold size for both Lancashire (~387,333) and South Wales (~1,460,667). Significant growth in fadeout duration was observed in the vaccine era for pertussis non-hotspots in both regions, consistent with geographical synchronisation of epidemic activity. Regional differences in endemic threshold populations reflect significant regional variations inspatial connectivity, population dispersion and level of geographical isolation

Barriers and facilitators to smoking cessation in a cancer context: A qualitative study of patient, family and professional views

Background  Continued smoking after cancer adversely affects quality of life and survival, but one fifth of cancer survivors still smoke. Despite its demands, cancer presents an opportunity for positive behaviour change. Smoking often occurs in social groups, therefore interventions which target families and individuals may be more successful. This qualitative study explored patients, family members and health professionals’ views and experiences of smoking and smoking cessation after cancer, in order to inform future interventions.  Methods  In-depth qualitative interviews (n=67) with 29 patients, 14 family members and 24 health professionals. Data were analysed using the ‘Framework’ method.  Results  Few patients and family members had used National Health Service (NHS) smoking cessation services and more than half still smoked. Most recalled little ‘smoking-related’ discussion with clinicians but were receptive to talking openly. Clinicians revealed several barriers to discussion. Participants’ continued smoking was explained by the stress of diagnosis; desire to maintain personal control; and lack of connection between smoking, cancer and health.  Conclusions  A range of barriers to smoking cessation exist for patients and family members. These are insufficiently assessed and considered by clinicians. Interventions must be more effectively integrated into routine practice

Do Multidisciplinary Team (MDT) processes influence survival in patients with colorectal cancer? A population-based experience

BACKGROUND: MDT (multidisciplinary team) meetings are considered an essential component of care for patients with cancer. However there is remarkably little direct evidence that such meetings improve outcomes. We assessed whether or not MDT (multidisciplinary team) processes influenced survival in a cohort of patients with colorectal cancer. METHODS: Observational study of a population-based cohort of 586 consecutive patients with colorectal cancer diagnosed in Tayside (Scotland) during 2006 and 2007. RESULTS: Recommendations from MDT meetings were implemented in 411/586 (70.1 %) of patients, the MDT+ group. The remaining175/586 (29.9 %) were either never discussed at an MDT, or recommendations were not implemented, MDT- group. The 5-year cause-specific survival (CSS) rates were 63.1 % (MDT+) and 48.2 % (MDT-), p < 0.0001. In analysis confined to patients who survived >6 weeks after diagnosis, the rates were 63.2 % (MDT+) and 57.7 % (MDT-), p = 0.064. The adjusted hazard rate (HR) for death from colorectal cancer was 0.73 (0.53 to 1.00, p = 0.047) in the MDT+ group compared to the MDT- group, in patients surviving >6 weeks the adjusted HR was 1.00 (0.70 to 1.42, p = 0.987). Any benefit from the MDT process was largely confined to patients with advanced disease: adjusted HR ((early)) 1.32 (0.69 to 2.49, p = 0.401); adjusted HR((advanced)) 0.65 (0.45 to 0.96, p = 0.031). CONCLUSIONS: Adequate MDT processes are associated with improved survival for patients with colorectal cancer. However, some of this effect may be more apparent than real – simply reflecting selection bias. The MDT process predominantly benefits the 40 % of patients who present with advanced disease and conveys little demonstrable advantage to patients with early tumours. These results call into question the current belief that all new patients with colorectal cancer should be discussed at an MDT meeting

A National Network of Safe Havens:A Scottish Perspective

For over a decade, Scotland has implemented and operationalized a system of Safe Havens, which provides secure analytics platforms for researchers to access linked, deidentified electronic health records (EHRs) while managing the risk of unauthorized reidentification. In this paper, a perspective is provided on the state-of-the-art Scottish Safe Haven network, including its evolution, to define the key activities required to scale the Scottish Safe Haven network’s capability to facilitate research and health care improvement initiatives. A set of processes related to EHR data and their delivery in Scotland have been discussed. An interview with each Safe Haven was conducted to understand their services in detail, as well as their commonalities. The results show how Safe Havens in Scotland have protected privacy while facilitating the reuse of the EHR data. This study provides a common definition of a Safe Haven and promotes a consistent understanding among the Scottish Safe Haven network and the clinical and academic research community. We conclude by identifying areas where efficiencies across the network can be made to meet the needs of population-level studies at scale

Stimulation of Chitin Synthesis Rescues Candida albicans from Echinocandins

Echinocandins are a new generation of novel antifungal agent that inhibit cell wall β(1,3)-glucan synthesis and are normally cidal for the human pathogen Candida albicans. Treatment of C. albicans with low levels of echinocandins stimulated chitin synthase (CHS) gene expression, increased Chs activity, elevated chitin content and reduced efficacy of these drugs. Elevation of chitin synthesis was mediated via the PKC, HOG, and Ca2+-calcineurin signalling pathways. Stimulation of Chs2p and Chs8p by activators of these pathways enabled cells to survive otherwise lethal concentrations of echinocandins, even in the absence of Chs3p and the normally essential Chs1p, which synthesize the chitinous septal ring and primary septum of the fungus. Under such conditions, a novel proximally offset septum was synthesized that restored the capacity for cell division, sustained the viability of the cell, and abrogated morphological and growth defects associated with echinocandin treatment and the chs mutations. These findings anticipate potential resistance mechanisms to echinocandins. However, echinocandins and chitin synthase inhibitors synergized strongly, highlighting the potential for combination therapies with greatly enhanced cidal activity

Simple direct formation of self-assembled N-heterocyclic carbene monolayers on gold and their application in biosensing

CRL acknowledges the Engineering and Physical Sciences Research Council (UK) for the funding of his PhD studentship (EP/M506631).The formation of organic films on gold employing N-heterocyclic carbenes (NHCs) has been previously shown to be a useful strategy for generating stable organic films. However, NHCs or NHC precursors typically require inert atmosphere and harsh conditions for their generation and use. Herein we describe the use of benzimidazolium hydrogen carbonates as bench stable solid precursors for the preparation of NHC films in solution or by vapour-phase deposition from the solid state. The ability to prepare these films by vapour-phase deposition permitted the analysis of the films by a variety of surface science techniques, resulting in the first measurement of NHC desorption energy (158±10 kJ mol−1) and confirmation that the NHC sits upright on the surface. The use of these films in surface plasmon resonance-type biosensing is described, where they provide specific advantages versus traditional thiol-based films.Publisher PDFPeer reviewe