Ordered and deterministic cancer genome evolution after p53 loss.

Although p53 inactivation promotes genomic instability and presents a route to malignancy for more than half of all human cancers, the patterns through which heterogenous TP53 (encoding human p53) mutant genomes emerge and influence tumorigenesis remain poorly understood. Here, in a mouse model of pancreatic ductal adenocarcinoma that reports sporadic p53 loss of heterozygosity before cancer onset, we find that malignant properties enabled by p53 inactivation are acquired through a predictable pattern of genome evolution. Single-cell sequencing and in situ genotyping of cells from the point of p53 inactivation through progression to frank cancer reveal that this deterministic behaviour involves four sequential phases-Trp53 (encoding mouse p53) loss of heterozygosity, accumulation of deletions, genome doubling, and the emergence of gains and amplifications-each associated with specific histological stages across the premalignant and malignant spectrum.

Estimating the potential for global dissemination of pandemic pathogens using the global airline network and healthcare development indices.

Pandemics have the potential to incur significant health and economic impacts, and can reach a large number of countries from their origin within weeks. Early identification and containment of a newly emerged pandemic within the source country is key for minimising global impact. To identify a country's potential to control and contain a pathogen with pandemic potential, we compared the quality of a country's healthcare system against its global airline connectivity.

Dose-Response Modeling: Extrapolating From Experimental Data to Real-World Populations.

Dose-response modeling of biological agents has traditionally focused on describing laboratory-derived experimental data. Limited consideration has been given to understanding those factors that are controlled in a laboratory, but are likely to occur in real-world scenarios. In this study, a probabilistic framework is developed that extends Brookmeyer's competing-risks dose-response model to allow for variation in factors such as dose-dispersion, dose-deposition, and other within-host parameters.

Factors that influence treatment-seeking expectations in response to infectious intestinal disease: Original survey and multinomial regression.

Background: Infectious intestinal disease affects 25% of the UK population annually; 1 in 50 affected people consult health professionals about their illness.

Aims: We tested if anticipated treatment-seeking decisions for suspected infectious intestinal disease could be related to emotional response, tolerance of symptoms, or beliefs about the consequential benefits and harms of seeking treatment (or not).

Methods: Questionnaire survey of adults living in the UK with statistical analysis of responses.

The use and reporting of airline passenger data for infectious disease modelling: a systematic review.

BackgroundA variety of airline passenger data sources are used for modelling the international spread of infectious diseases. Questions exist regarding the suitability and validity of these sources.AimWe conducted a systematic review to identify the sources of airline passenger data used for these purposes and to assess validation of the data and reproducibility of the methodology.

Assessment of the Public Health Threats Posed by Vector-Borne Disease in the United Kingdom (UK).

In recent years, the known distribution of vector-borne diseases in Europe has changed, with much new information also available now on the status of vectors in the United Kingdom (UK). For example, in 2016, the UK reported their first detection of the non-native mosquito , which is a known vector for dengue and chikungunya virus. In 2010, , a principal mosquito vector for West Nile virus was detected in large numbers in the Thames estuary.

Forced migrants involved in setting the agenda and designing research to reduce impacts of complex emergencies: combining with patient and public involvement.

Plain English Summary: The UK's National Institute for Health Research (NIHR) Health Protection Research Unit in Emergency Preparedness and Response was asked to undertake research on how to reduce the impact of complex national/international emergencies on public health. How to focus the research and decide on priority topics was challenging, given the nature of complex events. Using a type of structured brain-storming, the researchers identified the ongoing UK, European and international migration crisis as both complex and worthy of deeper research.

Spatial methods for infectious disease outbreak investigations: systematic literature review.

Investigations of infectious disease outbreaks are conventionally framed in terms of person, time and place. Although geographic information systems have increased the range of tools available, spatial analyses are used relatively infrequently. We conducted a systematic review of published reports of outbreak investigations worldwide to estimate the prevalence of spatial methods, describe the techniques applied and explore their utility.

Enhanced West Nile virus surveillance in the North Kent marshes, UK.

Background: As part of efforts to more fully understand the potential risks posed by West Nile virus (WNV) and Usutu virus (USUV) in the UK, and following on from previous reports of a potential bridge vector Culex modestus for these viruses, at wetland sites in North Kent, mosquito surveillance was undertaken more widely across the Isle of Sheppey, the Hoo Peninsula and the Kent mainland.

Methods: Larval surveys were conducted and Mosquito Magnet® adult traps were used to collect adult mosquitoes. Pools of female mosquitoes were tested for the presence of WNV using real-time reverse transcriptase polymerase chain reaction.

Effect of climate change on vector-borne disease risk in the UK.

During the early part of the 21st century, an unprecedented change in the status of vector-borne disease in Europe has occurred. Invasive mosquitoes have become widely established across Europe, with subsequent transmission and outbreaks of dengue and chikungunya virus. Malaria has re-emerged in Greece, and West Nile virus has emerged throughout parts of eastern Europe.

Zebrafish reporter lines reveal in vivo signaling pathway activities involved in pancreatic cancer.

Pancreatic adenocarcinoma, one of the worst malignancies of the exocrine pancreas, is a solid tumor with increasing incidence and mortality in industrialized countries. This condition is usually driven by oncogenic KRAS point mutations and evolves into a highly aggressive metastatic carcinoma due to secondary gene mutations and unbalanced expression of genes involved in the specific signaling pathways. To examine in vivo the effects of KRAS(G12D) during pancreatic cancer progression and time correlation with cancer signaling pathway activities, we have generated a zebrafish model of pancreatic adenocarcinoma in which eGFP-KRAS(G12D) expression was specifically driven to the pancreatic tissue by using the GAL4/UAS conditional expression system.

Transmission dynamics of methicillin-resistant Staphylococcus aureus in a medical intensive care unit.

Intensive care units (ICUs) play an important role in the epidemiology of methicillin-resistant Staphyloccocus aureus (MRSA). Although successful interventions are multi-modal, the relative efficacy of single measures remains unknown. We developed a discrete time, individual-based, stochastic mathematical model calibrated on cross-transmission observed through prospective surveillance to explore the transmission dynamics of MRSA in a medical ICU.

Suitability of European climate for the Asian tiger mosquito Aedes albopictus: recent trends and future scenarios.

The Asian tiger mosquito (Aedes albopictus) is an invasive species that has the potential to transmit infectious diseases such as dengue and chikungunya fever. Using high-resolution observations and regional climate model scenarios for the future, we investigated the suitability of Europe for A. albopictus using both recent climate and future climate conditions.

Behaviour and control of influenza in institutions and small societies.

A literature review was undertaken to assess the impact of influenza in enclosed societies. The literature spanned 120 years and included both readily accessible material from online keyword searches, as well as more obscure paper documents found through in-depth library research. Enclosed societies have been predominantly found in some type of institution through this period although noticeable similarities exist in communities isolated by distance and geography.

Modeling inhalational tularemia: deliberate release and public health response.

Two epidemic modeling studies of inhalational tularemia were identified in the published literature, both demonstrating the high number of potential casualties that could result from a deliberate aerosolized release of the causative agent in an urban setting. However, neither study analyzed the natural history of inhalational tularemia nor modeled the relative merits of different mitigation strategies. We first analyzed publicly available human/primate experimental data and reports of naturally acquired inhalational tularemia cases to better understand the epidemiology of the disease.

An individual-based simulation of pneumonic plague transmission following an outbreak and the significance of intervention compliance.

The existence of primary pneumonic plague outbreaks raises concerns over the use of the causative bacteria as an aerosol-based bioweapon. We employed an individual-based model, parameterised using published personal contact information, to assess the severity of a deliberate release in a discrete community, under the influence of two proposed intervention strategies. We observed that the severity of the resulting epidemic is determined by the degree of personal compliance with said strategies, implying that prior preparedness activities are essential in order that public awareness and willingness to seek treatment is achieved quickly.

Re-assessment of mitigation strategies for deliberate releases of anthrax using a real-time outbreak characterization tool.

Responding rapidly and appropriately to a covert anthrax release is an important public health challenge. A methodology to assist the geographical targeting of such a response has recently been published; as have a number of independent studies that investigate mitigation strategies. Here, we review and combine some of these published techniques to more realistically assess how key aspects of the public health response might impact on the outcomes of a bioterrorist attack.

Modeling Legionnaires' disease outbreaks: estimating the timing of an aerosolized release using symptom-onset dates.

Background: Over the last 30 years, there have been a number of reported Legionnaires' disease outbreaks resulting from the release of causative organisms from aerosol-producing devices.

Methods: We model a Legionnaires' disease epidemic curve as the convolution of an infection-time distribution (representing the aerosolized release) and an incubation-period distribution. The model is fitted to symptom-onset data from specific outbreaks to estimate the start and end dates of the release.

Modelling emerging viral epidemics for public health protection.

Mathematical models when applied to infectious disease data can provide extremely useful insights into the possible future impacts of potential emerging epidemics and how they might be best controlled or mitigated. Modelling, which is like any other hypothesis-driven approach, aims to develop a better understanding of biological phenomena. However, diseases processes generally, and particularly those related to transmission, will in many cases be imperfectly understood or too complex to systematically describe, so models will necessarily be simplifications of the overall system.

Stamping out fires! Controlling smallpox with targeted mass vaccination.

Background: More than 30 years have now passed since the last naturally occurring case of smallpox; however, the variola virus still exists in at least 2 locations. The possibility that any clandestine stocks could be used for bioterrorism is a continuing concern for the public health community.

Objective: .

Perceptions and reactions with regard to pneumonic plague.

We assessed perceptions and likely reactions of 1,005 UK adults to a hypothetical terrorist attack involving pneumonic plague. Likely compliance with official recommendations ranged from good (98% would take antimicrobial drugs) to poor (76% would visit a treatment center). Perceptions about plague were associated with these intentions.

Estimating the location and spatial extent of a covert anthrax release.

Rapidly identifying the features of a covert release of an agent such as anthrax could help to inform the planning of public health mitigation strategies. Previous studies have sought to estimate the time and size of a bioterror attack based on the symptomatic onset dates of early cases. We extend the scope of these methods by proposing a method for characterizing the time, strength, and also the location of an aerosolized pathogen release.