Ordered and deterministic cancer genome evolution after p53 loss.

Although p53 inactivation promotes genomic instability1 and presents a route to malignancy for more than half of all human cancers2,3, 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. Despite rampant heterogeneity, the deletion events that follow p53 inactivation target functionally relevant pathways that can shape genomic evolution and remain fixed as homogenous events in diverse malignant populations. Thus, loss of p53-the 'guardian of the genome'-is not merely a gateway to genetic chaos but, rather, can enable deterministic patterns of genome evolution that may point to new strategies for the treatment of TP53-mutant tumours.

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. Healthcare development was determined using three multi-factorial indices, while detailed airline passenger data was used to identify the global connectivity of all countries. Proximities of countries to a putative 'Worst Case Scenario' (extreme high-connectivity and low-healthcare development) were calculated. We found a positive relationship between a country's connectivity and healthcare metrics. We also identified countries that potentially pose the greatest risk for pandemic dissemination, notably Dominican Republic, India and Pakistan. China and Mexico, both sources of recent influenza and coronavirus pandemics were also identified as among the highest risk countries. Collectively, lower-middle and upper-middle income countries represented the greatest risk, while high income countries represented the lowest risk. Our analysis represents an alternative approach to identify countries where increased within-country disease surveillance and pandemic preparedness may benefit global health.

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. With data sets drawn from dose-response experiments of inhalational anthrax, plague, and tularemia, we illustrate how for certain cases, there is the potential for overestimation of infection numbers arising from models that consider only the experimental data in isolation.

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. A vignette was presented about a hypothetical gastrointestinal illness. People stated their emotional reactions, expected actions in response and beliefs about possible benefits or harms from seeking treatment (or not getting treatment). Multinomial regression looked for predictors of anticipated behaviour. RESULTS: People were inclined to consult a GP when they believed that seeking treatment would be beneficial and that its absence would be harmful. Seeking treatment was less anticipated if the condition was expected to improve quickly. Respondents were also more likely to consult if they strongly disliked fever or headache, and/or if the illness made them feel anxious or angry. Treatment-seeking (or lack of it) was not linked to harms from treatment-seeking, other specific symptoms and emotional responses. CONCLUSION: It was possible to link anticipated treatment-seeking behaviour to specific factors: expected prognosis, perceived benefits of seeking treatment, some emotions and some specific symptoms.

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.MethodsArticles matching our search criteria and describing a model of the international spread of human infectious disease, parameterised with airline passenger data, were identified. Information regarding type and source of airline passenger data used was collated and the studies' reproducibility assessed.ResultsWe identified 136 articles. The majority (n = 96) sourced data primarily used by the airline industry. Governmental data sources were used in 30 studies and data published by individual airports in four studies. Validation of passenger data was conducted in only seven studies. No study was found to be fully reproducible, although eight were partially reproducible.LimitationsBy limiting the articles to international spread, articles focussed on within-country transmission even if they used relevant data sources were excluded. Authors were not contacted to clarify their methods. Searches were limited to articles in PubMed, Web of Science and Scopus.ConclusionWe recommend greater efforts to assess validity and biases of airline passenger data used for modelling studies, particularly when model outputs are to inform national and international public health policies. We also recommend improving reporting standards and more detailed studies on biases in commercial and open-access data to assess their reproducibility.

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 Aedes albopictus, which is a known vector for dengue and chikungunya virus. In 2010, Culex modestus, a principal mosquito vector for West Nile virus was detected in large numbers in the Thames estuary. For tick-borne diseases, data on the changing distribution of the Lyme borreliosis tick vector, Ixodes ricinus, has recently been published, at a time when there has been an increase in the numbers of reported human cases of Lyme disease. This paper brings together the latest surveillance data and pertinent research on vector-borne disease in the UK, and its relevance to public health. It highlights the need for continued vector surveillance systems to monitor our native mosquito and tick fauna, as well as the need to expand surveillance for invasive species. It illustrates the importance of maintaining surveillance capacity that is sufficient to ensure accurate and timely disease risk assessment to help mitigate the UK's changing emerging infectious disease risks, especially in a time of climatic and environmental change and increasing global connectivity.

Forced migrants involved in setting the agenda and designing research to reduce impacts of complex emergencies: combining Swarm 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. To further focus the research, two representatives of forced migrant communities were invited to join the project team as patient and public (PPI) representatives. They attended regular project meetings, insightfully contributed to and advised on practical aspects of potential research areas. The representatives identified cultural obstacles and community needs and helped choose the final research study design, which was to interview forced migrants about their strategies to build emotional resilience and prevent mental illness. The representatives also helped design recruitment documents, and undertake recruitment and interviewer training. BACKGROUND: Many events with wide-ranging negative health impacts are notable for complexity: lack of predictability, non-linear feedback mechanisms and unexpected consequences. A multi-disciplinary research team was tasked with reducing the public health impacts from complex events, but without a pre-specified topic area or research design. This report describes using patient and public involvement within an adaptable but structured development process to set research objectives and aspects of implementation. METHODS: An agile adaptive development approach, sometimes described as swarm, was used to identify possible research areas. Swarm is meant to quickly identify strengths and weaknesses of any candidate project, to accelerate early failure before resources are invested. When aspects of the European migration crisis were identified as a potential priority topic area, two representatives of forced migrant communities were recruited to explore possible research ideas. These representatives helped set the specific research objectives and advised on aspects of implementation, still within the swarm framework for project development. RESULTS: Over ten months, many research ideas were considered by the collaborative working group in a series of six group meetings, supplemented by email contact in between. Up to four possible research ideas were scrutinised at any one meeting, with a focus on identifying practical or desirable aspects of each proposed project. Interest settled on a study to solicit original data about successful strategies that forced migrants use to adapt to life in the UK, with an emphasis on successfully promoting resilience and minimizing emotional distress. "Success in resettlement" was identified to be a more novel theme than "barriers to adaption" research. A success approach encourages participation when individuals may find discussion of mental illness stigmatising. The patient representatives helped with design of patient-facing and interview training materials, interviewer training (mock interviews), and aspects of the recruitment. CONCLUSION: Using patient and public involvement (PPI) within an early failure development approach that itself arises from theory on complex adaptive systems, we successfully implemented a dynamic development process to determine research topic and study design. The PPI representatives were closely involved in setting research objectives and aspects of implementation.

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. We identified 80 reports using spatial methods published between 1979 and 2013, ca 0.4% of the total number of published outbreaks. Environmental or waterborne infections were the most commonly investigated, and most reports were from the United Kingdom. A range of techniques were used, including simple dot maps, cluster analyses and modelling approaches. Spatial tools were usefully applied throughout investigations, from initial confirmation of the outbreak to describing and analysing cases and communicating findings. They provided valuable insights that led to public health actions, but there is scope for much wider implementation and development of new methods.

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. A subset of samples was tested for USUV. RESULTS: Culex modestus was found in both the pre-imaginal and imago stage at all five locations surveyed, accounting for 90% of adult mosquitoes collected. WNV or USUV were not detected in any sample. CONCLUSIONS: Although no mosquitoes have been shown to be virus positive, the field survey data from this study demonstrated the dominance of an important bridge vector species for WNV in this region. Its wide geographical distribution highlights the need to update risk assessments on WNV introduction, and to maintain vigilance for WNV in the South East of England.

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. Tick-borne diseases, such as Lyme disease, continue to increase, or, in the case of tick-borne encephalitis and Crimean-Congo haemorrhagic fever viruses, have changed their geographical distribution. From a veterinary perspective, the emergence of Bluetongue and Schmallenberg viruses show that northern Europe is equally susceptible to transmission of vector-borne disease. These changes are in part due to increased globalisation, with intercontinental air travel and global shipping transport creating new opportunities for invasive vectors and pathogens. However, changes in vector distributions are being driven by climatic changes and changes in land use, infrastructure, and the environment. In this Review, we summarise the risks posed by vector-borne diseases in the present and the future from a UK perspective, and assess the likely effects of climate change and, where appropriate, climate-change adaptation strategies on vector-borne disease risk in the UK. Lessons from the outbreaks of West Nile virus in North America and chikungunya in the Caribbean emphasise the need to assess future vector-borne disease risks and prepare contingencies for future outbreaks. Ensuring that adaptation strategies for climate change do not inadvertently exacerbate risks should be a primary focus for decision makers.

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. Outcrossing the inducible oncogenic KRAS(G12D) line with transgenic zebrafish reporters, harboring specific signaling responsive elements of transcriptional effectors, we were able to follow TGFß, Notch, Bmp and Shh activities during tumor development. Zebrafish transgenic lines expressing eGFP-KRAS(G12D) showed normal exocrine pancreas development until 3 weeks post fertilization (wpf). From 4 to 24 wpf we observed several degrees of acinar lesions, characterized by an increase in mesenchymal cells and mixed acinar/ductal features, followed by progressive bowel and liver infiltrations and, finally, highly aggressive carcinoma. Moreover, live imaging analysis of the exocrine pancreatic tissue revealed an increasing number of KRAS-positive cells and progressive activation of TGFß and Notch pathways. Increase in TGFß, following KRAS(G12D) activation, was confirmed in a concomitant model of medulloblastoma (MDB). Notch and Shh signaling activities during tumor onset were different between MDB and pancreatic adenocarcinoma, indicating a tissue-specific regulation of cell signaling pathways. Moreover, our results show that a living model of pancreatic adenocarcinoma joined with cell signaling reporters is a suitable tool for describing in vivo the signaling cascades and molecular mechanisms involved in tumor development and a potential platform to screen for novel oncostatic drugs.

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. Most input parameters were derived from locally acquired data. After fitting the model to the 46 observed cross-transmission events and performing sensitivity analysis, several screening and isolation policies were evaluated by simulating the number of cross-transmissions and isolation-days. The number of all cross-transmission events increased from 54 to 72 if only patients with a past history of MRSA colonization are screened and isolated at admission, to 75 if isolation is put in place only after the results of the admission screening become available, to 82 in the absence of admission screening and with a similar reactive isolation policy, and to 95 when no isolation policy is in place. The method used (culture or polymerase chain reaction) for admission screening had no impact on the number of cross-transmissions. Systematic regular screening during ICU stay provides no added-value, but aggressive admission screening and isolation effectively reduce the number of cross-transmissions. Critically, colonized healthcare workers may play an important role in MRSA transmission and their screening should be reinforced.

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. The results show that southern France, northern Italy, the northern coast of Spain, the eastern coast of the Adriatic Sea and western Turkey were climatically suitable areas for the establishment of the mosquito during the 1960-1980s. Over the last two decades, climate conditions have become more suitable for the mosquito over central northwestern Europe (Benelux, western Germany) and the Balkans, while they have become less suitable over southern Spain. Similar trends are likely in the future, with an increased risk simulated over northern Europe and slightly decreased risk over southern Europe. These distribution shifts are related to wetter and warmer conditions favouring the overwintering of A. albopictus in the north, and drier and warmer summers that might limit its southward expansion.

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. We observe that no matter how isolated a community is, it is not necessarily insulated from infection by influenza and that even where there are no complicating factors, such as the age distribution or the presence of individuals with greater susceptibility in the enclosed population, their organization tends to increase influenza transmission and the risk of secondary infection. The collected accounts demonstrate important features of outbreaks in such societies and the necessity of considering them in pandemic planning: in particular, rapid intervention is essential for the control of influenza spread in such circumstances. Recent experience has shown that administration of modern antiviral drugs, such as neuraminidase inhibitors are effective at moderating outbreaks of influenza, but only in combination with other methods of control. In more remote communities where such drugs are not, or less, readily available, and medical care is limited, such outbreaks can still pose particular difficulties. In all cases delay in correct diagnosis, detection of an outbreak or the implementation of control measures can result in the majority of the enclosed population succumbing to the disease.

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. We then simulated an aerosolized release of the causative agent, using airborne dispersion modeling to demonstrate the potential number of casualties and the extent of their spatial distribution. Finally, we developed a public health intervention model that compares 2 mitigation strategies: targeting antibiotics at symptomatic individuals with or without mass distribution of antibiotics to potentially infected individuals. An antibiotic stockpile that is sufficient to capture all areas where symptomatic individuals were infected is likely to save more lives than treating symptomatic individuals alone, providing antibiotics can be distributed rapidly and their uptake is high. However, with smaller stockpiles, a strategy of treating symptomatic individuals alone is likely to save many more lives than additional mass distribution of antibiotics to potentially infected individuals. The spatial distribution of symptomatic individuals is unlikely to coincide exactly with the path of the dispersion cloud if such individuals are infected near their work locations but then seek treatment close to their homes. The optimal mitigation strategy will depend critically on the size of the release relative to the stockpile level and the effectiveness of treatment relative to the speed at which antibiotics can be distributed.

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.

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. We also develop this retrospective "back-calculation" model into a prospective "real-time" model that can estimate the final size of an ongoing outbreak, in addition to the timing of its release. RESULTS: In the retrospective analysis, the estimated release end dates were generally earlier than reported end dates. This suggests that, in many outbreaks, the release might have already ended by the time the source was reportedly cleaned or closed. Prospective analysis showed that valid estimates of the release start date could be achieved early in the outbreak, the total number of cases could be reasonably determined shortly after the release had ended, and estimates of the release end date could be satisfactorily achieved in the latter stages of the outbreak. CONCLUSIONS: This model could be used in the course of a Legionnaires' disease outbreak to provide early estimates of the total number of cases, thus helping to inform public-health planning. Toward the end of the outbreak, estimates of the release end date could help corroborate standard epidemiologic, environmental, and microbiologic investigations that seek to identify the source.

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: . Mathematical modeling is used to assess the impact of mass vaccination following a smallpox release when either standard public health controls are failing or political/public opinion is urging more comprehensive methods. Two mass vaccination strategies are considered: a blanket nationwide campaign v. an approach targeted only at those geographic areas that experience smallpox cases. The study evaluates which intervention strategy results in the fewest combined disease and vaccine-related deaths. RESULTS: . Outbreaks that go unnoticed until up to 50 cases have occurred are optimally controlled with targeted mass vaccination of the affected administrative districts in the majority of scenarios considered. The number of people vaccinated is approximately two thirds fewer than when implementing a nationwide campaign. Similar results arise when contact tracing is either highly unsuccessful or reduced in favor of reallocating limited resources for a policy of mass vaccination. CONCLUSIONS: . Reactive nationwide mass vaccination remains a suboptimal strategy for controlling an expanding smallpox outbreak in all but the most extreme circumstances. Rather, targeted mass vaccination of affected areas is likely to result in fewer deaths. The vaccines administered are also likely to be much fewer because they would probably be distributed to a much smaller number of districts, thus relieving pressure on potentially stretched public health systems.

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. It is essential, therefore, that models are designed carefully and used appropriately. Key to this is identifying what specific questions a model might be expected to answer and what data is available to inform the model. A particular type of model might be fine for one particular situation but highly inappropriate for another. It is also important to appreciate and communicate what simplifications and assumptions have had to be made and how this might affect the robustness of the modelling results. It is also particularly important to understand that models frequently make what can be hidden assumptions about underlying processes because of the way they have been constructed and these assumptions also need to be carefully considered and made explicit, particularly for non-expert audiences. This chapter, therefore, provides a brief introduction to some of these aspects of epidemic modelling for those that might be less familiar with them.