Leveraging a natural murine meiotic drive to suppress invasive populations.

Invasive rodents are a major cause of environmental damage and biodiversity loss, particularly on islands. Unlike insects, genetic biocontrol strategies including population-suppressing gene drives with biased inheritance have not been developed in mice. Here, we demonstrate a gene drive strategy (tCRISPR) that leverages super-Mendelian transmission of the t haplotype to spread inactivating mutations in a haplosufficient female fertility gene (Prl). Using spatially explicit individual-based in silico modeling, we show that tCRISPR can eradicate island populations under a range of realistic field-based parameter values. We also engineer transgenic tCRISPR mice that, crucially, exhibit biased transmission of the modified t haplotype and Prl mutations at levels our modeling predicts would be sufficient for eradication. This is an example of a feasible gene drive system for invasive alien rodent population control.

Non-invasive markers of inflammation in alcohol-associated liver disease: A scoping review.

Clinical manifestations of liver inflammation in alcohol-associated liver disease (ALD) can range from asymptomatic to severe alcoholic hepatitis. While biopsy is the gold standard for identifying liver inflammation, it is an invasive procedure with risks of bleeding, visceral damage, and infection. We aim to establish the state of the current literature on non-invasive markers of inflammation in ALD. We searched Ovid MEDLINE, Embase, and the Cochrane Library for original studies on the association between one or more non-invasive biomarker(s) and histological inflammation or hepatitis in ALD patients. Exclusion criteria were lack of histological data, abstract only, non-English-language articles, and animal studies. Two independent reviewers screened abstracts, reviewed full texts, and extracted data from included papers. Our search identified 8051 unique studies. Title and abstract screening resulted in 563 studies, and full-text screening resulted in 31 studies for final inclusion. The majority were single-center observational cohorts with an average sample size of 124. Review of these studies identified 44 unique biomarkers and 8 calculated scores associated with histological inflammation and/or hepatitis, in addition to a metabolomic panel of 468 metabolites. Six studies examined diagnostic accuracy for histological inflammation and/or hepatitis. The highest area under the receiver operating characteristic curve was 0.932 using a model based on four metabolites. This review highlights the available literature on non-invasive markers of inflammation in ALD. There is a dearth of studies that evaluate the diagnostic accuracy of these biomarkers, and larger studies are needed to confirm findings identified in small cohorts.

Gene drives for vertebrate pest control: Realistic spatial modelling of eradication probabilities and times for island mouse populations.

Invasive alien species continue to threaten global biodiversity. CRISPR-based gene drives, which can theoretically spread through populations despite imparting a fitness cost, could be used to suppress or eradicate pest populations. We develop an individual-based, spatially explicit, stochastic model to simulate the ability of CRISPR-based homing and X chromosome shredding drives to eradicate populations of invasive house mice (Mus muculus) from islands. Using the model, we explore the interactive effect of the efficiency of the drive constructs and the spatial ecology of the target population on the outcome of a gene-drive release. We also consider the impact of polyandrous mating and sperm competition, which could compromise the efficacy of some gene-drive strategies. Our results show that both drive strategies could be used to eradicate large populations of mice. Whereas parameters related to drive efficiency and demography strongly influence drive performance, we find that sperm competition following polyandrous mating is unlikely to impact the outcome of an eradication effort substantially. Assumptions regarding the spatial ecology of mice influenced the probability of and time required for eradication, with short-range dispersal capacities and limited mate-search areas producing 'chase' dynamics across the island characterized by cycles of local extinction and recolonization by mice. We also show that highly efficient drives are not always optimal, when dispersal and mate-search capabilities are low. Rapid local population suppression around the introduction sites can cause loss of the gene drive before it can spread to the entire island. We conclude that, although the design of efficient gene drives is undoubtedly critical, accurate data on the spatial ecology of target species are critical for predicting the result of a gene-drive release.

Team Cognition in Handoffs: Relating System Factors, Team Cognition Functions and Outcomes in Two Handoff Processes.

OBJECTIVE: This study investigates how team cognition occurs in care transitions from operating room (OR) to intensive care unit (ICU). We then seek to understand how the sociotechnical system and team cognition are related. BACKGROUND: Effective handoffs are critical to ensuring patient safety and have been the subject of many improvement efforts. However, the types of team-level cognitive processing during handoffs have not been explored, nor is it clear how the sociotechnical system shapes team cognition. METHOD: We conducted this study in an academic, Level 1 trauma center in the Midwestern United States. Twenty-eight physicians (surgery, anesthesia, pediatric critical care) and nurses (OR, ICU) participated in semi-structured interviews. We performed qualitative content analysis and epistemic network analysis to understand the relationships between system factors, team cognition in handoffs and outcomes. RESULTS: Participants described three team cognition functions in handoffs-(1) information exchange, (2) assessment, and (3) planning and decision making; information exchange was mentioned most. Work system factors influenced team cognition. Inter-professional handoffs facilitated information exchange but included large teams with diverse backgrounds communicating, which can be inefficient. Intra-professional handoffs decreased team size and role diversity, which may simplify communication but increase information loss. Participants in inter-professional handoffs reflected on outcomes significantly more in relation to system factors and team cognition (p < 0.001), while participants in intra-professional handoffs discussed handoffs as a task. CONCLUSION: Handoffs include team cognition, which was influenced by work system design. Opportunities for handoff improvement include a flexibly standardized process and supportive tools/technologies. We recommend incorporating perspectives of the patient and family in future work.

A guide to using the internet to monitor and quantify the wildlife trade.

The unrivaled growth in e-commerce of animals and plants presents an unprecedented opportunity to monitor wildlife trade to inform conservation, biosecurity, and law enforcement. Using the internet to quantify the scale of the wildlife trade (volume and frequency) is a relatively recent and rapidly developing approach that lacks an accessible framework for locating relevant websites and collecting data. We produced an accessible guide for internet-based wildlife trade surveillance. We detailed a repeatable method involving a systematic internet search, with search engines, to locate relevant websites and content. For data collection, we highlight web-scraping technology as an efficient way to collect data in an automated fashion at regularly timed intervals. Our guide is applicable to the multitude of trade-based contexts because researchers can tailor search keywords for specific taxa or derived products and locations of interest. We provide information for working with the diversity of websites used in wildlife trade. For example, to locate relevant content on social media (e.g., posts or groups), each social media platform should be examined individually via the site's internal search engine. A key advantage of using the internet to study wildlife trade is the relative ease of access to an increasing amount of trade-related data. However, not all wildlife trade occurs online and it may occur on unobservable sections of the internet.

Resumen Una Guía para Usar el Internet para Monitorear y Cuantificar el Mercado de Fauna El crecimiento incomparable del comercio en línea de animales y plantas representa una oportunidad sin precedentes para monitorear el mercado de fauna y así orientar a la conservación, la bioseguridad y la aplicación de la ley. El uso del internet para cuantificar la escala del mercado de fauna (volumen y frecuencia) es una estrategia relativamente reciente y de rápido desarrollo que carece de un marco de trabajo accesible para la localización de sitios web relevantes y para la recolección de datos. Realizamos una guía accesible para la vigilancia del mercado de fauna en internet. Detallamos un método repetible que involucra una búsqueda sistemática por internet, por medio de buscadores, para localizar sitios web y contenidos relevantes. Para la recolección de datos, resaltamos la tecnología de web scraping como una manera eficiente de obtener datos de manera automatizada a intervalos regulares de tiempo. Nuestra guía puede aplicarse a la multitud de contextos basados en el mercado porque los investigadores pueden adaptar las palabras de búsqueda a taxones específicos o productos derivados y a localidades de interés. Proporcionamos información para poder trabajar con la diversidad de sitios web que se usan para el mercado de fauna. Por ejemplo, para localizar contenido relevante en las redes sociales (p. ej.: publicaciones o grupos), cada plataforma social debería ser examinada individualmente por medio del buscador interno del sitio. Una ventaja importante de usar el internet para estudiar el mercado de fauna es el acceso relativamente sencillo a una creciente cantidad de datos relacionados con el mercado. Sin embargo, no todo el mercado de fauna ocurre en línea y puede que suceda en secciones inobservables del internet.

Infectious disease pandemic planning and response: Incorporating decision analysis.

Freya Shearer and co-authors discuss the use of decision analysis in planning for infectious disease pandemics.

Key questions for modelling COVID-19 exit strategies.

Combinations of intense non-pharmaceutical interventions (lockdowns) were introduced worldwide to reduce SARS-CoV-2 transmission. Many governments have begun to implement exit strategies that relax restrictions while attempting to control the risk of a surge in cases. Mathematical modelling has played a central role in guiding interventions, but the challenge of designing optimal exit strategies in the face of ongoing transmission is unprecedented. Here, we report discussions from the Isaac Newton Institute 'Models for an exit strategy' workshop (11-15 May 2020). A diverse community of modellers who are providing evidence to governments worldwide were asked to identify the main questions that, if answered, would allow for more accurate predictions of the effects of different exit strategies. Based on these questions, we propose a roadmap to facilitate the development of reliable models to guide exit strategies. This roadmap requires a global collaborative effort from the scientific community and policymakers, and has three parts: (i) improve estimation of key epidemiological parameters; (ii) understand sources of heterogeneity in populations; and (iii) focus on requirements for data collection, particularly in low-to-middle-income countries. This will provide important information for planning exit strategies that balance socio-economic benefits with public health.

Identification of the relative timing of infectiousness and symptom onset for outbreak control.

In an outbreak of an emerging disease the epidemiological characteristics of the pathogen may be largely unknown. A key determinant of ability to control the outbreak is the relative timing of infectiousness and symptom onset. We provide a method for identifying this relationship with high accuracy based on data from simulated household-stratified symptom-onset data. Further, this can be achieved with observations taken on only a few specific days, chosen optimally, within each household. The information provided by this method may inform decision making processes for outbreak response. An accurate and computationally-efficient heuristic for determining the optimal surveillance scheme is introduced. This heuristic provides a novel approach to optimal design for Bayesian model discrimination.

Characterising seasonal influenza epidemiology using primary care surveillance data.

Understanding the epidemiology of seasonal influenza is critical for healthcare resource allocation and early detection of anomalous seasons. It can be challenging to obtain high-quality data of influenza cases specifically, as clinical presentations with influenza-like symptoms may instead be cases of one of a number of alternate respiratory viruses. We use a new dataset of confirmed influenza virological data from 2011-2016, along with high-quality denominators informing a hierarchical observation process, to model seasonal influenza dynamics in New South Wales, Australia. We use approximate Bayesian computation to estimate parameters in a climate-driven stochastic epidemic model, including the basic reproduction number R0, the proportion of the population susceptible to the circulating strain at the beginning of the season, and the probability an infected individual seeks treatment. We conclude that R0 and initial population susceptibility were strongly related, emphasising the challenges of identifying these parameters. Relatively high R0 values alongside low initial population susceptibility were among the results most consistent with these data. Our results reinforce the importance of distinguishing between R0 and the effective reproduction number (Re) in modelling studies.

Scabies in residential care homes: Modelling, inference and interventions for well-connected population sub-units.

In the context of an ageing population, understanding the transmission of infectious diseases such as scabies through well-connected sub-units of the population, such as residential care homes, is particularly important for the design of efficient interventions to mitigate against the effects of those diseases. Here, we present a modelling methodology based on the efficient solution of a large-scale system of linear differential equations that allows statistical calibration of individual-based random models to real data on scabies in residential care homes. In particular, we review and benchmark different numerical methods for the integration of the differential equation system, and then select the most appropriate of these methods to perform inference using Markov chain Monte Carlo. We test the goodness-of-fit of this model using posterior predictive intervals and propagate forward the resulting parameter uncertainty in a Bayesian framework to consider the economic cost of delayed interventions against scabies, quantifying the benefits of prompt action in the event of detection. We also revisit the previous methodology used to assess the safety of treatments in small population sub-units-in this context ivermectin-and demonstrate that even a very slight relaxation of the implicit assumption of homogeneous death rates significantly increases the plausibility of the hypothesis that ivermectin does not cause excess mortality based upon the data of Barkwell and Shields.

Predicting the Risk of Biological Invasions Using Environmental Similarity and Transport Network Connectedness.

Understanding the risk of biological invasions associated with particular transport pathways and source regions is critical for implementing effective biosecurity management. This may require both a model for physical connectedness between regions, and a measure of environmental similarity, so as to quantify the potential for a species to be transported from a given region and to survive at a destination region. We present an analysis of integrated biosecurity risk into Australia, based on flights and shipping data from each global geopolitical region, and an adaptation of the "range bagging" method to determine environmental matching between regions. Here, we describe global patterns of environmental matching and highlight those regions with many physical connections. We classify patterns of global invasion risk (high to low) into Australian states and territories. We validate our analysis by comparison with global presence data for 844 phytophagous insect pest species, and produce a list of high-risk species not previously known to be present in Australia. We determined that, of the insect pest species used for validation, the species most likely to be present in Australia were those also present in geopolitical regions with high transport connectivity to Australia, and those regions that were geographically close, and had similar environments.

Dodging silver bullets: good CRISPR gene-drive design is critical for eradicating exotic vertebrates.

Self-replicating gene drives that can spread deleterious alleles through animal populations have been promoted as a much needed but controversial 'silver bullet' for controlling invasive alien species. Homing-based drives comprise an endonuclease and a guide RNA (gRNA) that are replicated during meiosis via homologous recombination. However, their efficacy for controlling wild populations is threatened by inherent polymorphic resistance and the creation of resistance alleles via non-homologous end-joining (NHEJ)-mediated DNA repair. We used stochastic individual-based models to identify realistic gene-drive strategies capable of eradicating vertebrate pest populations (mice, rats and rabbits) on islands. One popular strategy, a sex-reversing drive that converts heterozygous females into sterile males, failed to spread and required the ongoing deployment of gene-drive carriers to achieve eradication. Under alternative strategies, multiplexed gRNAs could overcome inherent polymorphic resistance and were required for eradication success even when the probability of NHEJ was low. Strategies causing homozygotic embryonic non-viability or homozygotic female sterility produced high probabilities of eradication and were robust to NHEJ-mediated deletion of the DNA sequence between multiplexed endonuclease recognition sites. The latter two strategies also purged the gene drive when eradication failed, therefore posing lower long-term risk should animals escape beyond target islands. Multiplexing gRNAs will be necessary if this technology is to be useful for insular extirpation attempts; however, precise knowledge of homing rates will be required to design low-risk gene drives with high probabilities of eradication success.

Pediatric near-drowning events: do they warrant trauma team activation?

BACKGROUND: The purpose of this study was to determine the incidence of traumatic injuries, factors associated with mortality, and need for pediatric trauma surgery involvement for drowning and near-drowning events in children. MATERIALS AND METHODS: An institutional review board-approved, retrospective chart review was performed at three American College of Surgeons-verified Pediatric Trauma Centers (2011-2014). Patients with International Classification of Diseases, Ninth Revision, codes or E-codes for fatal-nonfatal drowning, fall into water, accidental drowning, or submersion were included. Bivariate analysis using chi-square or Fisher exact test for nominal variables and Mann-Whitney U test for continuous variables was performed. RESULTS: A total of 363 patients (median 3.17 y [18 d-17 y]) met the inclusion criteria. Drowning sites included pool (81.5%), bathtub (12.9%), and natural water (5.2%). A witnessed fall or dive was reported in 34.9%, 57.9% did not fall or dive, and 7% had an unwitnessed event. Most patients did not undergo cervical spine (83%) or brain imaging (75.5%). Seven patients (1.92%) had associated soft tissue injuries. Two patients (0.006%) received surgical intervention (bronchoscopy and extracorporeal membrane oxygenation) within 24 h of presentation. Only 2.2% were admitted to the pediatric trauma service. The percentage of patients discharged home from the emergency department was 10.2%. Overall mortality was 12.4%. Factors associated with mortality included transfer from outside hospital (P = 0.016), presence of hypothermia on arrival (P < 0.0001), Glasgow Coma Scale of 3 on arrival (P < 0.0001), drowning in a pool (P = 0.013), or undergoing brain cooling at admission (P = 0.011). CONCLUSIONS: This is the largest reported series of pediatric near-drowning events. Only rarely did patients require immediate surgical attention and the majority were admitted to nonsurgical services. These data suggest that routine pediatric trauma surgery service involvement in patients with near-drowning events may be unnecessary.

Quantifying the effect of experimental design choices for in vitro scratch assays.

Scratch assays are often used to investigate potential drug treatments for chronic wounds and cancer. Interpreting these experiments with a mathematical model allows us to estimate the cell diffusivity, D, and the cell proliferation rate, λ. However, the influence of the experimental design on the estimates of D and λ is unclear. Here we apply an approximate Bayesian computation (ABC) parameter inference method, which produces a posterior distribution of D and λ, to new sets of synthetic data, generated from an idealised mathematical model, and experimental data for a non-adhesive mesenchymal population of fibroblast cells. The posterior distribution allows us to quantify the amount of information obtained about D and λ. We investigate two types of scratch assay, as well as varying the number and timing of the experimental observations captured. Our results show that a scrape assay, involving one cell front, provides more precise estimates of D and λ, and is more computationally efficient to interpret than a wound assay, with two opposingly directed cell fronts. We find that recording two observations, after making the initial observation, is sufficient to estimate D and λ, and that the final observation time should correspond to the time taken for the cell front to move across the field of view. These results provide guidance for estimating D and λ, while simultaneously minimising the time and cost associated with performing and interpreting the experiment.

Choice of Antiviral Allocation Scheme for Pandemic Influenza Depends on Strain Transmissibility, Delivery Delay and Stockpile Size.

Recently, pandemic response has involved the use of antivirals. These antivirals are often allocated to households dynamically throughout the pandemic with the aim being to retard the spread of infection. A drawback of this is that there is a delay until infection is confirmed and antivirals are delivered. Here an alternative allocation scheme is considered, where antivirals are instead preallocated to households at the start of a pandemic, thus reducing this delay. To compare these two schemes, a deterministic approximation to a novel stochastic household model is derived, which allows efficient computation of key quantities such as the expected epidemic final size, expected early growth rate, expected peak size and expected peak time of the epidemic. It is found that the theoretical best choice of allocation scheme depends on strain transmissibility, the delay in delivering antivirals under a dynamic allocation scheme and the stockpile size. A broad summary is that for realistic stockpile sizes, a dynamic allocation scheme is superior with the important exception of the epidemic final size under a severe pandemic scenario. Our results, viewed in conjunction with the practical considerations of implementing a preallocation scheme, support a focus on attempting to reduce the delay in delivering antivirals under a dynamic allocation scheme during a future pandemic.

Understanding the biological invasion risk posed by the global wildlife trade: propagule pressure drives the introduction and establishment of Nearctic turtles.

Biological invasions are a key component of human-induced global change. The continuing increase in global wildlife trade has raised concerns about the parallel increase in the number of new invasive species. However, the factors that link the wildlife trade to the biological invasion process are still poorly understood. Moreover, there are analytical challenges in researching the role of global wildlife trade in biological invasions, particularly issues related to the under-reporting of introduced and established populations in areas with reduced sampling effort. In this work, we use high-quality data on the international trade in Nearctic turtles (1999-2009) coupled with a statistical modelling framework, which explicitly accounts for detection, to investigate the factors that influence the introduction (release, or escape into the wild) of globally traded Nearctic turtles and the establishment success (self-sustaining exotic populations) of slider turtles (Trachemys scripta), the most frequently traded turtle species. We found that the introduction of a species was influenced by the total number of turtles exported to a jurisdiction and the age at maturity of the species, while the establishment success of slider turtles was best associated with the propagule number (number of release events), and the number of native turtles in the jurisdiction of introduction. These results indicate both a direct and indirect association between the wildlife trade and the introduction of turtles and establishment success of slider turtles, respectively. Our results highlight the existence of gaps in the number of globally recorded introduction events and established populations of slider turtles, although the expected bias is low. We emphasize the importance of researching independently the factors that affect the different stages of the invasion pathway. Critically, we observe that the number of traded individuals might not always be an adequate proxy for propagule pressure and establishment success.

Incomplete penetrance: The role of stochasticity in developmental cell colonization.

Cell colonization during embryonic development involves cells migrating and proliferating over growing tissues. Unsuccessful colonization, resulting from genetic causes, can result in various birth defects. However not all individuals with the same mutation show the disease. This is termed incomplete penetrance, and it even extends to discordancy in monozygotic (identical) twins. A one-dimensional agent-based model of cell migration and proliferation within a growing tissue is presented, where the position of every cell is recorded at any time. We develop a new model that approximates this agent-based process - rather than requiring the precise configuration of cells within the tissue, the new model records the total number of cells, the position of the most advanced cell, and then invokes an approximation for how the cells are distributed. The probability mass function (PMF) for the most advanced cell is obtained for both the agent-based model and its approximation. The two PMFs compare extremely well, but using the approximation is computationally faster. Success or failure of colonization is probabilistic. For example for sufficiently high proliferation rate the colonization is assured. However, if the proliferation rate is sufficiently low, there will be a lower, say 50%, chance of success. These results provide insights into the puzzle of incomplete penetrance of a disease phenotype, especially in monozygotic twins. Indeed, stochastic cell behavior (amplified by disease-causing mutations) within the colonization process may play a key role in incomplete penetrance, rather than differences in genes, their expression or environmental conditions.

Eye on children: acute work-up for pediatric Horner's syndrome. case presentation and review of the literature.

BACKGROUND: Ptosis and anisocoria in a child may be subtle indications of occult pathology, and making the observation acutely in the emergency department (ED) is important in guiding patient management and treatment. Emergency physicians must evaluate patients to exclude serious or life-threatening emergencies and ensure correct disposition of patients. Horner syndrome in children may be considered congenital or acquired and may be from benign or malignant causes. When an isolated, acquired Horner syndrome is suspected in a pediatric patient, physical examination of the neck and abdomen for masses, as well as spot urine catecholamines, vanillylmandelic acid and homovanillic acid, and varying degrees of imaging are recommended as part of the initial evaluation. These evaluations may be performed in the ED or may require hospitalization, depending on the suspected anatomical localization and diagnostic considerations. CASE REPORT: A 21-month-old, normally developed girl presented to the University Hospital ED with a 2-h history of right-sided eyelid drooping in the setting of a febrile illness. An eventual diagnosis of Horner syndrome from cervical lymph node compression was made on the basis of history, examination, and imaging findings. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: ED evaluations of pediatric patients differ from adults. Evaluation and work-up of Horner syndrome in children can be challenging and can require varying degrees of assessment and evaluation, depending on the diagnostic considerations. This article will address the common pathologies responsible for isolated pediatric Horner syndrome and the recommended ED evaluation.

The effect of clumped population structure on the variability of spreading dynamics.

Processes that spread through local contact, including outbreaks of infectious diseases, are inherently noisy, and are frequently observed to be far noisier than predicted by standard stochastic models that assume homogeneous mixing. One way to reproduce the observed levels of noise is to introduce significant individual-level heterogeneity with respect to infection processes, such that some individuals are expected to generate more secondary cases than others. Here we consider a population where individuals can be naturally aggregated into clumps (subpopulations) with stronger interaction within clumps than between them. This clumped structure induces significant increases in the noisiness of a spreading process, such as the transmission of infection, despite complete homogeneity at the individual level. Given the ubiquity of such clumped aggregations (such as homes, schools and workplaces for humans or farms for livestock) we suggest this as a plausible explanation for noisiness of many epidemic time series.