Targeting Peritumoral Lesions Identified by Computed Tomography and Magnetic Resonance Imaging in Feline Injection-Site Sarcomas for Microscopic Examination.

Peritumoral lesions identified during in vivo imaging of feline injection-site sarcoma (FISS) are frequently interpreted as neoplastic. We recently showed that most peritumoral imaging-identified lesions (PTIILs) in FISS are non-neoplastic. In this article, we describe a protocol to target PTIIL for microscopic examination and report on the protocol's performance. Ten client-owned cats with FISS were prospectively enrolled. A fiducial marker sutured onto the skin, centered on the palpable mass, served as reference point throughout the study. Each FISS and surrounding tissue was imaged in vivo by dual phase computed tomography angiography and multiple magnetic resonance imaging pulse sequences and each PTIIL documented. Subgross measurements obtained during trimming aided localization and identification of PTIIL during microscopy. Histologic findings were categorized by descending clinical relevance: neoplastic, equivocal, non-neoplastic, within normal limits (WNL). Based on in vivo imaging resolution limits, histologic findings were ≥3 mm in at least one dimension and ≥3 mm apart. Surgical margins served as control tissue for PTIILs. Eighty-one of 87 PTIIL were examined histologically; 13 were neoplastic, 16 equivocal, and 28 non-neoplastic; 24 had no identified histologic correlate. Two neoplastic and 10 equivocal findings were located outside of PTIILs but none of them were located in sections of surgical margins. Computation of a simple confusion matrix yielded fair sensitivity (70.4%) and low specificity (59.7%) for prediction of PTIIL by histologic findings. After combining instances of normal microanatomy with non-neoplastic histologic findings, specificity increased (85.1%) and sensitivity decreased (35.8%). The protocol is a blueprint for targeting PTIIL for microscopic examination but may benefit from further refinement.

Optimizing the impact of low-efficacy influenza vaccines.

The efficacy of influenza vaccines varies from one year to the next, with efficacy during the 2017-2018 season anticipated to be lower than usual. However, the impact of low-efficacy vaccines at the population level and their optimal age-specific distribution have yet to be ascertained. Applying an optimization algorithm to a mathematical model of influenza transmission and vaccination in the United States, we determined the optimal age-specific uptake of low-efficacy vaccine that would minimize incidence, hospitalization, mortality, and disability-adjusted life-years (DALYs), respectively. We found that even relatively low-efficacy influenza vaccines can be highly impactful, particularly when vaccine uptake is optimally distributed across age groups. As vaccine efficacy declines, the optimal distribution of vaccine uptake shifts toward the elderly to minimize mortality and DALYs. Health practitioner encouragement and concerted recruitment efforts are required to achieve optimal coverage among target age groups, thereby minimizing influenza morbidity and mortality for the population overall.

Opposite outcomes of coinfection at individual and population scales.

Coinfecting parasites and pathogens remain a leading challenge for global public health due to their consequences for individual-level infection risk and disease progression. However, a clear understanding of the population-level consequences of coinfection is lacking. Here, we constructed a model that includes three individual-level effects of coinfection: mortality, fecundity, and transmission. We used the model to investigate how these individual-level consequences of coinfection scale up to produce population-level infection patterns. To parameterize this model, we conducted a 4-y cohort study in African buffalo to estimate the individual-level effects of coinfection with two bacterial pathogens, bovine tuberculosis (bTB) and brucellosis, across a range of demographic and environmental contexts. At the individual level, our empirical results identified bTB as a risk factor for acquiring brucellosis, but we found no association between brucellosis and the risk of acquiring bTB. Both infections were associated with reductions in survival and neither infection was associated with reductions in fecundity. The model reproduced coinfection patterns in the data and predicted opposite impacts of coinfection at individual and population scales: Whereas bTB facilitated brucellosis infection at the individual level, our model predicted the presence of brucellosis to have a strong negative impact on bTB at the population level. In modeled populations where brucellosis was present, the endemic prevalence and basic reproduction number ([Formula: see text]) of bTB were lower than in populations without brucellosis. Therefore, these results provide a data-driven example of competition between coinfecting pathogens that occurs when one pathogen facilitates secondary infections at the individual level.

Global analysis of a predator-prey model with variable predator search rate.

We consider a modified Holling-type II predator-prey model, based on the premise that the search rate of predators is dependent on the prey density, rather than constant. A complete analysis of the global behavior of the model is presented, and shows that the model exhibits a dichotomy similar to the classical Holling-type II model: either the coexistence steady state is globally stable; or it is unstable, and then a unique, globally stable limit cycle exists. We discuss the similarities, but also important differences between our model and the Holling-type II model. The main differences are that: 1. The paradox of enrichment which always occurs in the Holling-type II model, does not always occur here, and 2. Even when the paradox of enrichment occurs, predators can adapt by lowering their search rate, and effectively stabilize the system.

Effectiveness of UNAIDS targets and HIV vaccination across 127 countries.

The HIV pandemic continues to impose enormous morbidity, mortality, and economic burdens across the globe. Simultaneously, innovations in antiretroviral therapy, diagnostic approaches, and vaccine development are providing novel tools for treatment-as-prevention and prophylaxis. We developed a mathematical model to evaluate the added benefit of an HIV vaccine in the context of goals to increase rates of diagnosis, treatment, and viral suppression in 127 countries. Under status quo interventions, we predict a median of 49 million [first and third quartiles 44M, 58M] incident cases globally from 2015 to 2035. Achieving the Joint United Nations Program on HIV/AIDS 95-95-95 target was estimated to avert 25 million [20M, 33M] of these new infections, and an additional 6.3 million [4.8M, 8.7M] reduction was projected with the 2020 introduction of a 50%-efficacy vaccine gradually scaled up to 70% coverage. This added benefit of prevention through vaccination motivates imminent and ongoing clinical trials of viable candidates to realize the goal of HIV control.

The effectiveness of marine protected areas for predator and prey with varying mobility.

Marine protected areas (MPAs) are regions in the ocean where fishing is restricted or prohibited. Although several measures for MPA performance exist, here we focus on a specific one, namely the ratio of the steady state fish densities inside and outside the MPA. Several 2 patch models are proposed and analyzed mathematically. One patch represents the MPA, whereas the second patch represents the fishing ground. Fish move freely between both regions in a diffusive manner. Our main objective is to understand how fish mobility affects MPA performance. We show that MPA effectiveness decreases with fish mobility for single species models with logistic growth, and that densities inside and outside the MPA tend to equalize. This suggests that MPA performance is highest for the least mobile species. We then consider a 2 patch Lotka-Volterra predator-prey system. When one of the species moves, and the other does not, the ratio of the moving species first remains constant, and ultimately decreases with increased fish mobility, again with a tendency of equalization of the density in both regions. This suggests that MPA performance is not only highest for slow, but also for moderately mobile species. The discrepancy in MPA performance for single species models and for predator-prey models, confirms that MPA design requires an integrated, ecosystem-based approach. The mathematical approaches advocated here complement and enhance the numerical and theoretical approaches that are commonly applied to more complex models in the context of MPA design.

Disease elimination and re-emergence in differential-equation models.

Traditional differential equation models of disease transmission are often used to predict disease trajectories and evaluate the effectiveness of alternative intervention strategies. However, such models cannot account explicitly for probabilistic events, such as those that dominate dynamics when disease prevalence is low during the elimination and re-emergence phases of an outbreak. To account for the dynamics at low prevalence, i.e. the elimination and risk of disease re-emergence, without the added analytical and computational complexity of a stochastic model, we develop a novel application of control theory. We apply our approach to analyze historical data of measles elimination and re-emergence in Iceland from 1923 to 1938, predicting the temporal trajectory of local measles elimination and re-emerge as a result of disease migration from Copenhagen, Denmark.

COMPARISON OF CHEMICAL AND SURGICAL VASECTOMY ON TESTICULAR ACTIVITY IN FREE-ROAMING HORSES (EQUUS CABALLUS).

Free-roaming horse (Equus caballus) management is a complex issue incorporating social, economic, emotional, political, and environmental factors. Currently, few proven field techniques exist for managing free-roaming horse population growth, which can reach 20-25% annually. Although there are several strategies available for sterilizing mares when managing free-roaming horse populations, surgical vasectomy is the only method used in the field for stallions. Some managers believe that surgically vasectomizing dominant stallions would have significant effects on reducing horse populations. However, sterilizing only dominant harem stallions results in a relatively modest reduction in population growth as substantial reproduction may occur even when 100% of the dominant harem stallions are sterilized if other males perform as little as 10% of the breeding. The overall goal of the current project was to evaluate the efficacy of a novel nonsurgical method for sterilizing free-roaming horses (chemical vasectomy). In September of 2013, stallions that had been previously surgically vasectomized (SURG, n = 25), previously chemically vasectomized (CHEM, n = 16), or untreated (CONT, n = 32) were captured and surgically castrated in preparation for adoption. When comparing both sterilization methods to CONT, serum testosterone and estrone sulfate concentrations did not differ (P > 0.05), suggesting that these methods for sterilizing free-roaming stallions would not disrupt herd social hierarchy. However, similar to the CONT, all CHEM stallions had sperm present within the vas deferens seminal fluid samples. CHEM stallions had more morphologically abnormal sperm than did CONT stallions but it is not known if this affected the actual fertility. Additional research is needed using alternative sclerosing agents for chemical vasectomy in free-roaming horse populations.

A multiplex biomarker approach for the diagnosis of transitional cell carcinoma from canine urine.

Transitional cell carcinoma (TCC), the most common cancer of the urinary bladder in dogs, is usually diagnosed at an advanced disease stage with limited response to chemotherapy. Commercial screening tests lack specificity and current diagnostic procedures are invasive. A proof of concept pilot project for analyzing the canine urinary proteome as a noninvasive diagnostic tool for TCC identification was conducted. Urine was collected from 12 dogs in three cohorts (healthy, urinary tract infection, TCC) and analyzed using liquid chromatography tandem mass spectrometry. The presence of four proteins (macrophage capping protein, peroxiredoxin 5, heterogeneous nuclear ribonucleoproteins A2/B, and apolipoprotein A1) was confirmed via immunoblot. Of the total 379 proteins identified, 96 were unique to the TCC group. A statistical model, designed to evaluate the accuracy of this multiplex biomarker approach for diagnosis of TCC, predicted the presence of disease with 90% accuracy.

Country- and age-specific optimal allocation of dengue vaccines.

Several dengue vaccines are under development, and some are expected to become available imminently. Concomitant with the anticipated release of these vaccines, vaccine allocation strategies for dengue-endemic countries in Southeast Asia and Latin America are currently under development. We developed a model of dengue transmission that incorporates the age-specific distributions of dengue burden corresponding to those in Thailand and Brazil, respectively, to determine vaccine allocations that minimize the incidence of dengue hemorrhagic fever, taking into account limited availability of vaccine doses in the initial phase of production. We showed that optimal vaccine allocation strategies vary significantly with the demographic burden of dengue hemorrhagic fever. Consequently, the strategy that is optimal for one country may be sub-optimal for another country. More specifically, we showed that, during the first years following introduction of a dengue vaccine, it is optimal to target children for dengue mass vaccination in Thailand, whereas young adults should be targeted in Brazil.

Wolbachia symbiont infections induce strong cytoplasmic incompatibility in the tsetse fly Glossina morsitans.

Tsetse flies are vectors of the protozoan parasite African trypanosomes, which cause sleeping sickness disease in humans and nagana in livestock. Although there are no effective vaccines and efficacious drugs against this parasite, vector reduction methods have been successful in curbing the disease, especially for nagana. Potential vector control methods that do not involve use of chemicals is a genetic modification approach where flies engineered to be parasite resistant are allowed to replace their susceptible natural counterparts, and Sterile Insect technique (SIT) where males sterilized by chemical means are released to suppress female fecundity. The success of genetic modification approaches requires identification of strong drive systems to spread the desirable traits and the efficacy of SIT can be enhanced by identification of natural mating incompatibility. One such drive mechanism results from the cytoplasmic incompatibility (CI) phenomenon induced by the symbiont Wolbachia. CI can also be used to induce natural mating incompatibility between release males and natural populations. Although Wolbachia infections have been reported in tsetse, it has been a challenge to understand their functional biology as attempts to cure tsetse of Wolbachia infections by antibiotic treatment damages the obligate mutualistic symbiont (Wigglesworthia), without which the flies are sterile. Here, we developed aposymbiotic (symbiont-free) and fertile tsetse lines by dietary provisioning of tetracycline supplemented blood meals with yeast extract, which rescues Wigglesworthia-induced sterility. Our results reveal that Wolbachia infections confer strong CI during embryogenesis in Wolbachia-free (Gmm(Apo)) females when mated with Wolbachia-infected (Gmm(Wt)) males. These results are the first demonstration of the biological significance of Wolbachia infections in tsetse. Furthermore, when incorporated into a mathematical model, our results confirm that Wolbachia can be used successfully as a gene driver. This lays the foundation for new disease control methods including a population replacement approach with parasite resistant flies. Alternatively, the availability of males that are reproductively incompatible with natural populations can enhance the efficacy of the ongoing sterile insect technique (SIT) applications by eliminating the need for chemical irradiation.

The impact of imitation on vaccination behavior in social contact networks.

Previous game-theoretic studies of vaccination behavior typically have often assumed that populations are homogeneously mixed and that individuals are fully rational. In reality, there is heterogeneity in the number of contacts per individual, and individuals tend to imitate others who appear to have adopted successful strategies. Here, we use network-based mathematical models to study the effects of both imitation behavior and contact heterogeneity on vaccination coverage and disease dynamics. We integrate contact network epidemiological models with a framework for decision-making, within which individuals make their decisions either based purely on payoff maximization or by imitating the vaccination behavior of a social contact. Simulations suggest that when the cost of vaccination is high imitation behavior may decrease vaccination coverage. However, when the cost of vaccination is small relative to that of infection, imitation behavior increases vaccination coverage, but, surprisingly, also increases the magnitude of epidemics through the clustering of non-vaccinators within the network. Thus, imitation behavior may impede the eradication of infectious diseases. Calculations that ignore behavioral clustering caused by imitation may significantly underestimate the levels of vaccination coverage required to attain herd immunity.

The effects of taurolidine alone and in combination with doxorubicin or carboplatin in canine osteosarcoma in vitro.

BACKGROUND: Osteosarcoma (OS) affects over 8000 dogs/year in the United States. The disease usually arises in the appendicular skeleton and metastasizes to the lung. Dogs with localized appendicular disease benefit from limb amputation and chemotherapy but most die within 6-12 months despite these treatments. Taurolidine, a derivative of taurine, has anti-tumor and anti-angiogenic effects against a variety of cancers. The following in vitro studies tested taurolidine as a candidate for adjuvant therapy for canine OS. Tests for p53 protein status and caspase activity were used to elucidate mechanisms of taurolidine-induced cell death. RESULTS: Taurolidine was cytotoxic to osteosarcoma cells and increased the toxicity of doxorubicin and carboplatin in vitro. Apoptosis was greatly induced in cells exposed to 125 µM taurolidine and less so in cells exposed to 250 µM taurolidine. Taurolidine cytotoxicity appeared caspase-dependent in one cell line; with apparent mutant p53 protein. This cell line was the most sensitive to single agent taurolidine treatment and had a taurolidine-dependent reduction in accumulated p53 protein suggesting taurolidine's effects may depend on the functional status of p53 in canine OS. CONCLUSION: Taurolidine's cytotoxic effect appears dependent on cell specific factors which may be explained, in part, by the functional status of p53. Taurolidine initiates apoptosis in canine OS cells and this occurs to a greater extent at lower concentrations. Mechanisms of cell death induced by higher concentrations were not elucidated here. Taurolidine combined with doxorubicin or carboplatin can increase the toxicity of these chemotherapy drugs and warrants further investigation in dogs with osteosarcoma.

Dengue vector control strategies in an urban setting: an economic modelling assessment.

BACKGROUND: An estimated 2·5 billion people are at risk of dengue. Incidence of dengue is especially high in resource-constrained countries, where control relies mainly on insecticides targeted at larval or adult mosquitoes. We did epidemiological and economic assessments of different vector control strategies. METHODS: We developed a dynamic model of dengue transmission that assesses the evolution of insecticide resistance and immunity in the human population, thus allowing for long-term evolutionary and immunological effects of decreased dengue transmission. We measured the dengue health burden in terms of disability-adjusted life-years (DALYs) lost. We did a cost-effectiveness analysis of 43 insecticide-based vector control strategies, including strategies targeted at adult and larval stages, at varying efficacies (high-efficacy [90% mortality], medium-efficacy [60% mortality], and low-efficacy [30% mortality]) and yearly application frequencies (one to six applications). To assess the effect of parameter uncertainty on the results, we did a probabilistic sensitivity analysis and a threshold analysis. FINDINGS: All interventions caused the emergence of insecticide resistance, which, with the loss of herd immunity, will increase the magnitude of future dengue epidemics. In our model, one or more applications of high-efficacy larval control reduced dengue burden for up to 2 years, whereas three or more applications of adult vector control reduced dengue burden for up to 4 years. The incremental cost-effectiveness ratios of the strategies for two high-efficacy adult vector control applications per year was US$615 per DALY saved and for six high-efficacy adult vector control applications per year was $1267 per DALY saved. Sensitivity analysis showed that if the cost of adult control was more than 8·2 times the cost of larval control then all strategies based on adult control became dominated. INTERPRETATION: Six high-efficacy adult vector control applications per year has a cost-effectiveness ratio that will probably meet WHO's standard for a cost-effective or very cost-effective intervention. Year-round larval control can be counterproductive, exacerbating epidemics in later years because of evolution of insecticide resistance and loss of herd immunity. We suggest the reassessment of vector control policies that are based on larval control only. FUNDING: The Fulbright Programme, CAPES (Brazilian federal agency for post-graduate education), the Miriam Burnett trust, and the Notsew Orm Sands Foundation.

Vector host-feeding preferences drive transmission of multi-host pathogens: West Nile virus as a model system.

Seasonal epizootics of vector-borne pathogens infecting multiple species are ecologically complex and difficult to forecast. Pathogen transmission potential within the host community is determined by the relative abilities of host species to maintain and transmit the pathogen and by ecological factors influencing contact rates between hosts and vectors. Increasing evidence of strong feeding preferences by a number of vectors suggests that the host community experienced by the pathogen may be very different from the local host community. We developed an empirically informed transmission model for West Nile virus (WNV) in four sites using one vector species (Culex pipiens) and preferred and non-preferred avian hosts. We measured strong feeding preferences for American robins (Turdus migratorius) by Cx. pipiens, quantified as the proportion of Cx. pipiens blood meals from robins in relation to their abundance (feeding index). The model accurately predicted WNV prevalence in Cx. pipiens at three of four sites. Sensitivity analysis revealed feeding preference was the most influential parameter on intensity and timing of peak WNV infection in Cx. pipiens and a threshold feeding index for transmission was identified. Our findings indicate host preference-induced contact heterogeneity is a key mediator of vector-borne pathogen epizootics in multi-species host communities, and should be incorporated into multi-host transmission models.

Averting epidemics of extensively drug-resistant tuberculosis.

Extensively drug-resistant tuberculosis (XDR TB) has been detected in most provinces of South Africa, particularly in the KwaZulu-Natal province where several hundred cases have been reported since 2004. We analyzed the transmission dynamics of XDR TB in the region using mathematical models, and observed that nosocomial transmission clusters of XDR TB may emerge into community-based epidemics under the public health conditions of many South African communities. The effective reproductive number of XDR TB in KwaZulu-Natal may be around 2. Intensified community-based case finding and therapy appears critical to curtailing transmission. In the setting of delayed disease presentation and high system demand, improved diagnostic approaches may need to be employed in community-based programs rather than exclusively at tertiary hospitals. Using branching process mathematics, we observed that early, community-based drug-susceptibility testing and effective XDR therapy could help curtail ongoing transmission and reduce the probability of XDR TB epidemics in neighboring territories.

Endemic persistence of a highly contagious pathogen: Foot-and-mouth disease in its wildlife host.

Extremely contagious pathogens are a global biosecurity threat because of their high burden of morbidity and mortality, as well as their capacity for fast-moving epidemics that are difficult to quell. Understanding the mechanisms enabling persistence of highly transmissible pathogens in host populations is thus a central problem in disease ecology. Through a combination of experimental and theoretical approaches, we investigated how highly contagious foot-and-mouth disease viruses persist in the African buffalo, which serves as their wildlife reservoir. We found that viral persistence through transmission among acutely infected hosts alone is unlikely. However, the inclusion of occasional transmission from persistently infected carriers reliably rescues the most infectious viral strain from fade-out. Additional mechanisms such as antigenic shift, loss of immunity, or spillover among host populations may be required for persistence of less transmissible strains.

The impact of transgenic mosquitoes on dengue virulence to humans and mosquitoes.

Dengue is a major public health concern in the tropics and subtropics. Innovative transgenic strategies to render Aedes aegypti mosquitoes, the primary vector of dengue, incompetent for dengue transmission are under development. We modeled the evolutionary impact of different transgenic mosquito strategies on dengue-induced mortality, that is, dengue virulence, to both humans and mosquitoes. This model incorporates various evolutionary trade-offs in dengue virus epidemiological traits, for example, a trade-off between dengue transmission rate and its virulence to humans. Our results indicate that strategies that block transmission or reduce mosquito biting impose selection on dengue virulence in humans. This selection can be for either higher or lower virulence, depending on the interaction between the effect of the transgene and the trade-offs in epidemiological traits, highlighting the need for detailed quantitative data to understand more fully the impact of mosquito transgenesis on dengue virulence. Dengue virulence in mosquitoes can be selected on by transgenic strategies of blocking transmission, decreased mosquito biting, increased mosquito background mortality, and increased mosquito infection-induced mortality. Our results suggest that dengue control strategies that raise mosquito background mortality or mosquito infection-induced mortality pose less risk of causing increased virulence to humans than strategies that block transmission or reduce mosquito biting.

Species interactions affect the spread of vector-borne plant pathogens independent of transmission mode.

Within food webs, vectors of plant pathogens interact with individuals of other species across multiple trophic levels, including predators, competitors, and mutualists. These interactions may in turn affect vector-borne pathogens by altering vector fitness and behavior. Predators, for example, consume vectors and reduce their abundance, but often spur movement of vectors as they seek to avoid predation. However, a general framework to predict how species interactions affect vectors of plant pathogens, and the resulting spread of vector-borne pathogens, is lacking. Here we developed a mathematical model to assess whether interactions such as predation, competition, and mutualism affected the spread of vector-borne plant pathogens with nonpersistent or persistent transmission modes. We considered transmission mode because interactions affecting vector-host encounter rates were expected to most strongly affect nonpersistent pathogens that are transmitted with short feeding bouts; interactions that affect vector feeding duration were expected to most strongly affect persistent pathogens that require long feeding bouts for transmission. Our results show that interactions that affected vector behavior (feeding duration, vector-host encounter rates) substantially altered rates of spread for vector-borne plant pathogens, whereas those affecting vector fitness (births, deaths) had relatively small effects. These effects of species interactions were largely independent of transmission mode, except when interactions affected vector-host encounter rates, where effects were strongest for nonpersistent pathogens. Our results suggest that a better understanding of how vectors interact with other species within food webs could enhance our understanding of disease ecology.

Backward bifurcations and multiple equilibria in epidemic models with structured immunity.

Many disease pathogens stimulate immunity in their hosts, which then wanes over time. To better understand the impact of this immunity on epidemiological dynamics, we propose an epidemic model structured according to immunity level that can be applied in many different settings. Under biologically realistic hypotheses, we find that immunity alone never creates a backward bifurcation of the disease-free steady state. This does not rule out the possibility of multiple stable equilibria, but we provide two sufficient conditions for the uniqueness of the endemic equilibrium, and show that these conditions ensure uniqueness in several common special cases. Our results indicate that the within-host dynamics of immunity can, in principle, have important consequences for population-level dynamics, but also suggest that this would require strong non-monotone effects in the immune response to infection. Neutralizing antibody titer data for measles are used to demonstrate the biological application of our theory.