Developing control policies for zoonotic diseases is challenging, both because of the complex spread dynamics exhibited by these diseases, and because of the need for implementing complex multi-species surveillance and control efforts using limited resources. Mathematical models, and in particular network models, of disease spread are promising as tools for control-policy design, because they can provide comprehensive quantitative representations of disease transmission.A layered dynamical network model for the transmission and control of zoonotic diseases is introduced as a tool for analyzing disease spread and designing cost-effective surveillance and control. The model development is achieved using brucellosis transmission among wildlife, cattle herds, and human sub-populations in an agricultural system as a case study. Precisely, a model that tracks infection counts in interacting animal herds of multiple species  and in human subpopulations is introduced. The model is then abstracted to a form that permits comprehensive targeted design of multiple control capabilities as well as model identification from data. Next, techniques are developed for such quantitative design of control policies , and for model identification from snapshot and time-course data, by drawing on recent results in the network control community.The modeling approach is shown to provide quantitative insight into comprehensive control policies for zoonotic diseases, and in turn to permit policy design for mitigation of these diseases. For the brucellosis-transmission example in particular, numerous insights are obtained regarding the optimal distribution of resources among available control capabilities  and points in the spread network . In addition, a preliminary identification of the network model for brucellosis is achieved using historical data, and the robustness of the obtained model is demonstrated. As a whole, our results indicate that network modeling can aid in designing control policies for zoonotic diseases. Zoonotic diseases  exact a significant economic and human cost, especially in developing economies. Developing effective policies for mitigating zoonotic infections is often challenging, both because of the complexity of their spread and because very limited resources must be allocated among a range of control options. It is increasingly becoming clear that mathematical modeling, and in particular network modeling, of disease spread can aid in analyzing and mitigating these spreads. Here, we develop a network model for the spread and control of a zoonotic infection, focusing particularly on a case study of brucellosis transmission and control among wildlife, cattle herds, and human subpopulations in an agricultural community. After motivating and formulating the model, we introduce tools for 1) parameterization of the model from time-course and snapshot data, 2) simulation and analysis of the model, and 3) optimal design of control policies using the model. The study shows that the network model can inform design of heterogeneous control policies that mitigate zoonotic disease spread with limited resources. Zoonoses–infectious diseases that can be transmitted to humans from other animals–incur significant cost though their impact on both agricultural production and human communities. Zoonoses have particular prevalence and impact in the developing world, where low-cost yet effective strategies for their control and eventual eradication are badly needed e.g., . Controla priori comparison of the effectiveness of various control strategies and making explicit the roles played by various species in the spread of the disease  models for virus spread targeted controls can be designed for high performance. That is, via analytical means, they identify certain parts of networks  that have disproportionate impact on spread, and so suggest concentration of control resources on these components of the network. While such insights regarding control seems germane to mitigation of zoonoses, our results as yet have only been developed using generic models for transmission and control and have only measured spread in terms of one measure (the basic reproductive number), have not considered surveillance at all.Network modeling of infection spread has been a particular area of burgeoning interest over the last few years, see the articles Models for zoonotic diseases (including for brucellosis) classically have been simple compartmental models rather than network-structured models, with each compartment capturing homogeneous transmission within an entire species, or perhaps for an age group of that species e.g., . Very reThe purpose of this study is to give a comprehensive treatment of the modeling, surveillance, and cost-effective control of zoonoses, by bringing to bear and enhancing a network-control-theory approach to virus-spread control. As a specific case study, we explore modeling and design of surveillance and control for brucellosis in a prototypical agricultural setting in a resource-constrained area such as sub-Saharan Africa. To this end, a network model for brucellosis transmission among animal herds and to human populations is developed, that captures the mechanism of transmission of this zoonotic bacterium, allows repesentation of realistic surveillance and control mechanisms and their costs, and measures the performance of the control scheme with regard to the disease's financial and societal impact. Once the model has been formulated in a general way, we discuss approaches for inferring important network-model parameters from limited experimental data, which include both simple heuristic approaches and new network-estimation tools from the control sciences. Using the parametrized models, design of surveillance and control capabilities is pursued, with the aim of suggesting good targeted control/surveillance strategies as well as improvements to existing strategies. A particular focus of the design is to obtain simple insights into high-performance strategies that do not rely on model details, so that the developed strategies are in some measure robust to inaccuracies and limitations in the models and available data.network control theory methodology to comprehensively design the spread control capabilities. This network control theory approach is valuable, because it permits systematic design of multiple control and surveillance capabilities in a multi-faceted network, to meet multiple performance criteria or optimize a performance measure. We believe that this comprehensive design capability is of central importance for the zoonotic disease mitigation problems that are studied here, because very limited and heterogeneous control resources must be used in many zoonotic-disease control scenarios.This study advances the existing efforts on network modeling of infection spread, including our own earlier work, in several ways. First, it makes explicit the grapical modeling of spread in multiple species/breeds using a layered network structure. Second, it carefully models a family of surveillance and control capabilities for zoonoses, and brings to bear a system identification techniques to infer parameters of the spread model from snapshot and time-course data. In particular, these methods are used to parameterize the brucellosis spread model, using snapshot data on bovine brucellosis in West Africa, and time-course data from the Jackson bison herd.We find most illustrative to introduce the proposed layered-network modeling framework for zoonotic diseases using a case study of brucellosis transmission, both to allow careful illustration of how disease-specific characteristics can be captured using the modeling framework, and to permit development of quantitative control policies for this particular neglected zoonotic disease. To begin, Let us briefly overview the methods for modeling brucellosis spread and designing control strategies. In many communities with high brucellosis prevalence (e.g. in West Africa), transmission dynamics and control capabilities/costs vary significantly from herd to herd, because of variabilities in agricultural system, herd and pasture sizes, accessibility, and financial resources The section is organized as follows. After a brief overview of the brucellosis case study, we present the nominal network model for brucellosis transmission among multiple animal herds and human subpopulations that was developed. Subsequently, we present the modeling of control efforts and costs. Finally, methods for control design and model identification are discussed briefly.Brucellosis is a zoonotic bacterium with several species that cause illness in livestock . Pastoralists are often subject to both means of transmission, while a broader segment of the community in developing countries may be subject to infection from consumption of raw products, see e.g. The most common strain of herds or groups are present, labeled The developed model tracks brucellosis prevalence (numbers of infectives) in individual herds for multiple animal species and prevalence in human subpopulations (divided by susceptibility). Specifically, brucellosis infection is modeled in infection countsHere, we first develop a predictive mathematical model for the dynamics of the see e.g. . Thus, tinteraction scaling parameterNext, the model captures transmission from other herds of the same species. Specifically, consider transmission from a herd The rate of infection from herd inputThe model also captures changes in infection counts in a herd due to 1) natural death or (rarely) remission, and 2) incorporation of infected animals from outside the modeled system . The rate of decrease in infectives due to death/remission is well-modeled as proportional to the number of infectives in the herd. Specifically, in herd In the case where the linear model is in force, the following family of differential equations for nominal brucellosis transmission in the livestock/wildlife population is obtained, by summing the transmission rates to each herd and subtracting the natural death rate:rate at each time, thus yielding differential-equation models of transmission. To roughly capture these infectivity characteristics in a way that permits control design, a linearized population-dynamics model is again used to describe the spread. In particular, each subpopulation is assumed to have an infection rate that is a linear combination of the infective counts in various herds, i.e. the infection rate for human subpopulation A second core aspect of the nominal model is the representation of brucellosis transmission from livestock to the human population prior to control. As with the animal model, infection of the human population is captured through representation of the infection network model. In particular, viewing the herds and human subpopulations as components in a contact network, we see that there are interactions between pairs of these components if and only if commingling and transmission occur for that pair . To facilitate analysis and design, it is worthwhile to define a weighted and directed nominal spread graph or simply spread graph that captures the contact network structure. In particular, the spread graph is defined to have vertices or nodes, representing each livestock herd and human subpopulation. An arrow or edge is drawn from one vertex to another, if and only if the herd/subpopulation corresponding to the first vertex directly impacts the infection rate in the herd/subpopulation corresponding to the second vertex . The weight of the edge is set equal the corresponding coefficient in the linearized differential equation, since this coefficient captures the strength of the interaction. This formulation of a graph includes self-loops, or edges from vertices back to themselves, whose weights are chosen in the same way as for other edges . The self-loop weights will be negative, in the case that the rate of remission/death is larger than the spread rate in a herd. The spread graph never has arrows leading out from a vertex representing a human subpopulation, and the self-loops for these vertices are always negatively weighted, since humans do not transmit the bacteria. An illustration of a spread graph is given in The nominal model for brucellosis transmission described above can be viewed as a In that the spread graph specifies the contact network  among modeled populations, we note that specifying the spread graph accurately for examples of interest is of critical importance. Let us stress that, in general, three different approaches may be used to specify the spread graph: 1) the control-strategy planner may use intimate knowledge of an agricultural system to identify herd contacts and postulate transmission rates; 2) a formal system-identification methodology may be used to infer the spread graph; or 3) for large-scale networks, existing characterizations of typical network topologies  can be used to generate plausible spread graphs. In the illustrative example presented in the results, we will motivate and describe the specification of the spread graph that we have used for this example.Next, the nominal multi-group model for brucellosis transmission is enhanced to explicitly represent surveillance and control capabilities 1) within the animal population and 2) for transmission from animals to humans.In the animal population, control of spread is achieved through several means, including 1) vaccination, 2) surveillance for and culling of diseased animals, 3) limitation of herd commingling (through restriction of trade or movement of livestock), and 4) improvement in sanitation at farms e.g., . BroadlyVaccines for brucellosis have been developed for cattle and small ruminants. Application of a vaccine to a herd serves to make the members of the herd less susceptible to the disease. Vaccination capabilities are abstractly incorporated into our model as follows: vaccination of a particular herd Surveillance for brucellosis is non-trivial, since the signs of the disease are non-specific. Very broadly, to test for brucellosis with high fidelity requires either identification of the organism cultured from fluid or tissue samples, or identification of infected animals through serological tests; these tests typically trade off specificity and sensitivity, and may be costly. Typically, surveillance is used for control by depopulating livestock that are identified as infected. Thus, a surveillance and culling program is abstractly modeled as one that removes infectives from herds at some rate. Specifically, the rate at which infectives are removed from herd within herds in Equation 1, and hence can be modeled as scaling these infection rates.Two further methods for mitigating brucellosis spread among livestock are 1) limitation of commingling among herds, and 2) improved sanitation. Like vaccination and surveillance/culling controls, these further control methods can be naturally modeled as altering the nominal model and so the nominal interaction graph in various ways. Specifically, reducing commingling among herds will serve to reduce the interaction weights Brucellosis is a severe and in many cases incapacitating disease in humans, whose prevention is paramount. No vaccine for brucellosis exists for humans. Instead, transmission from livestock to humans is primarily limited in three ways: 1) pasteurization of milk products and proper preparation of meat products; 2) brucellosis surveillance and control programs; and 3) reduction of transmission to those handling livestock products through improved sanitation and training in safe handling of livestock products. These control methods fundamentally serve to reduce the transmission rates to one or more human subpopulations from some  of the animal herds. That is, the controls serve to scale the nominal rates of transmission Broadly, designing effective control strategies requires achieving a proper tradeoff between the costs resulting from disease prevalence and the costs of control. Altenatively, control design can be viewed as an effort to minimize disease prevalence or associated costs, while using limited control resources. Thus, to properly design control strategies, models are needed for the cost of infection as well as the costs associated with using the various control actions. As a framework for cost modeling, each infected individual in each herd and human subpopulation at each particular time is viewed as incurring a cost, and these costs are summed to obtain the full infection cost. Precisely, the infection cost at a particular time In addition to the costs incurred by brucellosis spread, the cost of control is modeled. For each possible control action , the cost is assumed to have three parts: 1) a global overhead cost for the infrastructure needed to implement the control strategy, 2) a per-herd (or per- human subpopulation) cost representing the additional cost of providing controls to the herd (which may depend on the size and type of herd), and 3) a cost per infected individual in the herd. For instance, for a testing and culling strategy, there is a fixed cost for developing the laboratory infrastructure for testing, a cost associated with testing each herd, and a cost to the farmer for each culled animal. Finally, the total cost of control is calculated as the sum of the costs for each implemented control action. The total cost of control during a period of time is denoted by full costA control strategy's overall performance is captured by the sum of the infection and control costs over a period of time, The dynamics of the spread and control model, and associated cost model, are illustrated in the following examples.network control theory, for the systematic design of limited control resources to achieve high performance (low spread cost), or equivalently to reduce totaled resource and spread cost. The approach is also promising in that the simple model structure can permit determination of model parameters (parameterization) from sparse historical data, and hence the approach is potentially applicable in the limited-data settings that are common in zoonotic disease spread. In this section, we overview the network-control-theory methodologies for high-performance design and model parameterizaton. We aim to present the methods in sufficient detail that the reader understands the concepts and essential methodologies underlying design/parameterization; to allow wide readership, we exclude technical justifications and algorithmic details, and refer the reader to specific results in the engineering literature for these.The layered network model for zoonotic disease transmission that we have introduced above, using brucellosis as a case study, is promising as a tool for systematic design of mulitfaceted control capabilities. Precisely, the formulation permits application of some new methodologies for Before describing the methodologies for control design and parameterization, let us stress that the modeling framework permits simple simulation and analysis of the spread dynamics, for a specified control policy. In particular, we note that both the linear and nonlinear differential-equation models can be solved numerically using standard derivative-approximation methods, and can be implemented readily using e.g. the Matlab software. The linearized model also readily permits analysis of the dynamics, including closed-form computation of steady-state and transient dynamics, and computation of features of the dynamics such as the basic reproductive number. This analysis is based directly on the classical analysis of linear systems or linear differential equations; we kindly refer readers who are not familiar with the classical methodology to see networksControl-systems engineers have recently engaged in a major effort to design surveillance and control capabilities in Previous work has already applied network controller design methods to spread-control problems, albeit for simpler models than the one considered here eigenvalue-sensitivity equations: we kindly ask the reader to see Initially, classical optimization machinery is applied to the design problem. That is, we consider the problem of minimizing the full cost Numerical solution of the Lagrangian can be achieved via numerous standard recursive solvers, such as are available in the Matlab software suite (or can easily be developed by hand). Under certain broad conditions on the network topology and cost definition (which guarantee convexity of the optimization problem), these methods can be shown to obtain a globally optimal design.Often, it is much more instructive to determine structural characteristics of high-performance or optimal designs, rather than to obtain a numerical design. This is especially true of the zoonotic disease control problems considered here, for which socio-political and geographic concerns may make implementation of a precise policy difficult and model parameterization difficult, so that an optimal design may only serve as a guideline rather than an implementable routine. Additionally, by understanding characteristics of high-performance designs, we can make explicit the role played by the network's graph topology in achieving control. For reasons such as these ones, a primary focus of our ongoing work has been to been characterize the system/graph structure of high-performance designs. This structural characterization of high-performance design can be achieved as follows: from the Lagrangian, relationships between the optimal design parameters and the state matrix of the linearized dynamics can be obtained: that is, the dynamics imposes a structure on the optimal resource allocation. Noting that the dynamics of the infection spread are specified using the network graph, we can thus immediately connect the optimal values of the design parameters with the structure of the network graph . Further, we can in turn relate the dynamics upon application of the optimal controller to the nominal graph's structure. In this way, we obtain very simple graphical insights into high-performance control designs, that are robust to implementation and modeling limitations. We will present the outcomes of this design methodology in the In the interest of conciseness and readability, we have not included many details of the mathematical techniques used and especially their justifications: we kindly ask the reader to see As we will describe in detail in the We have considered the model-identification task for the brucellosis spread application, from two viewpoints: first, from the viewpoint of identifying a model for a single herd using which a network model can be constructed; and, second, from the viewpoint of directly identifying the full network dynamics or important statistics thereof. In particular, a single-herd model has been parameterized using time-snapshot herd-size and seroprevalence data from several countries in West Africa and the Jackon bison herd, as well as using temporal data from the Jackson Bison herd We find it most illustrative to present the results of the modeling and control design methodology introduced here, in the context of a specific example of brucellosis spread. Specifically, model dynamics and control design are illustrated in an example that is representative at a small scale of largely agricultural communities with both transhumance and sedentary herding (such as in Ethiopia or the Sudan). Specifically, a non-intensive agricultural system with one breed of cattle, comprising The nominal spread graph, which illustrates the contact network prior to control, is shown in Remark 1. In the 20-herd example chosen above, we note that the graph topology of the contact network is one where half of the vertices have high degree, while the remaining vertices have low degree: the graph is generated to enforce a degree distribution, but chosen randomly within this constraint; the particular transmission rates used in the example are obtained through identification of the brucellosis spread model. Such random graphs with enforced low- and high- degree vertices have some properties in common with the common small-world graphs when they are of sufficient size, and in this sense our results for the example may be indicative of results when the topology is a small world. We stress, however, that our analysis methods (and subequent control design and identification methods) can be applied regardless of the graph topology, and that the specific topology that we have chosen is guided by our understanding of the agricultural practices governing brucellosis spread rather than by the typical model classes considered in the complex-systems literature.Remark 2: In the above example, we have excluded transmission to and from wildlife, because of the difficulty in parameterizing wildlife-related transmission rates. Model simulation and analysis when transmission to wildlife is considered is straightforward. For instance, we have completed simulations in which an identical rate of transmission between each herd and wildlife is assumed: as expected, disease prevalence increases with increasing transmission rate to and from the wildlife reservoir. In practice, we conjecture that the transmission rates between each herd and the wildlife reservoir are better modeled as random quantities, reflecting variability in the extent of contact with wildlife. We leave further development to future work.state matrix of the linearized model dynamics  Three strategies with identical total resource cost are compared: one that vaccinates only the transhumance herds, one that vaccinates sedentary and transhumance herds, and one that vaccinates only the sedentary herds. For the three vaccination strategies, the basic reproductive ratio It is hypothesized that improved surveillance techniques that permit fast and cheap decentralized surveillance/culling could significantly improve brucellosis control. The model permits evaluation of the benefits of faster surveillance/culling. Here, a uniform surveillance/culling policy at all herds is considered for the Here, we consider a homogeneous surveillance/culling procedure for all herds, and calculate the integrated infection size  for the 20-herd network, for a random initial condition. In this example, a culling rate of at least 0.43 (43% of the infected population per annum) is needed to make The modeling methodology that we have introduced permits systematic optimization of control resources, according to the methods outlined above. For illustration, we have found the optimal allocation of vaccination resources to minimize the basic reproductive number in the illustrative example, as a function of the level of available resources. The optimal basic reproductive number, and the fraction of the resources that are allocated to the transhumance herds, are plotted in so shown . FinallyThe techniques described above for identification of the bovine brucellosis model from snapshot and time-course described were applied. The results of the identification are displayed in We have found it convenient to illustrate the results of our methodology using an example. Let us stress, however, that the methodology has much broader application: the developed network modeling framework can be used to quantitatively capture transmission of a zoonotic disease within a particular agricultural system or community, and in turn can be used for control and surveillance policy design for such transmission. In addition to permitting concrete designs for examples, the tractability of the model also allows us to obtain broad insights into control and surveillance design for brucellosis (and other zoonotic diseases), and conceptual insight into model parameterization from historical data. Let us discuss some broader insights obtained using the modeling methodology, drawing on the example developed in the The network control methods allow a comprehensive study of the brucellosis controller design problem, and more generally of zooonotic-disease control. Below is a list of several aspects of the control design task that can be addressed using these methods, as well as a few of the key insights obtained through the design. These insights are envisioned as informing policy decision-making.1) Optimal or high-performance sub-divisions of control resources among the animal herds can be determined, based on the spread graph's structure. When resource allocation costs and infection costs due to prevalence in a herd are relatively homogeneous, then high-performance designs tend to equalize the spread-impacts of the herds, to within the extent allowed by the constraints on resources and on the control. Thus, limited resources  should be allocated to herds with high spread impact (sum of outgoing edge weights from that herd's vertex on the graph), until the spread impacts are equalized. If further resources are available, they should be equally distributed among the herds, if possible. When constraints prevent allocation of resources (or further resources) to some herds, the design becomes somewhat more intricate: some herds must be allocated extra resources so as to limit the spread-impact of their constrained neighbors. These characteristics of resource allocation are indicated in the optimal-vaccination design for the illustrative example, see 2) The design method permits comparison of multiple spread-control strategies in the animal population , and concurrent design of multiple strategies. For instance, we have pursued a comparison of an optimal vaccination strategy (strategy  and an ostrategy  for the 3) The design methodology can identify the tradeoff between allocating resources to human population groups rather than to the animal population, as a function of resource and infection costs. Given the significant heterogeneity in transmission of brucellosis (and other zoonotic diseases) in the human and animal populations, comparing policies that assign control resources to stop transmission among animals with those that prevent transmission to humans is of importance. The newly-developed network design methods permit such comparison, and in turn allow appropriate subdivision of resources for animal-level control and animal-to-human transmission control. As an illustration, let us interpret the concurrent design of surveillance/vaccination capabilities and pasteurization to prevent transmission that we presented for the 4) The core resource-allocation designs can be enriched to obtain dynamic or reactive strategies for mitigating zoonotic diseases. As real-time measurements of trends in infection counts (or costs) become available, strategies that dynamically allocate resources based on these trends can be developed. The reader is referred to Let us present some insights on the model identification methodology, using the results displayed in The snapshot data permits characterization of the ratio between the per-individual infection rate and the remission rate (through recovery or death and replacement), for a single herd. As seen in The time-course data further permits inference of the absolute per-individual infection rate, so that  a full single-herd model can be identified. In parameterizing the single-herd model, we did not have any quantitative data on the rates of infection in each herd from outside the herd: thus, the parameterization has been done assuming an identical rate of interaction/infection from outside the herd. This crude assumption clearly yields error in the parameterization result. For the data from West African herds, we have some qualitative insight into herds that have more significant interactions with other ones  and hence are more susceptible to infection from outside the herd. In Given the very limited and highly variable data available for model parameterization, the robustness of the model to parameter variations is of importance. As a first step in this direction, we have studied the ability of the model to predict single-herd brucellosis prevalence, when there is up to The uncertainty inherent to the data used for model parameterization highlights the importance of considering stochastics in modeling disease spread. Both intrinsic variability in transmission and uncertainties/variability in model parameters may significantly impact the model dynamics and hence modulate control design see e.g. . The desA network modeling methodology for capturing the spread of zoonotic agents at a herd/subpopulation granularity has been introduced, and used to compare and design control strategies for stopping the spread of zoonoses. The introduced methodology has been developed in detail in the context of a case study, namely modeling and control of brucellosis spread in animal and human populations. Parameter identification of the model from historical data has been pursued.This modeling and controller design effort should be viewed as a foundational step toward obtaining comprehensive policies for controlling zoonoses from mathematical models: the policies suggested by our methodology must be tested in experimental herds, and the social and political ramifications of control policies and spread mitigation must be considered carefully in defining costs for a zoonosis of interest. It is also important to stress that a wide range of experimental and conceptual methodologies from outside the mathematical-modeling domain must be brought to bear to address policy design for zoonotic diseases, and that mathematical modeling efforts  are complementary to core advances in epidemiological methods. Nevertheless, we believe that some promising outcomes have been obtained through this foundational study.Network modeling can give a clear pictorial representation of the spread of a zoonotic disease among subgroups of one or more species. The layered network model that we have developed also permits simulation and simple quantitative analysis of the spread dynamics. Also, a variety of control measures can naturally be captured in the layered network modeling framework.The network modeling approach that we have put forth here also permits systematic and quantitative comprehensive design of resources for control in the animal and human population. Specifically, for the linearized network model studied here, recently-developed tools from the network control theory literature can be applied to design heterogeneous control capabilities to minimize a resource and spread cost. We stress that much work still needs to be done to verify that the abstract controls suggested by the design can be implemented in reality, and can achieve performance similar to that predicted by the model.Network modeling approaches provide sufficient detail to permit comparison and design of heterogeneous control strategies, for instance ones that use surveillance and culling vs. ones that use vaccination, as well as ones that cater to the topology of interactions among the herds. Both qualitative and quantitative predictions and designs can be obtained.Although optimal controller design requires a precise model of spread dynamics and of costs, our design methodology can provide useful insights even when such precise models are unavailable. First, the methodology provides simple insights into good designs–for instance, that more resources should be placed in large and tightly-connected herds–that do not require a precise model to implement. Second, the designs obtained through the methodology show some degree of robustness to variations in model parameters.We have given some preliminary results on parameterizing the network model from data, and have also identified some challenges in fully addressing the parameterization problem. Given the very limited data available on the spread of various zoonotic diseases, model parameterization remains a significant challenge in using methods such as the ones proposed here. Nevertheless, our preliminary efforts on parameterization show promise, and also the model displays a degree of robustness to inaccuracies in parameterization.Clearly, when transmission among small heterogeneous groups is considered (as in our model), stochastics in transmission very significantly impact the spread dynamics. In particular, both intrinsic variabilities in the interactions among individuals that cause spread, and also environmental uncertainties that modify transmission patterns, can critically impact the spread dynamics. Not surprisingly, prevalences of zoonotic diseases such as brucellosis show a large herd-to-herd variability, that can only be explained by considering stochastics in transmission. We have chosen to exclude consideration of stochastics in transmission in this first design effort, 1) because of the great difficulty in parameterizing such stochastic models with limited data, and 2) because our key focus here is on gaining very simple insights into policy design for which even the deterministic multi-group model may be sufficient. We consider the development of stochastic models for transmission to be an outstanding research task of critical importance.


Providing support for research is one of the key issues in the ongoing attempts to improve Primary Care. However, when patient care takes up a significant part of a GP's time, conducting research is difficult. In this study we examine the working conditions and profile of GPs who publish in three leading medical journals and propose possible remedial policy actions.The authors of all articles published in 2006 and 2007 in three international Family Medicine journals - Annals of Family Medicine, Family Practice, and Journal of Family Practice - were contacted by E-mail. They were asked to complete a questionnaire investigating the following variables: availability of specific time for research, time devoted to research, number of patients attended, and university affiliation. Only GPs were included in the study. Three hundred and ten relevant articles published between 2006 and 2007 were identified and the authors contacted using a survey tool. 124 researchers responded to our questionnaire; 45% of respondents who were not GPs were excluded. On average GPs spent 2.52 days per week and 6.9 hours per day on patient care, seeing 45 patients per week. Seventy-five per cent of GPs had specific time assigned to research, on average 13 hours per week; 79% were affiliated to a university and 69% held teaching positions.Most GPs who publish original articles in leading journals have time specifically assigned to research as part of their normal working schedule. They see a relatively small number of patients. Improving the working conditions of family physicians who intend to investigate is likely to lead to better research results. The promotion of quality research contributes to a successful Primary Care service. However, when family physicians spend most of their time attending patients, their opportunities for conducting research are limited.Research in Primary Care has three positive effects: patients receive improved quality of care; physicians' job satisfaction and motivation increase; and the health system benefits from improved clinical efficacy and effectiveness -3.For many years, family physicians have sought to increase funding and to extend the time available for research that would aid public health and university teaching . GPs neeSeveral studies have investigated the factors associated with positive attitudes towards research among physicians , and havIn this study we intend to establish whether researchers who publish in international journals devote all their time to patient care or whether part of their schedule is set aside for research. In so doing, we aim to define the profile and working conditions of the GPs who publish in leading family practice journals.The research protocol of the pilot study was approved by the Institutional Review Board of the Jordi Gol i Gurina Primary Care Research Center in Barcelona, Spain. All the corresponding authors of articles published in 2006 and 2007 in three Family Medicine journals - Annals of Family Medicine (AFM), Family Practice (FP), and Journal of Family Practice (JFP), with impact factors of 3.8, 1.55 and 1.27 respectively - were contacted by E-mail. Journal selection was not based on a systematic search but on criteria such as high impact factor and indexation in Pubmed.Our sample comprises authors who published articles in "family medicine journals". These are defined as journals with "family medicine", "family practice," or "family physician" in their titles, and indexed in Pubmed. We also stipulated that the author's E-mail address had to be included.FAM in the title. Four had to be excluded: American Family Physician, because it does not include original articles, Canadian Family Physician and The Journal of the American Board of Family Medicine, because they contain only domestic articles, and Family Medicine, because it does not include the authors' E-mail addresses in the abstract.Seven indexed journals contained the descriptive term All non-original articles published in the three journals selected were also excluded.All the corresponding authors of the articles published during the period of study were contacted and invited to complete a questionnaire investigating the following items: the number of days per week and hours per day spent attending patients, the availability of paid time for research, time devoted to research, and the number of patients seen per week. Participants were also asked whether they had any academic affiliation with a university or engaged in any other kind of teaching. All corresponding authors were included in the study. Non-GPs were excluded.ANOVA was performed for the three journals and the three countries/groups of countries with the highest number of publications . The other countries  were grouped together for the analysis because they only produced a single publication each. The three cases of authors who published on two different occasions were classified as new. We used a t-test to assess the statistical significance.Three hundred and ten original papers were published between 2006 and 2007 in the three selected journals. Replies were received from 124 authors (40%). Of these replies, 45.2% were rejected because they were written by physicians other than GPs . There were no differences in the response rate between GPs who published in AFM and FP (56%), but this rate was substantially lower among the authors who published in JFP (16.7%) (Table The GPs attended patients for an average of 2.5 days per week (SD 1.38), for 7 hours (SD 2.8) per day, and saw 45 patients per week (SD 30). Seventy-five per cent were allocated time for research (mean 13.8 hours per week), 79.4% were affiliated to a university, and 69.1% were involved in teaching. Authors who published in AFM devoted fewer days to patient care (p = 0.11), and saw fewer patients (p = 0.005) (Table The authors from the US and the UK (the most prolific) devoted fewer days to patient care and saw fewer patients, but did not spend less time attending patients on workdays. They all had university affiliations Table .Analyzing the profile of GPs who publish their research can help design interventions able to stimulate general evidence-based research in the future. The main finding of this study is that GPs who publish in prestigious journals do not see patients every day; most of these doctors have time specifically set aside for research and are university-affiliated.Interestingly, these physicians continue to see more than 40 patients a week. This indicates that they are clinically active, often at the price of seeing too many patients on the days they practice, although seeing more patients per day and devoting entire days to scientific research may in fact be an effective way of optimizing the time they spend with patients. Unfortunately, the majority of family doctors devote considerably more hours per week to patient care: According to Wensing , GPs in These differences in the availability of time highlight the importance of raising the profile of Primary Care in the scientific environment. Observers of the discipline agree that family medicine does not contribute enough to research and note that increasing financial and other pressures within its academic departments are making research more difficult .The profile of our GPs from the countries with low publication rates is no different from that of their counterparts in the US or the UK. However, in terms of university affiliation, physicians in the US and the UK are at an advantage because the discipline of Family Medicine appears to be better established there.Today, the time factor is critically important for a GP aiming to achieve professional excellence. Salmon et al. found that it is not "time, money, and lack of relevance" that dissuade practitioners from taking part in research but a lack of prioritization based on perceived threats to their professional autonomy and a lack of personal incentive . Time maThe characteristics that were positively associated with initiating research in a study of practitioners in the UK  includedIn our study many of the GPs who published the most were affiliated to universities. We believe that doctors who are involved in teaching at the University are more motivated to carry out research and have more time to do so. As in other disciplines, the vast majority of family medicine research is carried out in academic departments. This suggests that the discipline should strategically focus its research and development efforts on the academic environment. Academic family medicine is now represented in most medical schools, and international family medicine journals receive excellent papers from all over the world . In factThe methods that different countries have applied to develop family medicine research vary, but they usually include a combination of international support, local enthusiasm, willingness to change, and some luck .We were unable to use all the journals devoted to Family Medicine. The reasons were the lack of original articles, the presence of studies by GPs from highly circumscribed regions, the influence of regional differences, and country affiliation, since journals are probably more likely to publish studies by researchers discussing locally relevant healthcare problems than those written by foreign GPs.We consider the response rate to be high (40%) and the data obtained from our respondents showed the expected trend. As we stated in the methods section, our study centered on family physicians, and all other medical specialists were excluded. In all cases we wrote to the corresponding authors, because they are usually the leaders of research projects and take responsibility for publication. The absolute number of responses we used was enough to make it comparable with other studies and the results were consistent with the referenced literature. Due to the time commitment needed for research, it is more practical for a GP to be a member of a research team rather than the chief investigator and/or first author of a publication. This means that the study may have captured only a subgroup of publishing GPs and that there may be a risk of an answering bias.We do not have data on the amount of clinical work done by GPs who do not publish academic work. Judgements about the relative clinical load of GPs who publish are therefore speculative. Many studies by GPs are published in non-indexed journals. These studies are obviously relevant to an assessment of the research conducted in primary care but they are not easy to locate . In a brSome of the best primary care research has been published in general medical journals. A single study in a leading general medical journal might be a greater contribution to the discipline than several in a family medicine journal, and would have been missed by the method we used for journal selection. However, we believe that the inclusion of these high impact journals would not have significantly altered the professional profile of the researchers recorded in our study.In this study we found that GPs who publish original articles in leading family practice journals have time specifically assigned to research as part of their normal working commitments and see relatively few patients per week. Many of them are also affiliated to universities. Primary care is first contact, continuous, comprehensive, and coordinated care for individuals and populations undifferentiated by age, gender, disease, or organ system .Primary health care research is directly relevant to policy and practice . This isResearch impact comes through complexities and therefore unpredictable social processes ,21. The Therefore, in order to promote quality medical research and teaching in Primary Care, we must seek strategies to allocate time for research during the normal working day. Further studies should explore ways of enabling more family doctors to perform research. For example, in 1998, the RCGP developed a pilot scheme to accredit UK general practices undertaking primary care research and development. The Assessment Schedule included two levels: a Collaborative Research Practice with little direct experience of gaining project or infrastructure funding; or an Established Research Practice with more experience of research funding and activity and a sound infrastructure to allow for growth in capacity. The process for assessment involved the review of written documentation and an assessment visit by a multidisciplinary team. In 2001, recommendations were made to launch the scheme, renamed Primary Care Research Team Assessment (PCRTA), formally. The role of primary care research networks has been highlighted in relation to support and mentoring for research practices undergoing assessment. The new assessment scheme will help primary care trusts and individual practices to prepare and demonstrate their approach to research governance in a systematic way .High profile researchers who lead competitive projects are well acquainted with the research world, but many GPs would be keen to participate if they received encouragement and support A key chaA possible solution would be to allow interested doctors to participate in research on a part-time basis and to provide them with institutional support and resources ,26. The Further studies are needed to define more precisely the mechanisms for increasing GP involvement in academic activities. Research on primary care provides the means to improve the organization of services and to question beliefs or behaviours. The generalist clinician stands at one of the most complex intersections in society, as science, represented by psychological, physiological, and pharmaceutical interventions, and the humanities, as represented by the social contexts, beliefs, narratives, and shared mythologies, intermingle in consultations to formulate, on the one hand, interventions and their resultant outcomes and, on the other, extended stories that serve to embellish lives with hopes and fears. It is no wonder that research in primary care has, in distinction to other realms of medicine that largely embrace positivistic perspectives, uses the most diverse set of research methods .The authors declare that they have no competing interests.JSG designed the study, participated in the planning of the study, wrote the first draft of the manuscript and was responsible for study coordination. CR and CS supervised the study including its design, and participated in the writing of the manuscript. JRM performed the statistical analysis, and participated in the writing of the manuscript. All authors read and approved the final manuscript.


Untreated maternal syphilis leads to adverse pregnancy outcomes. The use of point of care tests (POCT) offers an opportunity to improve screening coverage for syphilis and other aspects of health systems. Our objective is to present the experience of the introduction of POCT for syphilis in Peru and describe how new technology can catalyze health system strengthening.The study was implemented from September 2009–November 2010 to assess the feasibility of the use of a POCT for syphilis for screening pregnant women in Lima, Peru. Outcomes measured included access to syphilis screening, treatment coverage, partner treatment, effect on patient flow and service efficiency, acceptability among providers and patients, and sustainability.Before the introduction of POCT, a pregnant woman needed 6 visits to the health center in 27 days before she received her syphilis result. We trained 604 health providers and implemented the POCT for syphilis as the “two for one strategy”, offering with one finger stick both syphilis and HIV testing. Implementation of the POCT resulted in testing and treatment on the first visit. Screening and treatment coverages for syphilis improved significantly compared with the previous year. Implementation of POCT has been scaled up nationally since the study ended, and coverages for screening, treatment and partner treatment have remained over 92%.Implementation of POCT for syphilis proved feasible and acceptable, and led to improvement in several aspects of health services. For the process to be effective we highlight the importance of: (1) engaging the authorities; (2) dissipating tensions between providers and identifying champions; (3) training according to the needs; (4) providing monitoring, supervision, support and recognition; (5) sharing results and discussing actions together; (6) consulting and obtaining feedback from users; and (7) integrating with other services such as with rapid HIV testing. Mother-to-child transmission of syphilis continues to be a problem, with more than 2 million pregnancies each year in women with syphilis Most countries have existing policies for universal syphilis screening during pregnancy, but implementation of such policies is weak, especially in developing countries, where congenital syphilis remains a major public health problem Approvals from the Ethics Review Committees from the World Health Organization, Universidad Peruana Cayetano Heredia , University of Washington , Callao Directorate of Health, and INMP were obtained. All participants signed informed consents.During 2009–2010, as part of a multi-country project Immediate Cure for Neonatal Syphilis). During a baseline focus group, women were asked about options for possible project names and suggested the name CISNE. They explained that, when a woman is infected with syphilis, the associated stigmatization makes her feel like an “ugly duckling.” Once she is diagnosed and receives treatment, however, she is transformed into a beautiful swan.The Peruvian study was named, “CISNE”  was introduced in the public sector antenatal and reproductive health services . Intervention sites included the largest maternity hospital in Peru, the National Maternal Perinatal Institute (INMP) in Lima, and a network of 15 semi-urban health centers and one hospital in Ventanilla-Callao, a resource-poor district north of Lima.The study lasted 14 months and was divided into two phases. The preparation phase, from September to December 2009, included ethical approvals, coordination meetings with authorities and health professionals, baseline collection of information, development of standard operating procedures (SOP), and development of training materials. The implementation and follow-up phase started January 2010 and ended November 2010. Overall success of implementation was measured by outcomes including syphilis screening and treatment coverage, partner treatment, effect on patient flow and service efficiency, acceptability of POCT among providers and patients, and sustainability.Prior to and during the initial phase of implementation, a total of 37 meetings were held with local and national authorities. These meetings provided opportunities to involve them in the study design and to play an active part in the roll-out of POCT screening over the course of implementation.To coordinate logistical details of the upcoming implementation and the follow up of the achievements, 215 working meetings were also held during the same period with local personnel who would be involved in POCT implementation. These included the coordinators of health centers and programs for reproductive health and STDs, heads of the local laboratories, and heads of the pharmacy programs, logistics offices, and midwives.We collected national and local data from 2010 on screening coverage with RPR for pregnant women, and treatment coverage for syphilis-seroreactive women. We also collected information on health care providers' knowledge about syphilis and explored perceptions related to the introduction of POCT. The information gathered was used to determine training needs, how tests would be integrated into the existing flow of care, what category of health professionals would perform the test, and the counselling women would receive in conjunction with the test.The CISNE team completed a mapping process in the health network of Ventanilla, to understand the current flow of care at health establishments, and how POCTs could be effectively integrated into the existing algorithms of care. The mapping process included: (1) interviews with health care providers; (2) simulated patients who recorded each of the steps to complete an ANC visit; and (3) real patients interviewed and then invited to participate, documenting the process of seeking ANC including waiting times and barriers encountered with each step of the process.www.proyectocisne.org.Materials were prepared for training, implementation, and dissemination of information. Educational materials included brochures, waiting room posters, flip charts, and a short video on the importance of syphilis screening to be shown (and now still being shown) in the waiting rooms of intervention health establishments. All materials are available through our website Regular ANC is mainly performed at the peripheral centers by professional midwives, so they were the main focus for training. A total of 604 midwives and nurses and laboratory workers were trained during the project. Training included clinical information on syphilis, treatment regimens, performing and interpreting the syphilis POCT, biosafety, and appropriate test reagent storage. Since these POCT for syphilis are read by eye and are subjective, we added as a regular component to the training workshops an assessment visual acuity for reading and color vision.“two tests one stick, or two for one” was introduced to integrate syphilis and HIV screening with POCTs.In Ventanilla, the concept of Same Day Testing and Treatment (STAT)strategy was applied with the objective that any pregnant woman with a positive POCT syphilis test result would receive the first dose of treatment on the day she is tested.At all intervention sites, the We performed complementary evaluations comparing cost-effectiveness of POCT against the Rapid Plasma Reagin (RPR) test; a performance analysis of POCT; and a post-implementation study of the acceptability of POCT among providers and patients. At the ANC services, midwives had a registration form provided by the Ministry of Health to record HIV and Syphilis testing and treatment in pregnant women. During the study we monitored the completeness and accuracy of the data collected, and added the information of partner treatment. After the study we continue using those forms to capture information.At the national level screening coverage for syphilis in pregnant women, according to the reports from the National HIV/STI Program, has been 75% since 2000, but treatment coverage for syphilis seropositive women in ANC had fallen intermittently, from over 80% in 2000, to as low as 30% in 2004 . PrevaleDuring baseline surveys, providers demonstrated poor knowledge and little recognition of syphilis as a problem. Some health workers had worked with rapid tests for HIV. Their initial experience with rapid tests for HIV was reported as very bad, due to the high rates of false positives, which make them refer to rapid tests as “unreliable.” Several providers therefore shared their fear and distrust of any diagnostic test called rapid, saying “good things take time.” These health workers were hesitant about the introduction of a POCT syphilis test as it was seen similar to the “rapid HIV test.”Additionally, laboratory workers felt the test could compromise their “authority,” while clinicians were concerned that a POCT for syphilis would increase their workload.In order to dissipate fears, we defined different responsibilities for each provider in the implementation pathway, i.e., midwives screening in ANC and labor; nurses screening at miscarriage services; physicians prescribing the treatment; laboratory workers in charge of the quality control system; and pharmacists  to ensure that the test and the penicillin were always available.According to Peruvian National Guidelines for Care of Sexual and Reproductive Health Through the mapping process we found that to complete an ANC visit, a pregnant woman had to go to a health center a total of 6 times during a total of 27 days. HIV rapid testing was implemented in the country several years ago, but the test was performed with venous blood and at a central laboratory. In a case of a positive syphilis test (which was commonly an RPR test) there was a delay of almost a month between screening and treatment if penicillin was available, which we found was not always the case.These findings were presented to the district MOH officials, and helped lay the groundwork for stakeholder support throughout the implementation process.We found that 269 of 604 (44.5%) health providers participating in the training had difficulties with near vision which did not allow them to recognize the line in the POCT. Two (0.3%) were color blind, and did not recognize the red line. For the first group we were able, in coordination with the local authorities, to recommend and prescribe visual aids (reading glasses) based on this evaluation and the health provider's visual needs. We found it most helpful, when implementing this POCT, to include the visual evaluation, which improved the performance of the providers reading the tests, once the visual problem was corrected.After implementation began, the research team continued to hold coordination and training meetings as appropriate, in order to strengthen skills and dispel doubts related to the use of the syphilis POCT. Throughout the study period, it became increasingly clear that the physicians (who are not necessarily involved in the ANC but determined treatment regimes for patients with syphilis) also needed to be sensitized about POCT, despite the fact that they were not directly involved in the performance of tests. We held a series of five training sessions for physicians in the INMP and Ventanilla.The implementation of the POCT in all locations resulted in a change of the patient flow for ANC, and the offer of the testing and treatment for HIV and syphilis on the first visit. We documented a decrease from six visits to one .From a total of 18,105 women, 17,155 were screened with syphilis POCT in Ventanilla and the INMP. A total of 154 (0.9%) women had a positive POCT for syphilis. None of the seropositive women had lesions or symptoms of active infection. When asked, 48/154 (31.2%) reported a previous history of syphilis and none recall previous treatment. Screening coverage was 94.8% and treatment coverage with at least one dose of penicillin was 91.6%. Eighty percent received at least two doses of penicillin.As can be seen in Screening coverage improved at the peripheral network of health centers in Ventanilla from 35% to 93% (p<0.001) and at the INMP from 68% to 95% (p<0.001) from 2009 to 2010 . TreatmeThe syphilis POCT was only integrated into the well-established rapid testing program for HIV only in the Ventanilla Health Network as a model. At the first ANC visit, women were screened for both tests with one fingerstick. Integrating the two tests improved uptake of the syphilis POCT and simplified processes. A total of 4497 women were screened with the HIV rapid test and the POCT for syphilis during the study period. Thirteen (0.3%) women tested HIV positive and 43(1%) positive for syphilis. No cases of syphilis-HIV co-infection were found.During the implementation period we documented difficulties regarding stockouts and the use of multiple types of rapid HIV test by the health centers. Due to the fact that the tests are bought locally and in small quantities, stockouts are common, the “format” of the test varies, no quality control is available, and each time a new test is introduced there is no training for the health workers. Tests vary in the time for incubation, and the number drops of buffer added to the wells. We documented also the poor quality of the tests, with 15% of invalid in some brands of rapid HIV test. This situation was shared with the authorities, and the lessons learned were used to introduce a system of central procurement for the syphilis POCT and improve the available system for HIV.During the study the testing was done by Ministry of Health (MOH) personnel, with supervision from the CISNE team. Three months prior to the conclusion of the study, a plan was put in place for the gradual transfer of supervision from the CISNE team to the MOH administrators and health establishments. The plan outlined how CISNE supervision slowly decreased over time, and responsibilities were transferred to the public sector and how the scale up will be done.Due to their involvement in the planning and follow up of the study, the local directorate authorities and authorities from the MOH witnessed the tangible improvements made possible through the POCT, and became vocal proponents for the inclusion of the syphilis POCT in guidelines governing prevention of congenital syphilis.The first policy change that occurred as a result of the research was the revision of the INMP's institutional guidelines, this being the main national training institution on issues of maternal health. The second policy change, and the more important, is the one we have promoted at National level. After several meetings with the MOH authorities and members of the Reproductive Health and STI/HIV Programs, the syphilis POCT was introduced in the new “Guidelines for the Prevention of Mother-to-Child Transmission of HIV and Syphilis.” The Minister of Health launched in February 2011 the campaign “Yes to life, No to syphilis.” We collaborated with the MOH on the training at the national level, identifying the providers with the best performance, and “champions” within the project, and training them to become “trainers of trainers.” The syphilis POCT is now implemented in all centers in Peru, for screening in ANC, labor and miscarriage services.CISNE's successful involvement of key stakeholders throughout the process of implementation resulted in immediate change in policy and practice to include syphilis POCT in national syphilis screening algorithms. We continued following the development of the use of the POCT for screening in the areas where we started. Coverages for screening, treatment and partner treatment have remained over 92%.We have been able to catalyze the interactions between cooperation agencies such as PAHO and UNICEF and the MOH, and with their support the MOH of Peru bought the first 500,000 tests for 2011 and national distribution of the tests was performed. For 2012 the supplies for syphilis POCT have been bought and distributed nationally.www.proyectocisne.org). Another resource available in Spanish is an online course on Maternal and Congenital Syphilis and POCT, which was elaborated with the INMP, and can be accessed at http://sicavirtual.vis.com.pe/campus/.We collaborated with the London School of Hygiene and Tropical Medicine in the development and adaptation of a “Rapid Syphilis Test Toolkit” which is a document including tools for the introduction of rapid syphilis tests into country programs This implementation research project assessed the feasibility of introducing POCT for syphilis for antenatal screening and reproductive health services in Lima, Peru. It not only proved to be feasible, but the introduction improved several aspects of the health system. We were able to simplify processes, decrease the number of times a pregnant woman had to go to ANC, increase coverage of syphilis screening and treatment, improve information, and improve relations between providers by clarifying their roles within the system.There are publications which refer to the implementation of syphilis POCT in developing countries and its successes Prior to and during to implementation we found it critical to meet with authorities from different levels and stakeholders  to inform, discuss and make decisions about the project. Dealing with many institutions could be challenging, but bringing all stakeholders to the table issues like specific interests, discussing openly how best we could to work together and how to avoid duplications, helps. The time and effort spent on these meetings were well worth it and were largely responsible for the success of the program. In our case, important themes to discuss included syphilis and congenital syphilis prevalence, actual screening and treatment coverages, the need for improvement, treatment protocols and importance of partner treatment, performance of POCT compared with RPR, quality control issues, and general short and long-term goals for test implementation and data from the follow up and supervision. Throughout the study period, meetings were convened periodically to report progressive research results and answer questions arising. We involved all stakeholders wherever possible to cultivate their interest and increase long-term buy-in.We found it extremely important to meet with all health care providers involved in the process of ANC and reproductive health prior to POCT implementation. Although the midwives were those who would be working directly with the test, we included all the levels of health professionals – nurses, physicians, lab technicians, and pharmacists – allowing us to dissipate tensions, overcome barriers, answer questions, clarify roles, and discover “champions” at all levels. Champions are those individuals who are proactive, interested in making things better, passionate in their job, capable of communicating well and to influencing their peers.Those laboratory technicians who opposed the introduction of POCT changed their minds when they understood their key role in quality control; pharmacists helped to improved the logistics to assure penicillin availability at the clinic for treatment when needed, and nurses found their role in performing the POCT at the miscarriage services.Quality training, based on the knowledge gaps and fears, proved essential to overcome barriers presented by health providers and administrators.We highlighted the issues not known by the providers, that could motivate them to act, e.g.,“Syphilis is 20 times more frequent in Peru than HIV”; included practical sessions to learn how to perform fingersticks and how to read the test more accurately, sessions on the importance of quality control and a session directed to dispel myths and misbeliefs regarding maternal and congenital syphilis and the syphilis POCTs. One important issue that arose over the study period, however, was the refusal of some physicians to administer immediate treatment with a positive POCT because of doubts about test performance. Mainly they were those doctors who did not attend the training sessions. We had to incorporate “in situ” training  and created also the online course mentioned above. Furthermore, by widely diffusing information about syphilis POCT, it is likely that more providers will support implementation from the onset and the spread of misinformation will be kept to a minimum.In addition to pre-implementation training, the CISNE team conducted periodic training sessions with health care providers to present results, reinforce key messages, and dispel doubts that had arisen along the way. These sessions were important to gain and maintain support from health providers. Furthermore, meeting periodically with providers created a feedback mechanism through which the study coordinators could glean information and make necessary changes.Especially during the first months of implementation, daily monitoring and supervision provided the support and accountability that providers needed to incorporate a new process into their already challenging workload. As the project evolved, the supervision frequency was lowered to once a week and later once a month.Initially, providers resisted the added responsibility of syphilis POCT. Over time, however, we observed that they adapted to the process and came to recognize its merits. Daily “support” was indispensable to the change in attitudes over time. For this reason, as part of an implementation process of new technology , it is critical to include a team of well trained supervisors. We also included a system of recognition for their accomplishments, which included certificates of good performance given to the providers. They could receive a copper, bronze, silver, gold, or platinum certificate according their achievements, using different color papers, but very much appreciated! The award levels were successive and related to their performance during training or during supervisions, evaluations during quality assurance, training of other personnel and numbers of tests performed.We included in the monthly meetings that the midwives had as part of their regular activities a short section of “How is the POCT implementation evolving?” In five minutes, we presented the latest data on screening with the syphilis POCT and treatment in their establishments, from their records, and the findings of the supervision. Then we took ten minutes for discussion, to answer questions, and to recognize those doing a good job.After some educational materials had already been printed with pictures of midwives performing POCT, other worker cadres  complained that the project had excluded them. We had to reprint the materials, this time including other providers in different activities related to the implementation. They helped in the design of these new booklets and also in the dissemination, and suggested new types of educational materials to develop such as posters and videos, which became very popular. This highlighted the need to consult health providers throughout the process of implementation, respect the complicated structure and processes present at each site, and take advantage of their experience.Integration of syphilis and HIV screening with POCT is feasible and very well accepted by health workers and pregnant women in our study. The provision through the delivery of an integrated package increases synergy and efficiency since both aim at the same population of pregnant women. Time of the provider and the women can be saved doing the two tests at once; women only need one fingerstick; health services can save supplies , the training for both tests can be done together and ANC and reproductive health services can be strengthened. If both tests are from the same company, procedures are likely similar, making training easier.According to the World Health Organization Report 2000, health systems consist of all the people and actions whose primary purpose is to improve health; the four key functions are: governance, financing, human and physical resources, and organization and management of service delivery This study has shown that the use of the syphilis POCT is a feasible and acceptable maternal health intervention to prevent congenital syphilis in Peru. Rates of patient and partner screening and treatment during the study period show that implementation of POCT has the potential to increase timely screening and treatment coverage for syphilis for women. Through our research, policy makers and health care administrators were provided with applicable, current data with which to make evidence-based changes to existing policy. Furthermore, our study has demonstrated that POCT implementation can contribute to long-term improvements in service delivery, strengthening health systems and maternal and child health programs in Peru and potentially in other countries in the Latin American and Caribbean region.


By the 1950s, pollution had extirpated Atlantic salmon in the river Mersey in northwest England. During the 1970s, an extensive restoration program began and in 2001, an adult salmon was caught ascending the river. Subsequently, a fish trap was installed and additional adults are now routinely sampled. In this study, we have genotyped 138 adults and one juvenile salmon at 14 microsatellite loci from across this time period (2001–2011). We have used assignment analysis with a recently compiled pan-European microsatellite baseline to identify their most probable region of origin. Fish entering the Mersey appear to originate from multiple sources, with the greatest proportion  assigning to rivers in the geographical region just north of the Mersey, which includes Northwest England and the Solway Firth. Substantial numbers also appear to originate from rivers in western Scotland, and from rivers in Wales and Southwest England; nonetheless, the number of fish originating from proximal rivers to the west of the Mersey was lower than expected. Our results suggest that the majority of salmon sampled in the Mersey are straying in a southerly direction, in accordance with the predominantly clockwise gyre present in the eastern Irish Sea. Our findings highlight the complementary roles of improving water quality and in-river navigability in restoring salmon to a river and underlines further the potential benefits of restoration over stocking as a long-term solution to declining fish stocks. Salmo salar L.  in Norway  in France  in Pacific northwestern USA  is being recognized as a viable alternative, which can subsequently facilitate natural recolonization. Examples have been reported for trout . A recent study, which followed 30 salmon caught at the weir, found that eight successfully ascended into the upper reaches of the River Mersey  were carefully removed from the trap, measured, weighed, and scales removed for aging and genotyping. The three juvenile fish sampled were caught during routine Environment Agency electric fishing surveys in the upper reaches of various Mersey tributaries. The total sample for genetic analysis was 149 Atlantic salmon .Genomic DNA was extracted from individual scales using a Chelex protocol . PCR conditions were as follows: an initial denaturation step of 5 min at 95The size of the fluorescently labeled PCR products was determined using a Beckman Coulter CEQ8000 automatic DNA sequencer and the associated fragment analysis software . Data were checked for scoring errors due to stutter peaks, large allele dropout, and null alleles using the program MICRO-CHECKER v2.2.3 .In order to address the possibility that adult salmon sampled in the Mersey were salmon farm escapees, four populations from Norway were included in the baseline as surrogates for farmed fish. The vast majority of fish farmed in Britain are descended from Norwegian stock , assignment programs can be unreliable , which was less than the 0.05 recommended by Latch et al. . The clustering of rivers within the corresponding k = 7 run agreed strongly with the clustering by BAPS, except for the following exception: BAPS placed the southern Irish rivers, the Barrow, Boyne, and Suir, together with the rivers from Scotland, whereas STRUCTURE identified that each river contained a mosaic of genetic signatures matching those from Northern Ireland, Scotland, and from around the Solway Firth  of fish correctly assigned back to the river from which they were sampled. After the formation of reporting regions, the proportion of correctly self-assigned individuals increased to 78% in GeneClass 2 and 79% in ONCOR .Exclusion analysis found that for 21 of the 135 salmon sampled from the Mersey, the probability of their assigning to any of the recognized reporting regions was less than 0.05 (Supporting Information 5). Therefore, the results of assignment analysis for these individuals are not considered further, but can be found in Supporting Information 1.Genetic assignment showed the remaining salmon from the Mersey to have a variety of different origins . Both GeThis study aimed to identify the origins of Atlantic salmon recolonizing the river Mersey and in doing so, has revealed some limitations for genetic assignment of wild salmon within this region. Although most of the salmon now entering the Mersey could not be assigned to an exact river of origin, by identifying distinct genetic signatures of groups of salmon rivers, we were able to identify their region of origin with a high degree of probability. The reporting regions identified here matched those identified by Griffiths et al.  and, accThe genetic baseline used for assignment of Mersey fish was a subset of the populations used in the ASAP , it was striking that so few  appeared to have origins in the neighboring southwest England & Wales region . In particular, this reporting region contains the river Dee, a highly productive salmon river that enters the sea in close proximity to the Mersey; the estuaries of these two major rivers are separated by the 11-km-wide Wirral peninsula. This finding may be due to the prevailing clockwise gyre in the eastern Irish Sea and an associated current, which for much of the year runs southwards down the northwest coast of England  at least, this is beyond current means. The results of the leave-one-out test showed that less than one in two fish could be correctly assigned back to their river of origin; unfortunately, such a figure is insufficient for meaningful assignment. This was somewhat to be expected as previous research by Griffiths et al. , also foKey to improving the accuracy of genetic assignment is improving the genetic distinction between populations within a baseline. One way of doing this might be to increase the number of markers used, either via the addition of more microsatellites, or with the use of Single Nucleotide Polymorphisms (SNPs) (Beacham et al. Overall, this study and others like it (e.g., Knutsen et al. Alternatively, in situations where the need for fish population restoration is urgent – for example, post-pollution mitigation – then assignment studies such as this offer, in combination with river restoration, robust insights as to which populations might best serve as donors for translocation, and thus more rapid recolonization.bona fide methodology for the re-establishment of salmonid populations in rivers from which they have been previously extirpated; our results also serve to reconfirm the capacity for straying in this species otherwise famous for its homing ability.In conclusion, this study overcomes limitations in genetic assignment in order to ascertain the origins of Atlantic salmon recolonizing the river Mersey. Fish entering the Mersey appear to be from multiple regions primarily within England, Scotland, and Wales, and, in particular, from the rivers in close proximity to the Solway Firth and the northwest of England. This key finding highlights an apparent clockwise direction of straying by Atlantic salmon in this region, which we speculate to be due to the clockwise Gyre in the eastern Irish Sea. The one successfully analyzed juvenile assigned consistently to this same region, which may indicate that not only is this region responsible for the greatest number of strays, but that these strays are also the most likely to successfully reproduce in this river. This study also finds that a small fraction of their colonizers are from northern Ireland, whereas a similarly small proportion appears to originate from France. The evidence suggests that salmon farm escapees with a distinct Norwegian signature may be a fraction of the recolonizers; however, incongruence between the methods used prevented firm conclusions on this topic. Although the information gained from this study increases our scientific understanding of the salmon life cycle, our findings are also especially useful for river management, as they demonstrate clearly the benefits of river restoration as a


Realist reviews offer a rigorous method to analyze heterogeneous data emerging from multiple disciplines as a means to develop new concepts, understand the relationships between them, and identify the evidentiary base underpinning them. However, emerging synthesis methods such as the Realist Review are not well operationalized and may be difficult for the novice researcher to grasp. The objective of this paper is to describe the development of an analytic process to organize and synthesize data from a realist review.Clinical practice guidelines have had an inconsistent and modest impact on clinical practice, which may in part be due to limitations in their design. This study illustrates the development of a transparent method for organizing and analyzing a complex data set informed by a Realist Review on guideline implementability to better understand the characteristics of guidelines that affect their uptake in practice . The data organization method consisted of 4 levels of refinement: 1) extraction and 2) organization of data; 3) creation of a conceptual map of guideline implementability; and 4) the development of a codebook of definitions.Language, Format, Rigor of development, Feasibility, Decision-making.This new method is comprised of four steps: data extraction, data organization, development of a conceptual map, and operationalization vis-a-vis a codebook. Applying this method, we extracted 1736 guideline attributes from 278 articles into a consensus-based set of categories, and collapsed them into 5 core conceptual domains for our guideline implementability map: This study advances analysis methods by offering a systematic approach to analyzing complex data sets where the goals are to condense, organize and identify relationships. Complex interventions, such as those used to improve quality of health care, are informed by principles from health services research, management, psychology and engineering, in addition to medicine. Despite this, they often lack a clear theoretical basis, making it hard to summarize this disparate literature in a way that can inform intervention design or interpretation of results . A realiprocess for organizing and relating findings  may be To address this issue, we describe the development of a process for organizing and analyzing complex evidence derived from findings of our realist review on guideline implementability as a means to advance the science of knowledge synthesis.Figure Two groups of investigators extracted 1736 intrinsic guideline attributes  from 278 included articles on study discipline , attribute name and definition (as documented by authors), attribute operationalization , attribute relationship with uptake, and any potential tradeoffs. To ensure reliability, consistency and accuracy of the data extraction, we used an auditing process whereby secondary reviewers checked data extractions of primary reviewers. Disagreements were resolved through consensus-based group discussions involving all investigators.The 1736 identified attributes were sorted with the same name or root  in an Excel database. Two groups of investigators  then took the same list of sorted attributes and independently clustered them into logical categories. This involved a process of building up groups of similar or like attributes (including their synonyms and antonyms) that conceptually “fit” within a larger theme, and creating a label and description for each category. Table Language, Format, Rigor of Development, Feasibility, Decision-making. Based on the evidence around these domains, we developed broad and common sense definitions for each as well as their included categories, which informed a conceptual map of guideline implementability. The development of this map was guided by a web-based visualization tool, MindMeister (http://www.mindmeister.com), which was used iteratively by all investigators to determine the structure of the framework , and to facilitate the decision-making process for grouping and identifying patterns in the data. Such visualization techniques have been shown to facilitate comprehension, identify the inferences about the qualities of parts and the relations among them, and be useful for revealing the hierarchy of groupings and important relationships [Using a consensus approach among the two groups of investigators via discussions of the attribute definitions and their similarities and relationships, the final set of 27 categories . Through consensus-based discussions amongst our team, findings of this survey were used to make modifications to the organization and structure of our data .To validate and to identify potential flaws in categorization and to obtain agreement on the sensibility and fit of attributes within and across the categories, a group of 9 stakeholders with knowledge translation and guideline development expertise were surveyed. These experts were asked to review the content of the 5 domains and its sub-domains, and to rename, rearrange and condense attributes as they saw fit. The survey comprised Likert-type and open-ended questions about the operational definition of the domains, and the fit of categories and their attributes within them . The codebook was developed one domain at a time using a modified duplicate reviewing process that involved a set of primary reviewers extracting and documenting the information, and a second group of reviewers “auditing”  primary reviews in small-group discussions; a third group of reviewers resolved disagreements. The main objectives of the auditing process were to verify the completion of documentation, to ensure the appropriate understanding of concepts, and to determine the best fit of attributes and information within and between categories and domains.The two groups collectively developed a codebook of definitions to better understand each of the 5 domains of implementability, the relationships between guideline attributes and their uptake, and potential tradeoffs. The process involved documenting definitions for modifiable attributes  and their operationalization , the context and setting in which these occur, for whom, any relationship with uptake, and attribute tradeoffs if they existed Language, Format, Rigor of development, Feasibility, Decision-making. These findings will be used to answer our Realist review question: What is it about guidelines that facilitate or impede their uptake, for whom and in what circumstances this happens, and how and why this happens.Complex interventions are often atheoretical and loosely draw on a broad literature that includes different disciplines and is difficult to summarize systematically. Qualitative synthesis methods are poorly operationalized and do not describe how to organize and analyze large heterogeneous datasets. We used a systematic process of analysis to build a conceptual map of guideline implementability through the classification of 1736 attributes into a consensus-based set of categories, which were then collapsed into 5 core conceptual domains of guideline implementability: et al. is currently underway to determine which knowledge synthesis methods are available, and to develop a systematic process to help researchers select the most appropriate method(s) to address their research questions about complex evidence [We reviewed a range of review methods to answer our research. The details explaining the rationale for selecting a Realist Review is published in our protocol . Brieflyevidence .A limitation of our work is that the approach we used was largely interpretive. However, the quality of synthesis is dependent on reviewers’ explicitness and reflexivity of the methods. In our process to make sense of the complex data that emerged from our Realist Review, we ensured transparency of the methods and included several validity measures to minimize sources of error. This was important given the interpretive nature of our process and the anticipated learning curve involved in data abstraction. The measures included an auditing process whereby primary data extractions was checked by secondary reviewers, and a process to verify this data against a codebook of definitions during Level 4 analysis. Lastly we tested the validity of our data organization and analysis through an expert survey to verify the sense and fit of attributes and categories within the framework.In our realist review, we considered each attribute and integrated like-attributes into common themes and domains. Further, we considered evidence of impact or effectiveness on our relevant outcome. For example, evidence indicates that a guideline recommendation is more actionable if it clearly specifies when, who should do precisely what action; if a recommendation does not specify these steps or uses passive verbs, its actionability will be diminished. Such conceptualization of the evidence can then be useful to support or refute various theories or their elements in the literature about guideline implementability. These strategies enabled us to embrace the whole of the data, with few preconceived expectations, to identify and carefully define elements that are relevant to guideline uptake. The approach described in this paper is an example of how new analytic methods can emerge and respond to the challenges related to finding the best fit between methods and research questions. Based on our experience, Table Our work has the potential for wide influence. The proposed method will appeal to more investigators because the process has now been operationalized, is fairly straightforward to apply, it can be applied to a wide range of topics and the return on effort is significant. Expanding this knowledge base will become particularly important as these rapidly expanding fields most often require more sophisticated techniques to analyze data, which is informed by complex interventions that cut across multiple disciplines and from the input of multiple stakeholders.This study represents a novel contribution to advancing complex data analysis methods by offering a systematic approach to analyzing any large and disparate data sets where the goals are to condense, organize and identify relationships.None of the authors have any financial or non-financial competing interests to declare.All authors contributed in the design of the study. MK, LH, AC, JM, LD executed the study and MK, LH, JM, AC, LD, OB, MB conducted the analysis and interpreted the results. MK drafted the manuscript, and all authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2288/13/112/prepubExpert feedback review form on the Guideline Implementability Framework.Click here for fileExample of a Codebook of definitions.Click here for file