Population health planning aims to improve the health of the entire population and to reduce health inequities among population groups. Socioeconomic factors are increasingly being recognized as major determinants of many aspects of health and causes of health inequities. Knowledge of socioeconomic characteristics of neighbourhoods is necessary to identify their unique health needs and enhance identification of socioeconomically disadvantaged populations. Careful integration of this knowledge into health planning activities is necessary to ensure that health planning and service provision are tailored to unique neighbourhood population health needs. In this study, we identify unique neighbourhood socioeconomic characteristics and classify the neighbourhoods based on these characteristics. Principal components analysis (PCA) of 18 socioeconomic variables was used to identify the principal components explaining most of the variation in socioeconomic characteristics across the neighbourhoods. Cluster analysis was used to classify neighbourhoods based on their socioeconomic characteristics.Results of the PCA and cluster analysis were similar but the latter were more objective and easier to interpret. Five neighbourhood types with distinguishing socioeconomic and demographic characteristics were identified. The methodology provides a more complete picture of the neighbourhood socioeconomic characteristics than when a single variable (e.g. income) is used to classify neighbourhoods.Cluster analysis is useful for generating neighbourhood population socioeconomic and demographic characteristics that can be useful in guiding neighbourhood health planning and service provision. This study is the first of a series of studies designed to investigate health inequalities at the neighbourhood level with a view to providing evidence-base for health planners, service providers and policy makers to help address health inequity issues at the neighbourhood level. Subsequent studies will investigate inequalities in health outcomes both within and across the neighbourhood types identified in the current study. Traditional health planning has typically focused on the practice and delivery of health care services. Population health planning, on the other hand, aims to improve the health of the entire population and to reduce health inequities among population groups . The heaSince socioeconomic and demographic characteristics are important determinants of population health, adopting a population health approach to health planning at the neighbourhood level requires improved knowledge of the distribution of population socioeconomic and demographic characteristics at this level. Globally, there is an increasing interest in understanding the relationship between neighbourhood of residence and health of the population -19. To tCurrently, the lowest geographical level at which most health-planning data in Canada are analyzed is the municipal (city) level. Obviously, the use of such a large unit of analysis limits the ability to identify specific population characteristics as well as health variations and needs at the lower levels. The implication is that disparities in health outcomes and access to health care services across population sub-groups at these lower levels are unclear. Moreover, most large cities have diverse populations -24; therStudies of geographical distribution of determinants of health have mainly used one of three approaches. The first involves either production of a single map showing the spatial distribution of a single variable  or production of a series of maps each showing the distribution of a single determinant of health -45. The The objectives of this study were to use multivariate statistical techniques to identify the socioeconomic and demographic characteristics of neighbourhoods in the city of Hamilton, Ontario, Canada; and to classify the neighbourhoods based on similarities of these characteristics. Potential applications of the methodology in needs-based neighbourhood population health planning, service delivery, and policy development are proposed.The study was carried out in the city of Hamilton, Ontario, Canada. The city has a population of over 490,000 people and spans over 1,117 square kilometres . A numbeBased on the above criteria, census tracts were chosen as the most appropriate level of geography for the analysis. A census tract (CT) is a small, relatively stable geographic unit usually having a population of 2,500 to 8,000 persons with an average of approximately 4,000 . There aSocioeconomic and demographic data for 833 dissemination areas (DA) in the city of Hamilton, Ontario, Canada, were extracted from the 2001 Canadian census data . A DA isAll statistical analyses were performed in STATA . To overPrincipal component analysis (PCA) was used to reduce the dimensionality of data and to investigate the nature of the relationships among the CTs with the main objective of isolating the general features that best describe the variations in the data. Using this method, 18 inter-correlated socioeconomic and demographic factors were reduced to 5 principal components each of which represented different aspects of the original data. Kaiser criterion  was used to guide the decision on the number of principal components to retain; all components with eigenvalues equal to or less than 1 were not retained since they explained variations equal to or less than any one of the original variables ,59. To mCluster analysis is a multivariate statistical technique used to organize observations into groups (or clusters) such that observations within a cluster have a high degree of similarity  among themselves while the clusters are relatively distinct from each other . There aThere are two major classifications of cluster analysis techniques: hierarchical and non-hierarchical (or partition) techniques. This study adopted the partition cluster analysis, using k-means clustering methodology, to group CTs (or neighbourhoods) based on socioeconomic and demographic characteristics into clusters or neighbourhoods types. Using this methodology, the user specifies the number of clusters, say x, to create. These x clusters are formed through an iterative process. The algorithm begins with x seed values which act as the initial x group means. Observations are then assigned to the nearest group seed. After all observations have been assigned, cluster means are computed for each group. The initial cluster seeds are then replaced by their respective cluster means. The observations are then re-assigned to the nearest cluster mean. These steps continue until no observations change groups (clusters).The optimum number of groups or clusters or "neighbourhood types" to be identified was decided upon using Calinski-Harabasz pseudo-F test  as well The similarity (or dissimilarity) measure  used for the classification of the CTs was Minkowski distance metrics with argument 2 (L2) . This meik and xjk are the values of variable k for CTs i and j respectively. The summations are over the p (or 18) variables involved in the cluster analysis. The 5 initial cluster centres were obtained randomly from among the CTs or neighbourhoods in the study area. For reproducibility a random number seed was applied before the 5 CTs were randomly chosen.where: p (in this case 18) is the number of variables included in the cluster analysis; xSince neighbourhoods belonging to the same group have certain socioeconomic and demographics characteristics in common, the resultant grouping provides useful insights into understanding the socioeconomic and demographic characteristics of each group (or neighbourhood type).All cartographic manipulations were performed in ArcView GIS . The priAll the observed correlations were in the expected directions Table . For insOnly the first five principal components, that had eigenvalues greater than 1, were extracted Table . The firThe first Principal Component is the most important since most (12) of the variables loaded heavily on it Table . The comPrincipal component 1 is mainly an economic status component but also had a social component. Neighbourhoods (CTs) with high values of this PC had high proportions of aboriginal people, low median income, high percentage of low-income earners, relatively high percentage of individuals receiving government transfer income, high unemployment rates, low dwelling values, a high percentage of single-parent families, few owner-occupied dwellings, few married people, high percentage of persons living alone and high population density Figure . These nPrincipal component 2 was generally a demographic component. Neighbourhoods with high values of PC 2 had high percentages of children less than 20 years of age, but low percentages of seniors Figure . NeighboFigure Neighbourhood Type A is primarily located within an inner ring surrounding the downtown core. These neighbourhoods can be described as "mature" areas  with some indications of transition . Neighbourhood type A consists of 46 census tracts. A high population density, percentage of seniors and low-income earners, and a medium percentage of new immigrants characterize this neighbourhood type. It also has a high percentage of single-parent families, low dwelling values and a medium percentage of persons not able to speak English or French. Approximately 32.7% of Hamilton residents live in this neighbourhood type.Neighbourhood Type B includes high economic status neighbourhoods in low-density rural or suburban environments. Since it covers the largest geographical area, its low population density has a great impact on the overall population density of Hamilton. These areas constitute the geographic periphery of the city, forming an outer ring from east to west. Neighbourhood type B is comprised of 24 census tracts and has approximately 23% of Hamilton residents. It has high median income, dwelling values, and percentage of owner-occupied dwellings and a medium percentage of seniors. This neighbourhood type also has a low percentage of new immigrants, single-parent families, and individuals with less than grade 9 education.Neighbourhood Type C represents a relatively high economic status neighbourhoods within a more urban environment. Unlike Neighbourhood Type B, an area similar in income and dwelling value levels, this NT has a relatively high percentage of visible minority groups. It consists of 17 census tracts and is characterized by high median income, and dwelling values. In addition, this NT has few seniors and persons living alone, but a medium percentage of individuals who cannot speak either English or French. It also has high dwelling values and population density. Approximately 16.9% of Hamilton residents live in this type of neighbourhood.Neighbourhood Type D depicts a "mature" urban area with a high percentage of seniors and owned dwellings. It has a relatively low percentage of low-income earners and a high percentage of individuals with less than grade 9 education. In addition, this neighbourhood type has few recent immigrants and internal migrants, low unemployment rate, high percentage of owner-occupied dwellings and medium percentage of persons not able to speak English or French. It is composed of 20 census tracts and 9.6% of Hamilton residents live in this type of neighbourhood.Neighbourhood Type E constitutes the inner city core and a few areas scattered in the inner ring around the core, and is comprised of 24 census tracts. It has a high prevalence of low-income earners, new immigrants, visible minority groups, and persons with less than grade 9 education. It also has many single-parent families, those receiving government transfer income and high unemployment rate. Approximately 17.7% of Hamiltonians live in these neighbourhoods. Note that the sum of the population percentages of the groups is not 100% because one census tract was not included in the analysis because of missing data.This study has used multivariate techniques to characterize neighbourhoods based on differences and/or similarities of their socioeconomic and demographic characteristics. The positive correlation between single-parenthood and low-income is consistent with observations from other studies that single-parents generally tend to spend more time in low-income neighbourhoods compared to childless couples and unattached individuals . MoreoveThe negative correlation between housing ownership and visible minority has been reported in other studies . In addiThe low uniqueness values of the PCA imply that the five PCs appropriately represent the socioeconomic and demographic variables included in the analysis. Uniqueness values higher than 0.6 are considered high . The advChoice of the unit of analysis is critical in these kinds of analyses due to the modifiable areal unit problem (MAUP) since choice of a different and/or inappropriate unit could lead to quite different results ,71. As hIn this study, the results of the PCA were generally similar to those of cluster analysis since the distribution of areas identified as high risk by PC1 tended to follow similar spatial patterns as the high risk areas identified by cluster analysis. Both methods are therefore useful in identifying neighbourhood socioeconomic characteristics that would enhance health planning. However, as has been pointed out by Luginaah and co-workers , interprSimilar to the pattern seen in other industrial North American cities ,73-75 moThe current study is the first of a series of projects designed to investigate neighbourhood health inequalities and provide information to foster health planning with a view to reducing health inequities. The identified neighbourhood clusters will be used, in subsequent studies, as units of analyses in investigating equity in health status, access and utilization of health services. Additionally, the identified of neighbourhood characteristics are expected to provide useful information on which health planning decisions will be based in order to:1) Identify population health needs at the neighbourhood level2) Assess health service utilization patterns across neighbourhoods and compare these with neighbourhood population characteristics and needs3) Create geographic boundaries for the integrated delivery of social and community health care services4) Allow for the development of strategies tailored and responsive to the unique characteristics and needs of each neighbourhood.5) Enhance the use of empirical data for local advocacy for marginalized and under-served neighbourhoods and other populations in need.Incorporation of the differences in neighbourhood socioeconomic characteristics in population health planning decisions such as decisions on funding allocation to community health agencies will help ensure that health planning strategies are best tailored to address the unique needs of each population. This is because a "one-size-fits-all" planning approach is neither efficient nor practical due to the different socioeconomic and demographic characteristics of the different neighbourhoods. It is expected that inclusion of neighbourhood socioeconomic and demographic characteristics in population health planning will provide health planners with more evidence to guide needs-based decisions that would be more appropriate for the socioeconomically diverse neighbourhoods. Therefore, it is hoped that the results of these analyses will be useful in ensuring that planning is tailored to the unique needs of the different neighbourhood population groups. For instance, neighbourhood types A and D have very similar median incomes and therefore if income was the only variable used to characterize the neighbourhoods, they would be treated similarly. However, the rest of the characteristics of these neighbourhood types are different. For example, neighbourhood type D has a much lower percentage of new immigrants, visible minority population and single-parent families than neighbourhood type A. Moreover, there are significantly more owner occupied dwellings in neighbourhood type D than A. The implication is that these neighbourhoods have potentially different challenges and health needs. If only median income was used (as is most often done) to classify the neighbourhoods, the two NTs would inevitably erroneously be treated as similar. Planning strategies based on such single variable analysis may not be appropriate since the strategies would not be tailored to the unique characteristics and therefore needs of the NTs.In this study, we have used multivariate techniques to identify unique neighbourhood characteristics and classify the neighbourhoods into groups with similar characteristics. Since the identified neighbourhood types are homogeneous with respect to the broad determinants of health, they offer potentially excellent opportunities for health planners and service providers to understand the characteristics and potential health needs of the different neighbourhoods and therefore better plan for them. Through continuous monitoring of health information across these neighbourhoods, health planners, service providers and policy makers could better make decisions based on knowledge of the local communities.AO was involved in the study design, execution and writing up of the draft and final copies of the manuscript. RW conceived the need for the study, was involved in the study design and preparation of the manuscript. ME, SB, BH, JE, and TA participated in the study design, guiding implementation and preparation of the draft of the manuscript.


Software tools that model and simulate the dynamics of biological processes and systems are becoming increasingly important. Some of these tools offer sophisticated graphical user interfaces (GUIs), which greatly enhance their acceptance by users. Such GUIs are based on symbolic or graphical notations used to describe, interact and communicate the developed models. Typically, these graphical notations are geared towards conventional biochemical pathway diagrams. They permit the user to represent the transport and transformation of chemical species and to define inhibitory and stimulatory dependencies. A critical weakness of existing tools is their lack of supporting an integrative representation of transport, transformation as well as biological information processing.Co-dependence models. The Co-dependence Methodology complements the representation of species transport and transformation together with an explicit mechanism to express biological information processing. Thus, Co-dependence models explicitly capture, for instance, signal processing structures and the influence of exogenous factors or events affecting certain parts of a biological system or process. This combined set of features provides the system biologist with a powerful tool to describe and explore the dynamics of life phenomena. Narrator's GUI is based on an expressive graphical notation which forms an integral part of the Co-dependence Methodology. Behind the user-friendly GUI, Narrator hides a flexible feature which makes it relatively easy to map models defined via the graphical notation to mathematical formalisms and languages such as ordinary differential equations, the Systems Biology Markup Language or Gillespie's direct method. This powerful feature facilitates reuse, interoperability and conceptual model development.Narrator is a software tool facilitating the development and simulation of biological systems as .Narrator is a flexible and intuitive systems biology tool. It is specifically intended for users aiming to construct and simulate dynamic models of biology without recourse to extensive mathematical detail. Its design facilitates mappings to different formal languages and frameworks. The combined set of features makes Narrator unique among tools of its kind. Narrator is implemented as Java software program and available as open-source from  One goal of investigating the dynamic behavior of biochemical systems and processes is to understand biological causality in terms of regulation and control mechanisms. Computerized mathematical models of such dynamic behavior have become an important methodology in the pursuit of this goal. Many modeling and simulation tools have been reported in the literature. The Systems Biology Markup Language (SBML) Web site  lists moSeveral excellent tools have been developed for modeling and simulating biochemical networks, some of which provide sophisticated, GUI-based design tools for visual model development. Most of these tools are freely available as software packages or as online tools. Examples include Copasi , VirtualA critical weakness of the symbolic notations of these tools is their lack of supporting an integrative representation of biological transformation and transportation processes as well as biological information processing.species transformation as the alteration or change of species participating in biochemical processes. Examples of species transformation include stoichiometric reactions, enzymatic reactions, synthesis and degradation processes or modification processes such as methylation and phosphorylation. Biological transport refers to processes that transport organic, biochemical or inorganic substances between or within cells. Protein translocation across subcellular compartments or material flow through biological membranes are examples of biological transport. Biological information processing controls the processes involved in species transformation and species transport. By processing the information provided by one or more information sources and by regulating biological transport and transformation processes accordingly, biological systems can control both the maintenance of a state and also state transitions from one state to the next. Based on this definition information sources can be of different biological and non-biological nature such as a set of transcription factors controlling the expression of a gene, or physical parameters influencing a biological process . Typical examples of biological information processing include gene regulatory processes and cell-cell or cell-environment interactions mediated through receptor proteins. To simultaneously model species transformation and biological information processing is important because only this integrative approach can describe biochemical processes including the influencing factors that control such processes and their interplay. For example, a model of osmotic shock in yeast should capture species transformation and information processing because it is not possible to formulate the causal dependencies of osmotic shrinking and swelling of yeast cells by defining transformation processes exclusively. Instead the processing of internal and external ion concentration levels is fundamental in the response processes initiated by the yeast cells and thus must be integrated into the model to provide contextual causality of the underlying system. While the main focus of most existing tools is placed on the description of species transformation, the modeling of information processing which controls such transformations is an important feature missing in those tools. The main novelty of the Narrator tool is that it facilitates the integrative modeling and simulation of biological transformation, transport and information processing.Within the context of this work, we define The following illustrative example is to demonstrate the necessity of an integrative modeling approach that combines transformation and information processing. It is based on a model of osmotic shock in yeast and was developed by Klipp and coworkers . This moCo-dependence Methodology [The Narrator tool presented in this paper implements the hodology , which c1. Enable life scientists to express the full complexity of biological functioning, including species transport, transformation and information processing which guides these processes.2. Provide a visual or graphical notation suitable for use in informal pen-and-paper discussions and implementation as sophisticated graphical user interface of computerized modeling tools.in silico.3. Be executable on a computer to enable the testing of proposed dynamics The conceptual architecture of the Co-dependence Methodology can be divided into four layers Figure . Narratobipartite graphs or directed hypergraphs. A bipartite graph (or bigraph) is defined by a set of graph vertices (nodes) decomposed into two disjoint sets such that no two graph vertices within the same set are adjacent, i.e., they are not joined by a graph edge (link or arc). A directed hypergraph is a graph in which generalized edges  may connect more than two nodes. The two types of graphs have been shown to be equivalent when used for representing transport and transformation of chemical species [sets of reactants to sets of products, where each set belong to the same kind of node. Additionally, both notations can represent inhibitory and stimulatory dependencies between chemical species and their transformation processes. Petri nets [Most notations currently used in systems biology tools facilitate the description of conventional biochemical pathways and are based on mathematical  species ,40. In btri nets , the E-CAs illustrated in Figure information sources using small, unfilled circles. Interpreted dynamically, information sources are considered as mathematical variables that are integrated into the function or rate law of their associated process. This is illustrated in Figure A novel aspect in the Co-dependence Notation is the explicit labeling of co-dependent relationship between a species and a process, the species influences the process that is transforming the species.A thick arc in combination with a small circle indicates that there exists material as well as informational flow between a species and a process node. In this Co-dependence models are fully isomorph to systems of ordinary differential equations (ODEs). The rate of change of each species represents an ODE and, as shown in Figure information processing nodes to represent constants or computed logical entities such as rate constants, external stimuli or genetic switches. Information processing nodes also belong to the class of process nodes, yet, as shown in Figure An additional novel aspect of the Co-dependence Notation is the optional use of informationally is of considerable value in scenarios illustrated by the following four scenarios.From a graph-theoretical point of view the visual representation of information processing is made possible by defining a link or edge type which is able to connect process and species nodes as well as relating two process nodes. Such an informational relation between two process nodes has no direct biochemical interpretation and therefore is not considered in notations derived from biochemical pathway diagrams. Yet, as we shall demonstrate, this extension is extremely useful when incorporating abstractions or additional information into models as is for example required when integrating biochemical and biophysical aspects in one model. Consequently, in Co-dependence models, process nodes describe both the transformation of concentration levels of their participating species as well as the processing and supply of information. In particular, the ability to link processes SLN1 is directly affected by the Turgor pressure which again depends on the Internal and External osmotic pressure. Thus, we can visually describe which species is contributing as an osmosensor to the regulation of the HOG pathway and how this species depends on various biophysical influences.A link between two process nodes can describe how exogenous factors affect a biological system. For example, Klipp et al. describe the phosphorelay mechanism of the yeast high osmolarity glycerol (HOG) pathway which controls the transcriptional response of yeast cells to high osmolarity . In the detailed steps of information processing. Sometimes it is convenient to elaborate a single informational dependency into a sequence of processing steps. For example, in Figure v1 on the species glycerol has been expanded into the more detailed description involving Experimental input signal, External and Internal osmotic pressure, and Turgor pressure. These detailed steps of information processing allow us to visually close the loop between the biological system internal osmotic pressure and its environments .Figure differential-algebraic equations are often used to reduce the complexity of the differential equations by simplifying their right-hand expressions with auxiliary variables. Biochemical models frequently make use of this method. However, although SBML's AssignmentRule tag provides support for it, the process nodes in Narrator can improve the readability of equation systems by structuring information processing in a similar way. Differential-algebraic equations thus translate to Co-dependence models without any increase in diagram complexity.In ODE-based modeling, src_activity is used to calculate the total enzymatic activity of that kinase. In the model depicted in Figure src_activity node is then reused in processes that represent reactions catalyzed by this kinase  model functionality from the presentation and control logic that uses this functionality .nd and 4th order Runge-Kutta and Runge-Kutta-Fehlberg with adaptive step size . Additi example . To exam example  and tabuspecies, process, compartment and link. Compartment objects encapsulate a finite number of Species and Process objects and can be used to model cellular compartments or to decompose a model into constituent elements. Link objects connect Process objects with Species or other Process objects. They model the propagation of change between species and processes  or the transport of information to the processes .Figure Each model created using Narrator contains one root compartment, which in turn can contain additional compartments, processes and species. The relationship among the classes Link, Process and Species further enables the mapping to and execution of numerical simulations of Narrator models directly within the model structure. Process objects coordinate via Link objects the augmentation and depletion of the concentration levels represented by Species objects. As shown in Figure Similarly, the class structure can be used to instantiate and simulate stochastic processes. Currently, Narrator implements Gillespie's direct method  where thNarrator provides two reporting components to present the resulting dynamics data of a Narrator model. These are portraits and tables respectively. Portraits are based on the open-source chart library jfreechart  and can The user can visually simulate the dynamics of the model by animating the species nodes of the graphical network. As shown in Figure To facilitate a standard-compliant exchange of Co-dependence models, Narrator provides an export and import mechanism for storing Co-dependence models in SBML level 2 version 1 . HoweverFor transforming mathematical String expressions into MathML we make use of the open-source library jeks  and for To evaluate Narrator, we described and simulated a model of the protein kinase C (PKC) pathway taken from Pettinen et al.  which usThe PKC model contains 11 differential equations and two further reactants which are kept constant in the simulation. Based on the ODE definition of the model  we builtCAStimulus linked to the reaction R7 to model the exogenous Ca2+ stimulus for the PKC pathway following a sine wave with time period of 50 seconds.A larger section of the PKC model described with Narrator is shown in Figure 2+ to a constant value.We used the same model to evaluate the SBML compatibility of Narrator. The PKC Narrator model was exported into SBML and the generated XML file was validated with the SBML Validator available on the SBML Web site . SBML coIn another recent study by Alves and co-workers , 12 kineNarrator provides a set of example models which are directly accessible via the menu bar. Some models are taken from Klipp et al.  and demostructure and govern the behavior of a biological system or process. Some of the existing notations and tools emphasize the structural and others the behavioral dimension. Typically, structure-oriented notations use a plethora of graphical symbols and notational conventions to characterize qualitative details of species types and their biochemical transformations. Dynamics-oriented notations, on the other hand, capture information relevant mainly to the dynamic aspects of a system and usually subsume different species and transformation types within a small collection of graphical symbols  , processdynamic models. This is explained by Narrator's main focus on the dynamic structure and properties of a biological system. With regard to SBML, structure-oriented notations correspond to SBML including Systems Biology Ontology terms for the SBML model elements, while dynamics-oriented notations can be understood as the notational counterpart of pure SBML, focusing on the dynamic description of biochemical models. In SBML level 2 version 2, Systems Biology Ontology (SBO) terms [The graphical notation of the Narrator software tool emphasizes the development and exploration of O) terms  can be oA recently initiated effort called Systems Biology Graphical Notation aims to develop and standardize a structure-oriented graphical notation for representing biochemical networks . Once avThere are many methods listed in Table While ongoing developments implement more features such as bifurcation analysis, the objective of Narrator is not to cover the full spectrum of systems biology methods. Instead, the emphasis of Narrator and one of its major advantages over similar tools lies in the expressiveness and intuitiveness of its graphical notation and the sophisticated and highly usable implementation of a GUI supporting the use of this notation in the context of dynamics modeling and simulation. The focus of Copasi, for example, lies in the many numerical integration, parameter estimation and parameter scan methods. The graphical user interface of Copasi, however, is based on simple dialog boxes providing entry masks to define the chemical equation and rate expression for each reaction. The dynamics-based graphical design tools of JDesigner, Virtual Cell and CellWare, on the other hand, are based on directed hypergraphs or bipartite graphs. As shown in Figure Narrator uses the simple, intuitive graphical notation of Co-dependence models  to expreNarrator is a stand-alone Java application for the graph-based modeling of dynamic network structures of biochemical systems. It extends the visual description of species transformation with the notion of information processing and therefore introduces a new concept into the multitude of graphical modeling tools used in the field of systems biology. Here, the provided intuitive design tool, which implements the Co-dependence Notation, supports the model building in a way that is accessible without an advanced mathematical background but which is still more oriented to mathematical dynamic systems than to biochemical pathway diagrams. This makes Narrator also applicable to any discipline requiring dynamic modeling.The primary purpose of Narrator is to facilitate the creation and manipulation of computational models. Therefore, an ongoing effort in the development of Narrator is to maintain and improve the tool's SBML compatibility allowing a further exploration of Narrator models with simulation and analysis methods implemented in other tools..Narrator is available at  under thJJM and NMP developed the idea of Co-dependence modeling and developed the software tool Narrator. HF was involved in the implementation and gave a realistic user perspective. WD guided the development of this project. All authors read and approved the final version of the manuscript


The clinical and economic consequences of the emergence of multidrug-resistant Gram-negative bacteria in the intensive care unit (ICU) setting, combined with the high mortality rate among patients with nosocomial pneumonia, have stimulated a search for alternative therapeutic options to treat such infections. The use of adjunctive therapy with aerosolized colistin represents one of these. There is extensive experience with use of aerosolized colistin by patients with cystic fibrosis, but there is a lack of data regarding the use of aerosolized colistin in patients without cystic fibrosis.We conducted the present study to assess the safety and effectiveness of aerosolized colistin as an adjunct to intravenous antimicrobial therapy for treatment of Gram-negative nosocomial pneumonia. We retrospectively reviewed the medical records of patients hospitalized in a 450-bed tertiary care hospital during the period from October 2000 to January 2004, and who received aerosolized colistin as adjunctive therapy for multidrug-resistant pneumonia.Acinetobacter baumannii (in seven out of eight cases) and Pseudomonas aeruginosa (in one out of eight cases) strains. Half of the isolated pathogens were sensitive only to colistin. The daily dose of aerosolized colistin ranged from 1.5 to 6 million IU (divided into three or four doses), and the mean duration of administration was 10.5 days. Seven out of eight patients received concomitant intravenous treatment with colistin or other antimicrobial agents. The pneumonia was observed to respond to treatment in seven out of eight patients (four were cured and three improved [they were transferred to another facility]). One patient deteriorated and died from septic shock and multiple organ failure. Aerosolized colistin was well tolerated by all patients; no bronchoconstriction or chest tightness was reported.Eight patients received aerosolized colistin. All patients had been admitted to the ICU, with mean Acute Physiological and Chronic Health Evaluation II scores on the day of ICU admission and on day 1 of aerosolized colistin administration of 14.6 and 17.1, respectively. Six of the eight patients had ventilator-associated pneumonia. The responsible pathogens were Aerosolized colistin may be a beneficial adjunctive treatment in the management of nosocomial pneumonia (ventilator associated or not) due to multidrug-resistant Gram-negative bacteria. Pseudomonas aeruginosa and Acinetobacter baumannii strains, is among the most serious complications that occur in the intensive care unit (ICU) setting. Mortality, morbidity and health care costs are substantially increased by this type of infection  or leucocytosis ), and at least two of the following: new onset of purulent sputum, change in the character of sputum, increased respiratory secretions, or increased requirement for suctioning; new onset or worsening of cough, or dyspnoea or tachypnoea; rales or bronchial breath sounds; or worsening gas exchange. Pneumonia was considered to be ventilator associated (VAP) when its onset occurred 48 hours after the initiation of mechanical ventilation, and was judged not to have been incubating before the initiation of mechanical ventilation  versus 30/45 patients [66.7%], P = 0.67).Of 152 patients who received treatment with intravenous colistin for infections with multidrug-resistant Gram-negative bacteria during the period of study, 55 had received less than 72 hours of intravenous colistin and were excluded from all analyses. Medical records were not available for three patients; in addition, one patient was in the hospital during data collection. Thus, 93 patients were further analyzed. Forty-five of these patients received intravenous colistin for the treatment of nosocomial pneumonia due to Gram-negative bacteria. Survival and clinical cure rates for the infection were better, although not statistically significantly so, in patients with pneumonia who received additional aerosolized colistin than in patients who received only intravenous colistin treatment  in the nebulized form for the management of pneumonia due to Gram-negative bacteria is not new. In 1963, Pino and coworkers  reportedonchitis -23.P aeruginosa strains. Notably, studies found that nebulized colistin reduced the number of relapses of lung infections and subsequently the decline in lung function among patients with cystic fibrosis [There is extensive experience with administration of aerosolized colistin to patients with cystic fibrosis, in whom this type of treatment is used to prevent or treat lung infections with fibrosis -27.The pharmacokinetic properties and dosing strategies of aerosolized colistin are not well defined. Whether the various forms of colistin used for inhalation therapy  or the different types of nebulizing systems influence the effectiveness and safety of colistin remains to be determined -31.2 agonists before the initiation of aerosolized colistin was able to prevent the development of such side effects in the respiratory system. Another significant concern regarding the use of aerosolized colistin for the treatment of nosocomial pneumonia is dissemination of multidrug-resistant bacteria through nebulizer devices [Adverse effects of aerosolized colistin or polymyxin B are a major concern; potential adverse effects include bronchoconstriction, chest tightness and apnoea due to neuromuscular blockade. One study conducted in 58 children with cystic fibrosis who received nebulized colistin for the treatment of lung infections  reported devices ,35. HoweOur study is not without limitations. It is a small case series and is of a retrospective design. In addition, there is no control group of patients receiving treatment with only intravenous antimicrobial agents. Furthermore, some of the patients also received intravenous treatment with other antimicrobial agents, which might have influenced the outcomes.P aeruginosa and A baumannii, resistant to colistin; and an increase of infections due to Gram-positive and Gram-negative pathogens, such as Proteus and Serratia spp., inherently resistant to colistin. Consequently, there is an urgent need to restrict the use of colistin use in order to minimize these risks.Two major risks are arising from the wide use of colistin: the emergence of Gram-negative bacteria, such as P aeruginosa strains is commonly treated with aerosolized colistin alone. Randomized controlled trials studying the possible additional benefits and risks associated with use of nebulized colistin, as an adjunct to intravenous antimicrobial treatment, in patients with pneumonia due to multidrug-resistant Gram-negative bacteria are urgently needed.Inhaled colistin may be beneficial in the treatment of nosocomial pneumonia (ventilator associated or not) due to multidrug-resistant, Gram-negative bacteria. However, the severity of these infections in the ICU setting means that treatment just with aerosolized colistin is unlikely to be sufficient. This is in contrast to therapeutic strategies employed in patients with cystic fibrosis, in which initial lung colonization with • 	Aerosolized administration of colistin is a promising adjunctive therapy for management of patients with pneumonia (whether ventilator associated or not) due to multiresistant Gram-negative bacteria• 	Aerosolized colistin was safe in this group of patients.• 	There is an urgent need for randomized controlled trials examining the efficacy and safety of aerosolized colistin for the management of patients with nosocomial pneumonia.ICU = intensive care unit; VAP = ventilator-associated pneumonia.The author(s) declare that they have no competing interests.AM and MEF conceived the study. SKK, ZM, KR and AMK collected data. All authors contributed to the writing and preparation of the manuscript.


In November 2002, an anonymous postal survey of sheep farmers in Great Britain (GB) was conducted to identify factors associated with the flock-level occurrence of scrapie. This survey was undertaken to update an earlier postal survey in 1998, and was the first occasion in which a large-scale postal survey had been repeated.The results of the 2002 survey indicated that scrapie was more likely to occur in certain geographic regions; in purebred compared to commercial flocks; in larger flocks; in flocks which lambed in group pens compared to those which lambed in individual pens; in flocks which always lambed in the same location compared to those which did not; and in farms which kept certain breeds of sheep. In addition to these factors, the likelihood of the disease occurring in homebred animals was higher in flocks which bred a greater proportion of replacement animals or which bought-in lambs. Finally, within-flock transmission following exposure was more likely to occur in hill flocks compared to other farm types; in flocks which bred a greater proportion of replacement animals; and in farms which kept a certain crossbreed of ewe.The risk factors identified from the 1998 and 2002 anonymous postal surveys in Great Britain were similar. However, differences between the surveys were identified in the influence of region and of purchasing behaviour on the risk of scrapie. These differences are most likely a consequence of changes in farmer awareness and the impact of the 2001 foot-and-mouth disease epidemic, respectively. In 1997 the Spongiform Encephalopathy Advisory Committee (SEAC) recommended that a postal survey of sheep farmers in Great Britain (GB), to which farmers could respond anonymously, should be carried out -4, and aFarmer-based surveys have been used to estimate the prevalence and incidence of scrapie in GB ,3,5, TheTo update the findings of the 1998 survey a further postal survey was undertaken in November 2002  and animEstimates for the prevalence and incidence of scrapie based on the 2002 survey have been reported elsewhere ,12 and hComparing farms that have ever had scrapie (n = 331) with those which have never had the disease n = 2180)  there was little regional variation in risk, except in Shetland (SH) where the odds of having a homebred case were 7.5 times higher . A further interaction was identified between flock size and lambing practices. However, the frequencies for some combinations of factor levels were zero or very small (with correspondingly large standard errors for the coefficients) and, therefore, this interaction was not included in the final model.Comparing farms that have had scrapie in homebred animals (n = 96) with those which have had cases in purchased animals only n = 204) indicated that the risk of transmission occurring within a flock increased 1.4-fold for each 10% increase in the proportion of homebred animals  or lambs for human consumption . The effects of farm and flock type were similar in both the 1998 and 2002 surveys , flock size, sheep breed, trading practices and the use of certain lambing practices.The results of the two surveys differed in the influences of specific geographical regions and purchasing of lambs on the risk of scrapie. Rather than reflecting changes in scrapie risk, these differences are most likely a consequence of changes in farmer awareness and the impact of the 2001 foot-and-mouth disease epidemic, respectively.Full details of the survey are presented elsewhere  and hereWe first explored the results using univariate analyses to identify potential risk factors and decide appropriate coding for the variables. The list of attributes and their interpretation is given in Table P-value of less than 0.05. Adjusted odds ratios (AOR) significantly different from one were used as an indicator of raised or lowered risk of scrapie. The goodness-of-fit of the final model was judged using a Hosmer-Lemeshow goodness-of-fit test [Binary logistic regression models were used to explore relationships between scrapie occurrence and a farm's attributes. Models were built using forward stepwise regression through the first twelve attributes listed in Table fit test .KMM carried out the statistical analyses and drafted the manuscript. SG carried out the statistical analyses and critically revised the manuscript. SKS and MB conceived and designed the study and critically revised the manuscript. All authors read and approved the final manuscript.


In medical education, feedback from students is helpful in course evaluation. However, the impact of medical students' feedback on long-term course development is seldom reported. In this project we studied the correspondence between medical students' descriptive evaluations and key features of course development over five years.Qualitative content analysis was used. The context was consultation skills courses in the middle of the Göteborg undergraduate curriculum during five years. An analysis of 158 students' descriptive evaluations was brought together with an analysis of key features of course development; learning objectives, course records, protocols from teachers' evaluations and field notes. Credibility of data was tested by two colleagues and by presenting themes at seminars and conferences. Authors' experiences of evaluating the course over many years were also used.A corresponding pattern was found in students' descriptive evaluations and key features of course development, indicating the impact of students' open-ended feed-back. Support to facilitators and a curriculum reform also contributed.Students' descriptive feedback was both initiating and validating longitudinal course implementation. During five years, students' descriptive evaluations and teachers' course records were crucial sources in a learner-centred knowledge-building process of course development.Students' descriptive evaluations and course records can be seen as important instruments in developing both courses and students' learning. Continuity and endurance in the evaluation process must be emphasized for achieving relevant and useful results. How can students' views be used for developing courses in the transition to clinical education? This question is discussed in recent reports of students' opinions and learning experiences in the transitional phase ,2.th century version of the medical curriculum contain a preclinical phase of biomedical sciences followed by a later clinical phase [Since the days of Flexner, a conventional 20al phase . To studal phase . Even thal phase . On basial phase ,2,5.On a course level, students' course descriptions or portfolios might be a suitable instrument for monitoring changes of the transition. Students' evaluations are often used for developmental purposes. However, administrative purposes are also involved and these aims need to be separated from the developmental purposes ,7. ScienIn this study we intend to analyse the impact of students' descriptive feedback in the transition to clinical education during five years of factual course development.In 1993, a nine-week clinical introduction course 'Consultation Skills' started in the Göteborg undergraduate curriculum. The consultation was launched as a unique concept by British researchers in the 1980' . A patieIn 1995, two years later, we felt more familiar with the new context and searched for a student-centred, global and uncomplicated evaluation approach. Two of the authors  attended university courses of learning in higher education. Qualitative research methods and a local study on course evaluations inspired in trying unconventional descriptive evaluation methods ,15.tool for listening and understanding in course development. Consequently, the purpose of students' evaluations shifted, from mapping values of particular events to grasping students' learning experiences in the course as a whole.The general idea was to adapt and harmonize the evaluation idiom to the central knowledge of the course. Student-centred descriptive evaluations would better correspond to the patient-centred approach learned in the course. Instead of asking for structured, closed and short answers, we invited students to expand on their learning experiences during the course. A very substantial student evaluation in the form of a letter also contributed to the shift. This meant that we deliberately used evaluations primarily as a After each course, the documentation including teachers' views and reflections were also collected, forming an evaluation cycle in course development Fig . Thus, tThe aim of the project was to study the correspondence between students' descriptive evaluations and key features of course development over five years.The study started in 1995 and covers five years of course development.Five hundred and thirty seven medical students attended nine Consultation Skills courses during the study period.During the last day of the Consultation Skills course, students were asked to anonymously answer only one open-ended question:"What do you think of the course in Consultation Skills, with reference to the course design and examination? "From spring 1996, a tick box for marking students' gender was included in evaluations.Materials from teachers were course records and documents; plan of learning objectives, course schedules, teachers' schedules and assessment guides; teachers' protocols from systematic evaluations after each course and weekly protocols from course team meetings.Students were given 45 minutes of the last part of the course schedule to finish their evaluations. The evaluation question was attached to two blank sheets of paper and was distributed to students in a lecture room. Most students spent over 30 minutes writing their evaluation.Four evenly distributed courses over the five-year period produced 158 evaluation stories that were used as sample. Student data consisted of 214 pages of written text from autumn 1995, spring 1996, spring 1997 and autumn 1998. . The text material was abundant. Therefore, Biggs' framework of main components in university education  was used . Thus, cIn the last, third step, results from content analysis of students' descriptive evaluations and content analysis of key features of course development were brought together. By these measures a corresponding pattern was searched for, thus reflecting the impact of students' open-ended evaluations on course development.To increase reliability and concordance of the three steps of analysis, AS and CB who participated in course development read half of the evaluations, assessed and checked analysis themes. Interpretations were discussed by main author and co-authors AS and CB during several meetings. Initial data was expanded and after re-analyses, concordance was reached. Theoretical perspectives used in interpretation were an educational learner-centred perspective and patient-centeredness in medicine. The trustworthiness of data was further tested at a seminar by two external assessors from the medical faculty and at a Nordic conference of education and research in medical communication. The assessors and research colleagues recognized our main experiences and it seems as if our findings are transferable to their context.Students' descriptive evaluations and records of course documentation presented a very rich and varied material. Results of the three steps of analysis are presented below. The third step analyse the correspondence between students' descriptive evaluations and key features of course development over five years.Seven main themes emerged in the analysis of students' descriptive evaluations. A framework of the content analysis is presented in Table Some students articulated basic learning goals; how to interview patients, how to perform a physical examination and how to write a medical record.Most students were eager to express the importance of meeting GPs and to be trained in physical examination skills. Consultation training was specially appreciated in primary care.A rather harsh tone of disappointment was present in some of these statements of students' learning experiences in earlier medical studies. Expressions used were e.g. "cramming" and an "anonymous" or even "inhumane" learning environment.Some students expressed that the content in lectures of consultation skills and issues of the professional role would be more suitable for interactive group discussions.In the first parts of the material compulsory activities were put in question and a clear protest could be traced. This category vanished after changes in 1997 to a reduction in compulsory activities.Some students were confused by too many different learning activities, not finding "the red thread" of the course.These statements were complaints of different standards in training of physical examination skills and assessment.Students made a positive remark on the course design's mixture of practice training and didactic modules. Some were surprised that their fast introduction to patient encounters in primary care turned out so well.New ways of learning in new settings compared to earlier studies were mentioned. In some of these statements, students were astonished that they became so emotionally tired from clinical experiences.The practical examination was appreciated throughout the study period. Some students expressed satisfaction of their growing clinical competence shown in the examination.From 1997, students were asked in a home essay assignment to reflect on observed consultations in primary care and to use conceptions of core learning objectives. Students admitted that they were initially hesitant but were later surprised that the home essay served its purpose.Students expressed that they were well received by facilitators in practice and appreciated that facilitators were student-centred.Students were challenged by facilitators to perform new tasks for which they were highly motivated. A sense of optimism and hope is clearly present in these statements.These statements were conveyed as a consequence of events and experiences during the course.A combination of personal involvement and team work were elicited in statements of an art-of- interviewing week and of small group work.These reflecting statements express that the awareness and the confidence in becoming a physician had changed, often in comparison to experiences in earlier stages of medical education.The deviant cases of the analysis displayed predominantly minimal and general remarks. An example is the statement 'Very good' as an evaluation of the whole course. Some cases not fitting into main themes were seen in spring 1996 and consisted of extensive comments on a debate held in a single lecture.Analysis of key features of course development is depicted in Table As seen from Table There were also dead ends and drawbacks in course development. Many of them were due to over-ambitious goals and efforts to cover too much content. Thus, learning from less successful events was also an important part of course development and applies in particular to the key features 'concentration' and 'core learning objectives'.Main themes of students' descriptive evaluations and key features of course development are brought together and depicted in Table A corresponding pattern is seen in main themes of descriptive evaluations and key features of course development. A number of observations support this relation.Students' reported urge to learn professional knowledge and skills mirrors that these areas being gradually selected and communicated as core learning objectives. In addition, a lack of unity of course content perceived by the students corresponds with education of facilitators in core learning objectives. Students' main theme 'To be active and to have a choice' corresponds to themes 'Active learning in practice enhanced' and 'Student's degree of choice strengthened' in course development. Assessment in context of core learning objectives matches students' perception of an authentic and relevant examination. The pattern of correspondence indicates that students' descriptive evaluations had an impact on course development.Since course development occurred in a process over five years, it is possible to discern reciprocity. Students' evaluations affected course development and course development also affected students' evaluations. Thus, structured support and education of facilitators parallels students' main theme 'Support and encouragement from facilitators'. Similarly, reinforcement of student-facilitator relationships might be associated with students' theme 'Awareness and confidence'.In addition, external factors contributed to course development. A curriculum reform in 1996 implied reorganization and concentration of course content. Another external influence was input of educational knowledge; from local scientific evaluations of the Göteborg curriculum and attending university courses of learning in higher education ,15.In an evaluation of a course in the transition to clinical education, students' descriptive evaluations and teachers' course documentation was analysed. A corresponding pattern of students' descriptive evaluations and key features of course development was seen in several dimensions, indicating the impact of students' feed-back on course development.In three consecutive steps of analysis, a quite voluminous text material covering five years of systematic evaluation and course development was brought together and condensed.Limitations of the qualitative method in our study concerns credibility of data and the analysis method. Credibility is increased by conveying the analysis performed and the theoretical perspective used in interpretation ,20. CredResearch on student ratings of university teaching has been thoroughly reviewed by Marsh . UniversAnother concern may be the questions put in evaluations. Some students might have been restricted by asking about their thoughts of the course, course design and examination. The opening question could perhaps have been even more open-ended to cover a wider spectrum of student's learning experiences. However, the material we received in descriptive evaluations was rich and many facets of students' personal experiences and thoughts emerged spontaneously in statements, thus transforming students' evaluation feed-back into a "legible choir of students' voices". Despite the restricting components, we think the question was open enough to yield useful feed-back in course development.Content analysis as a method of analysing evaluation data is discussed by Lincoln & Guba . They seGroup dynamics may represent another source of bias. Student-teachers relationships in medical education are not symmetrical . EnlargeThe student sample was collected from four evenly distributed courses in order to avoid accidental results. Students in the study were not different from other courses in terms of student characteristics and passed/approved rates. In a Scandinavian context of undergraduate medical education, a mean response rate of 70% of voluntary evaluations, obtained over four years, seems acceptable . HoweverStudents descriptive feed-back was both initiating and validating a longitudinal process of course development and implementation. Through the analysis, an overview of five years of this process was achieved. A corresponding pattern between students' descriptive evaluations and key features of course development was found.An eagerness for professional training was evident in students' descriptive evaluations. The analyses enabled a deeper understanding of students' perceptions of learning conditions and resulted in a selection of core learning goals. It emerged that hands-on training of clinical examination skills is pivotal in the transition to clinical education, forming a rite of passage in student's professional socialization process. A student's self-image as a future physician appears to depend on learning doctor's professional skills . The conAn important part of the result are the corresponding themes 'To be active and to have a choice' and adherent changes carried out in course development. From students' point of view, the correspondence of these themes may be interpreted as signs of an empowering process in which students' voices were heard. The examination in an authentic setting was clearly appreciated throughout the study period and corresponded in course development to assessment of core learning objectives and extended time for feed-back. In fact, a change of the examination was the main tool to achieve clarity of learning goals in relation to students. An obvious linkage of learning objectives, learning activities and assessment was organised and communicated . IntroduInterestingly, students theme 'Awareness and confidence' might be associated with the key feature 'Student-facilitator relationships and reflection reinforced'  chaired the Curriculum Committee of the Medical Faculty and another author (CB) was a member of the committee during the study period. These circumstances probably contributed to a climate positive to educational development and to implementation of the Action Programme in Education of Göteborg University . MoreoveStudents' descriptive evaluations and teachers' course records were helpful in a long-term evaluation forming a learner-centred knowledge-building process. Students' feedback was both initiating and validating longitudinal course implementation. Asking students to write an individual course description appears to bring a sense of mutuality to evaluations and create a new understanding of how students' learning events were experienced in the whole of a course. Evaluators and course organizers should also consider organizational factors affecting course development. Continuity and endurance in the evaluation process must be emphasized for achieving relevant and useful results. In conclusion, students' descriptive evaluations and can be seen as important instruments in developing both courses and students' learning.The author(s) declare that they have no competing interests.MW acted as the principal researcher, collected data and performed analyses. BM substantially contributed to conception and design of the study and revised the manuscript. AS and CB made substantial contributions in interpretation of analyses performed, in revising the manuscript and in the acquisition of data. GD and KL contributed to conception and design of the study and in revision of the manuscript.The pre-publication history for this paper can be accessed here:


The assessment of coronary flow reserve by transthoracic echocardiography has recently been introduced into clinical practice with gratifying results for the diagnosis of left anterior descending artery disease simultaneously reported by several independent laboratories. This technological novelty is changing the practice of stress echo for 3 main reasons. First, adding coronary flow reserve to regional wall motion allows us to have – in the same sitting – high specificity  and a high sensitivity (coronary flow reserve) diagnostic marker, with an obvious improvement in overall diagnostic accuracy. Second, the technicalities of coronary flow reserve shift the balance of stress choice in favour of vasodilators, which are a more robust hyperemic stress and are substantially easier to perform with dual imaging than dobutamine or exercise. Third, the coronary flow reserve adds a quantitative support to the exquisitely qualitative assessment of wall motion analysis, thereby facilitating the communication of stress echo results to the cardiological world outside the echo lab. The next challenges involve the need to expand the exploration of coronary flow reserve to the right and circumflex coronary artery and to prove the additional prognostic value – if any – of coronary flow reserve over regional wall motion analysis, which remains the cornerstone of clinically-driven diagnosis in the stress echo lab. Normally coronary blood flow can increase approximately four-to-six fold to meet increasing myocardial oxygen demands. This effect is mediated by vasodilation at the arteriolar bed, which reduces vascular resistance, thereby augmenting flow. The coronary reserve (CFR) represents the capacity of the coronary circulation to dilate following an increase in myocardial metabolic demands and can be expressed by the difference between the hyperemic flow and the resting flow curve figure . In 1974Up to now, coronary flow reserve has been evaluated invasively in the cath. lab and in nuclear medicine through perfusion imaging. Only recently has coronary flow reserve entered the echo lab, with the combination of coronary flow assessment by Doppler and vasodilator stress. With either TEE  figure  or TTE , the corThe coronary flow signal on LAD was first made possible by TEE figure  – with eThe Doppler assessment of coronary flow reserve has some limitations. The assessment of absolute blood velocity can be limited in some patients by the large incident angle between the Doppler beam and blood flow. However, calculation of the flow reserve allows assessment of flow patterns without the need for absolute values. More importantly, the velocity ratio is used as a surrogate of flow reserve: flow within the coronary artery is not calculated because cross-sectional visualization of the vessel does not allow an accurate measurement of the diameter of the vessel. The estimated flow reserve can be accurate if the coronary functions only as a conduit, without changing in diameter during drug infusion. This assumption is reasonable with dipyridamole  and lessThe use of CFR as a "stand-alone" diagnostic criterion suffers from so many structural limitations as to make it little more than an academic somersault: firstly, only LAD is sampled; secondly, the coronary flow reserve cannot distinguish between microvascular and macrovascular coronary disease . TherefoIn addition, the flow information is relatively unaffected by concomitant antianginal therapy, which markedly reduces the sensitivity of ischemia-dependent regional wall motion abnormality  and doesIn our experience of a single center since 2000, the combination of the CFR study on LAD and the analysis of left ventricular wall motion abnormalities represents the best choice in echo-lab evaluation of the flow-function relationship . This caThe combination of regional wall motion and coronary flow reserve identifies distinct patterns with 2 different parameters, coronary flow reserve and regional wall motion analysis. At one end of the spectrum, there is the totally normal pattern, with normal left ventricular function and normal coronary flow reserve, which is highly predictive of normal coronary anatomy and normal physiological response of coronary micro and macrocirculation. At the opposite end of the spectrum, there is abnormal left ventricular functional and abnormal coronary flow response, which is highly predictive of diseased epicardial coronary anatomy and impaired flow reserve. In between these extreme black-and-white responses, "gray zone" responses can be found, with mild-to-moderate abnormal coronary flow reserve and normal function with normal coronary flow reserve.From PubMed search, we identified all papers with head-to-head comparison of dipyridamole stress echo  versus dipyridamole stress echo (0.84 mg/kg in 10' plus atropine or 0.84 mg/kg in 6' without atropine) with wall motion analysis and CFR evaluation. A total of 5 papers  were found, involving 725 patients (355 with LAD stenosis and 370 without CAD -21(tableIf we consider the latest papers on the diagnostic role of the Dipirydamole stress-test, it becomes clear that by adding the CFR-LAD evaluation to wall motion analysis we significantly increase the sensitivity of the test, whilst maintaining an excellent value in terms of specificity. As a result, diagnostic accuracy value is also extremely good. Up to now, this kind of relationship has only been valid for the LAD coronary artery, although this of course represents the most important coronary vessel in terms of clinical and prognostic impact.Coronary circulation has in itself the possibility of modulating blood flow variation in response to metabolic requests. The magnitude of this adaptive variation may be objectively expressed as a number such as coronary flow velocity reserve. The potential impact of this number still has to be clarified in the clinical arena.Since 2000 we have evaluated the CFR-LAD behaviour of 1235 patients consecutively in our stress echo lab. We obtained the values summarized in Table The additional diagnostic value of coronary flow reserve is represented by the possibility of monitoring different heart pathologies objectively and thereby obtaining important functional information over time in patient follow-up. Although the importance of the prognostic role played by stress-echo in patients with coronary artery disease has been demonstrated, there has also been emphasis on how the presence of antiischemic therapy at the time of testing can heavily modulate the predictive value of pharmacological stress-echo. In fact, a positive test in therapy is more prognostically malignant, and a negative test less prognostically benign . The potEven if we need confirmation of the prognostic role of CFR through further and larger study, this parameter could have a very useful role to play in daily clinical practice.At present, the impossibility of discriminating pathological behaviour of CFR due to microvascular or epicardial stenosis has represented a major limitation in the final diagnosis, as has the impossibility of investigating all the three major coronary arteries simultaneously .We are trying to overcome this bias by introducing the contemporary analysis of at least two coronary arteries ,36. The My 5-year personal experience of evaluating CFR added to wall motion abnormalities during a vasodilator stress-echo has led me to reach some final considerations. Such an integrated analysis is feasible and non time-consuming in any stress-echo Lab., after a short training period. By integrating these two pieces of information, we can improve our diagnostic and prognostic accuracy as together they offer a better and more complete pathophysiologic finding. This allows us to choose the best treatment for patients with coronary artery disease and to follow them up over time.I believe that soon we will be in a position to make an accurate and exhaustive study of the posterior coronary artery, too and therefore to obtain a more complete functional cardiac evaluation. It follows that the integrated study of coronary flow and reserve and contractility will, in the near future, become the test of choice in guiding decision-making in the treatment of coronary stenosis before undergoing interventional procedures.CFR-coronary flow reserveLAD-left anterior descending arteryRCA-right coronary arteryWMSI-wall motion score indexVisualization by color-Doppler of the mid-distal tract of the right coronary artery and posterior descending with perforans branches.Click here for fileImaging of the blood flow inside the left anterior descending coronary artery depicted by color-Doppler in real anatomical direction.Click here for fileVisualization by color-Doppler of the proximal-mid tract blood flow of Circumflex coronary artery in real anatomical direction.Click here for file


Pregnancy is a well-recognised risk factor in precipitating obsessive-compulsive disorder. We present and discuss a case with the onset of obsessive-compulsive disorder in the fourth month of gestation, which fully recovered two weeks after delivery. The phenomenology of the observed disorder was similar to earlier reports of obsessive-compulsive disorder in pregnancy, i.e. the obsessions and compulsions were predominantly related to the concern of contaminating the foetus resulting in washing compulsions. Despite the initial success with anti-obsessional drugs, the patient stopped the medication in the last month of gestation. Nevertheless, she fully recovered two weeks after the delivery without any psychiatric intervention. There were no obsessive-compulsive symptoms at one-year follow up. The possible mechanisms involved in the aetiology of this case, and future research directions in understanding the role of pregnancy in OCD are discussed. Pregnancy and the postpartum period are known to influence the onset and course of various psychiatric disorders such as mood disorders, psychotic disorders, and anxiety disorders. -3 There Postpartum OCD has been described as having onset within the first three weeks of delivery. ,9 Here wA 30-year old primigravida woman presented to the outpatient department in the fourth month of gestation. She had no past history of psychiatric illness. Her chief complaints were contamination obsessions and washing compulsions in the preceding one month. Preoccupied with thoughts of contamination, she had started spending the majority of time washing herself or cleaning various household items. She described these thoughts as being her own and recognised them to be "irrational", but she could not resist them. She was distressed and unable to maintain her employment. Washing compulsions relieved her anxiety. However, she could not offer an explanation as to what she feared about contamination. No depressive or psychotic symptoms were elicited. Biochemical investigations, including metabolic and thyroid function studies, were in the normal range. She was diagnosed with OCD according to ICD-10 criteria [Pharmacotherapy, offered at the first consultation, was refused by the patient because of her  concerns about teratogenic effects of drugs. Behavioural therapy in the form of thought stopping was begun. The patient reported exacerbation of symptoms at the next consultation and subsequently disclosed that her obsessional thoughts also concerned the fear of contaminating her unborn baby. She repeatedly washed to avoid damage to her foetus. One month after her initial presentation, fluoxetine was started, at an initial dose of 20 mg/day gradually and gradually increased to 60 mg/day over the next four weeks. The patient reported reduction of obsessional and compulsive symptoms, and was able to resume her work. She remained on fluoxetine until the eighth month of pregnancy with no reports of exacerbation. However, the patient stopped the medication during the last month of gestation on the alleged advice of family members. The patient again experienced the relapse of intrusive obsessional thoughts followed by compulsions, but refused to resume pharmacotherapy until delivery. The patient returned to the outpatient clinic fifteen days postpartum. The patient described no obsessive thoughts or washing compulsions for the preceding one week. She was followed up for five visits in the next one year without any reports of obsessions or compulsions.There is evidence supporting the role of major life events including pregnancy and delivery in precipitating OCD.  However,The underlying mechanism can only be speculative at this stage. As full recovery was seen after delivery, our case report negates the proposed mechanism in postpartum OCD of adverse impact on serotonergic functions by rapid withdrawal of oestrogen and progesterone in postpartum period . We propAn underlying mechanism proposed for chorea gravidarum of enhanced dopaminergicsensitivity under the effect of elevated levels of female sex hormones due to pregnancy  could alCareful prospective studies of pregnancy-associated OCD will help in understanding predisposing and aetiological factors involved in such cases. Comparison of chorea gravidarum and OCD in pregnancy by functional imaging techniques like PET/SPECT/fMRI might prove useful in understanding pathophysiological processes responsible for these disorders.The author(s) declare that they have no competing interests.


In March of 2003, an outbreak of Severe Acute Respiratory Syndrome (SARS) occurred in Northern Vietnam. This outbreak began when a traveler arriving from Hong Kong sought medical care at a small hospital  in Hanoi, initiating a serious and substantial transmission event within the hospital, and subsequent limited spread within the community.We surveyed Hospital A personnel for exposure to the index patient and for symptoms of disease during the outbreak. Additionally, serum specimens were collected and assayed for antibody to SARS-associated coronavirus (SARS-CoV) antibody and job-specific attack rates were calculated. A nested case-control analysis was performed to assess risk factors for acquiring SARS-CoV infection.One hundred and fifty-three of 193 (79.3%) clinical and non-clinical staff consented to participate. Excluding job categories with <3 workers, the highest SARS attack rates occurred among nurses who worked in the outpatient and inpatient general wards . Nurses assigned to the operating room/intensive care unit, experienced the lowest attack rates (7.1%) among all clinical staff. Serologic evidence of SARS-CoV infection was detected in 4 individuals, including 2 non-clinical workers, who had not previously been identified as SARS cases; none reported having had fever or cough. Entering the index patient's room and having seen (viewed) the patient were the behaviors associated with highest risk for infection by univariate analysis .This study highlights job categories and activities associated with increased risk for SARS-CoV infection and demonstrates that a broad diversity of hospital workers may be vulnerable during an outbreak. These findings may help guide recommendations for the protection of vulnerable occupational groups and may have implications for other respiratory infections such as influenza. Transmission of SARS-CoV among staff, visitors, and patients of Hospital A, and their close contacts outside the hospital, ultimately resulted in 62 cases of SARS in Northern Vietnam. Ninety percent of the 62 cases and all of the deaths (n = 6) occurred among individuals who visited or worked at Hospital A, which was temporarily closed on March 18th, 2003.Enhanced infection control practices, cohorting of patients, and increased use of barrier protections were initiated on March 6Hospital A is a small (<60 bed) private facility in Hanoi, providing inpatient specialist, laboratory, and nursing services. At the time of the outbreak, in addition to Vietnamese staff, several expatriate nurses and physicians were employed, often as clinical specialists on short-term contract from France. This report describes SARS-CoV secondary attack rates among the cohort of hospital staff at Hospital A and presents the results of a nested case-control study designed to identify risk-factors for SARS-CoV transmission after admission of the index patient. The primary objectives were to ascertain the extent of SARS-CoV transmission among the clinical and non-clinical staff at the hospital and to determine the nature of the initial exposures to the index patient that resulted in a substantial transmission event.We conducted a survey of symptoms and exposures among the cohort of workers at Hospital A, and a nested case-control study to assess risk factors for acquiring SARS-CoV infection after admission of the index case. For the latter study, only individuals who had worked at least one shift during the time the index patient was hospitalized were included Figure .th (evening) to March 5th, as well as their symptoms from the time the index patient was admitted to the hospital until 10 days after he was transferred , investigators obtained a comprehensive list of hospital employees and held meetings with individual units  to recruit study participants. Upon providing written consent, participants were asked to complete a short, self-administered questionnaire and to provide a serum specimen for determination of antibodies to SARS-CoV. Questionnaires were translated into Vietnamese and responses were back-translated into English. Information was collected regarding the participant's contact with the index patient during his stay in the hospital from February 26did you enter the general ward, referred to whether or not the subject entered the general ward at least once at any time during the index patient's hospitalization. Variables were not all exclusive. For example subjects were asked whether they ever came within 1 meter of the index patient, and whether they ever did so without a mask (respirator). Further information pertaining to the number and duration of potential encounters was not requested due to time constraints and concerns about recall bias.All exposure variables were comprehensive for the period that the index patient was hospitalized at Hospital A. For example, A physician who provided care for SARS patients at Hospital A throughout the outbreak  served as a proxy respondent for the staff who had died (n = 6) or were too ill (n = 1) to respond at the time of the survey. This physician had assisted WHO investigators in conducting the initial staff interviews in early March following recognition of respiratory illnesses among staff. Work shift schedules were available for 30.0% of the Hospital staff and were used to verify staff responses. The protocol was approved following expedited review by the hospital institutional review board and the Vietnamese Ministry of Health.via reverse transcriptase polymerase chain reaction assays, RT-PCR), or by serology, as previously described [Laboratory confirmation of SARS-CoV infection was performed at the Centers for Disease Control and Prevention  and was based either on detection of RNA from SARS-CoV in clinical specimens  the presence of SARS-CoV antibody in at least one serum specimen collected prior to March 24th; or (ii) for SARS cases confirmed by means other that serologic testing , illness onset on or before March 5th, the last day the index patient received care at Hospital A. SARS Co-V infections resulting from exposure to the index patient were presumed to have resulted in antibody conversion on or before March 24th (18 days after the index patient's discharge) based on a conservative estimated timeline that includes a 6 day incubation period plus a 12 day interval to seroconversion. The estimated 6 day incubation period is based on the observed median number of days from exposure to illness onset among persons in Vietnam who reported only a single potential exposure to a SARS patient (n = 28). The 12 day estimated interval to seroconversion is based on the observed median number of days from illness onset to SARS-CoV antibody seroconversion among cases in Vietnam for whom the date of seroconversion is known within 48 hours (n = 17). This time frame is expected to exclude individuals who contracted infection from someone other than the index, while capturing the majority of individuals who were infected during index case's hospitalization in Hanoi, including a proportion of those who could have been infected on the last day of exposure to the index patient. The timing of illness onset alone was insufficient as a case selection criterion for the case-control study as this information was unavailable for many study enrollees.Study cases were defined as persons having: (i) were never identified as SARS cases, (ii) worked at least one shift during the time the index patient was hospitalized, and (iii) did not exhibit evidence of SARS-CoV specific antibodies within at least 18 days after last exposure to the index case.Controls were defined as individuals within the study cohort who  or odds ratios (OR) with 95% confidence intervals (CI) were used to assess differences between groups using negative responses as the referent. The threshold for statistical significance was established at a p-value < 0.05.Exposure and demographic variables used for analyses were dichotomous categorical; unknown or missing data was rendered as a negative response. Non-parametric tests .Advanced age (> 50 years) and underlying medical conditions were not significant correlates of case status in this outbreak [A staff census prepared in February 2003, indicated that 193 individuals were employed at Hospital A at the time of the SARS outbreak. The distribution of personnel between clinical and non-clinical roles is shown in Table th, and 9 days later on the 13th , but in both instances participation increased to over 64% for the serosurvey , therefore these responses were included analyses as appropriate.Results of the survey regarding symptoms of illness experienced by study participants are summarized in Figure Consistent with findings from a clinical study of SARS patients conducted in Vietnam , fever, Of the 124 Hospital A staff who participated in the serosurvey, 36 (29%) had at least one serum specimen that tested positive for the presence of antibody to SARS-CoV antigen  had mild illness and were not identified during the outbreak despite active surveillance conducted among staff at Hospital A. Among this group, the 2 General Ward nurses reported having had at least three symptoms associated with SARS illness in this outbreak , but neither reported having experienced fever or cough, which were inclusion criteria in the WHO SARS case definition used at the time. Both nurses also reported experiencing diarrhea during the study period. However, diarrhea was common among all Hospital A workers  regardless of SARS case status. Neither the laundry worker nor the receptionist reported having experienced symptoms significantly associated with SARS illness in Vietnam, with the exception that the latter reported vomiting.Twenty-two study cases and 45 controls were identified Figure .  was designated to care for suspect SARS cases. There were no SARS cases among staff at Hospital B, and a serosurvey conducted among workers at the facility revealed no inapparent or asymptomatic infections despite the presence of numerous confirmed SARS cases in the wards . The reaA previous study of clinical workers at Hospital A suggested that the proportion of doctors and nurses using masks as a precautionary measure increased significantly after the initiation of secondary cases and that the use of masks had a significant impact on diminishing SARS-CoV transmission . The potDuring the course of this study, four workers, none of whom had been previously identified as cases, were found to have been infected with SARS-CoV. None of the four reported having had cough or fever, but two complained of diarrhea and another had a sore throat. A similar study conducted among health care workers in Singapore, revealed serologic evidence of SARS-CoV infection in two workers  who experienced only mild symptoms of illness . Both ofThere were several limitations to this study. The first is the small sample size employed for the nested case-control, which contributed to a general lack of precision in measures of effect (odds ratios), and precluded our ability to look for independent risk factors through multivariate analyses. In addition, because of the need to minimize the complexity of the questionnaire, we were unable to assess either the duration, or the intensity of potential exposures, both of which are likely to be important modifiers of absolute risk. However, our streamlined approach using generalized questions allowed us to rapidly survey a large fraction of the hospital worker population, rather than just medical professionals. Finally, there were several potential sources of bias in this study which could have affected our results and conclusions. Although we performed the study prior to closure of the hospital, while the staff were still actively engaged in the outbreak investigation, we failed to achieve full staff participation, particularly among physicians and certain categories of nurses. This could have introduced a selection bias favoring enrollment of persons with less opportunity for direct contact with the index patient. Similarly, we questioned individuals about their exposure to the index patient 13 days after he was transferred to Hong Kong, and used a proxy to complete exposure questionnaires for deceased individual. Either of these could have introduced non-systematic information  bias to our findings. We attempted to minimize the influence of these potential sources of bias by using case investigation forms and physician notes to verify self-reported information when ever possible.Many of the job-related activities identified in this study as potential risk factors for SARS-CoV infection, such as entering the patient's room, and touching a visibly contaminated surface relate to 'proximity' contacts and possibly fomite involvement. These types of contact are broadly applicable to many different job categories from receptionist to physician, implying that our concept of occupational categories at risk for nosocomial infection may need to be broadened to include many different kinds of workers without direct patient care duties ,7,15,16.The outbreak of SARS in northern Vietnam investigated here serves as a tragic reminder of the profound impact that the introduction of a highly communicable, virulent pathogen can have on the relatively closed community of a small hospital. In such instances, very early events following introduction can be pivotal in determining the ultimate magnitude of the outbreak and the degree of spread within the hospital. Appropriate recognition of those at highest risk of exposure and illness in conjunction with rapid, accurate identification of potential cases at the earliest stages of illness, are vital to minimizing the extent of spread. The results of this investigation highlight the diversity of workers at risk for nosocomial exposures and contribute to our understanding of risk factors for SARS-CoV transmission, which may include being in proximity to an infected patient or touching a contaminated surface.The author(s) declare that they have no competing interests.All authors read and approved the final manuscript. MR participated in the design of the study performed the statistical analyses and drafted the manuscript; BA participated in the design and coordinated implementation of the study; VT participated in the implementation of the study; JM participated in data analyses and preparation of the manuscript; DB participated in design of the study and preparation of the manuscript; JS participated in implementation of the study; SM participated in design of the study; KL participated in implementation of the study; VH participated in collection and analysis of laboratory diagnostic specimens; PH participated in data analysis and manuscript preparation; AP participated in design of the study; TU participated in design and implementation of study and supervised manuscript preparation.The pre-publication history for this paper can be accessed here: