'Delayed discharges and boarders': a 2-year study of the relationship between patients experiencing delayed discharges from an acute hospital and boarding of admitted patients in a crowded ED.

OBJECTIVE: Many believe that hospital crowding manifesting in the ED with the boarding of admitted patients is a result of significant numbers of acute hospital beds being occupied by patients awaiting discharge to nursing homes, step-down facilities or home with or without additional support. This observational study was performed to establish the actual relationship between boarders in the ED and patients experiencing delayed discharge. METHODS: Data relating to the number of patients in the ED and their points in their patient pathway were entered into a logbook on a daily basis by the most senior doctor on duty. 630 days of observations of patients boarded in the ED were compared with the number of inpatients with delayed discharges, obtained from the hospital information system, to see if large numbers of inpatients with delayed discharges are associated with crowding in the ED. RESULTS: Two years of data showed an annual ED census of more than 47 000, with a daily mean ED admission rate of 29.85 patients and a daily mean ED boarding figure of 29 patients. A mean of 15.4% of the 823 hospital beds was occupied by patients with delayed discharges, and the hospital ran at, or near, full capacity (99%-105%) all the time. Results obtained highlighted a statistically significant relationship between delayed discharges in the hospital and ED crowding as a result of boarders (p value<0.001, with a regression coefficient of 0.16, 95% CI 0.12 to 0.20). The study also showed that the number of boarders was related to the number of ED admissions in the preceding 24 hours (p=0.036, with a regression coefficient of 0.14, 95% CI 0.05 to 0.28). CONCLUSIONS: Delayed hospital discharges significantly contribute to crowding in the ED. Healthcare systems should target timely discharge of inpatients experiencing delayed discharge in an urgent and efficient manner to improve timely access to acute hospital beds for patients requiring emergency admission.

Polyaniline-graphene based α-amylase biosensor with a linear dynamic range in excess of 6 orders of magnitude.

α-amylase is an established marker for diagnosis of pancreatic and salivary disease, and recent research has seen a substantial expansion of its use in therapeutic and diagnostic applications for infection, cancer and wound healing. The lack of bedside monitoring devices for α-amylase detection has hitherto restricted the clinical progress of such applications. We have developed a highly sensitive α-amylase immunosensor platform, produced via in situ electropolymerization of aniline onto a screen-printed graphene support (SPE). Covalently binding an α-amylase specific antibody to a polyaniline (PANI) layer and controlling device assembly using electrochemical impedance spectroscopy (EIS), we have achieved a highly linear response against α-amylase concentration. Each stage of the assembly was characterized using a suite of high-resolution topographical, chemical and mechanical techniques. Quantitative, highly sensitive detection was demonstrated using an artificially spiked human blood plasma samples. The device has a remarkably wide limit of quantification (0.025-1000IU/L) compared to α-amylase assays in current clinical use. With potential for simple scale up to volume manufacturing though standard semiconductor production techniques and subsequently clinical application, this biosensor will enable clinical benefit through early disease detection, and better informed administration of correct therapeutic dose of drugs used to treat α-amylase related diseases.

Clinical applications of amylase: Novel perspectives.

BACKGROUND: Amylase was the first enzyme to be characterized, and for the previous 200 years, its clinical role has been restricted to a diagnostic aid. Recent interface research has led to a substantial expansion of its role into novel, viable diagnostic, and therapeutic applications to cancer, infection, and wound healing. This review provides a concise "state-of-the-art" overview of the genetics, structure, distribution, and localization of amylase in humans. METHOD: A first-generation literature search was performed with the MeSH search string "Amylase AND (diagnost∗ OR therapeut$)" on OVIDSP and PUBMED platforms. A second-generation search was then performed by forward and backward referencing on Web of Knowledge™ and manual indexing, limited to the English Language. RESULTS: "State of the Art" in amylase genetics, structure, function distribution, localisation and detection of amylase in humans is provided. To the 4 classic patterns of hyperamylasemia (pancreatic, salivary, macroamylasemia, and combinations) a fifth, the localized targeting of amylase to specific foci of infection, is proposed. CONCLUSIONS: The implications are directed at novel therapeutic and diagnostic clinical applications of amylase such as the novel therapeutic drug classes capable of targeted delivery and "smart release" in areas of clinical need. Future directions of research in areas of high clinical benefit are reported.

The CellML 1.1 Specification.

This document specifies CellML 1.1, an XML-based language for describing and exchanging models of cellular and subcellular processes. MathML embedded in CellML documents is used to define the underlying mathematics of models. Models consist of a network of reusable components, each with variables and equations manipulating those variables. Models may import other models to create systems of increasing complexity. Metadata may be embedded in CellML documents using RDF.

European survey on imaging referral guidelines.

UNLABELLED: The objective of this study was to devise and implement a Europe-wide study on referral guidelines for radiological imaging in the EU Member States in order to identify potential major issues, important differences between Member States and good practices. A web-based survey was used to assess the availability of imaging referral guidelines, development methodology and preferences for future initiatives for European community action to facilitate justification and appropriate use of radiological diagnostic procedures. A questionnaire was distributed to representatives of national radiological and nuclear medicine societies as well as to competent authorities for radiation protection in 30 European countries, including all 28 EU Member States. Responses were collated and analysed to produce a series of conclusions and recommendations. MAIN MESSAGES: • Survey respondents in 21/30 countries were aware of legal requirements for Guidelines • Survey respondents in 18/30 countries were aware of the availability of Guidelines in their country. • The majority of responders support the development of European Guidelines. These may either be from a combination of multiple national Guidelines with consensus or Pan-European Guidelines developed centrally. • Guidelines developed in two countries included all of the following important features: radiation dose information; specific advice for imaging children; specific advice for the pregnant woman/unborn child; an evidence-based process; a formal consensus for recommendations. • Suggestions for additional measures needed to reinforce the use of Guidelines include: educational initiatives; integrating Guidelines into clinical decision support systems; clinical audit for monitoring of the availability, use and implementation of Guidelines.

Dependence of spontaneous neuronal firing and depolarisation block on astroglial membrane transport mechanisms.

Exposed to a sufficiently high extracellular potassium concentration ([K( + )]0), the neuron can fire spontaneous discharges or even become inactivated due to membrane depolarisation ('depolarisation block'). Since these phenomena likely are related to the maintenance and propagation of seizure discharges, it is of considerable importance to understand the conditions under which excess [K( + )]0 causes them. To address the putative effect of glial buffering on neuronal activity under elevated [K( + )](o) conditions, we combined a recently developed dynamical model of glial membrane ion and water transport with a Hodgkin-Huxley type neuron model. In this interconnected glia-neuron model we investigated the effects of natural heterogeneity or pathological changes in glial membrane transporter density by considering a large set of models with different, yet empirically plausible, sets of model parameters. We observed both the high [K( + )]0-induced duration of spontaneous neuronal firing and the prevalence of depolarisation block to increase when reducing the magnitudes of the glial transport mechanisms. Further, in some parameter regions an oscillatory bursting spiking pattern due to the dynamical coupling of neurons and glia was observed. Bifurcation analyses of the neuron model and of a simplified version of the neuron-glia model revealed further insights about the underlying mechanism behind these phenomena. The above insights emphasise the importance of combining neuron models with detailed astroglial models when addressing phenomena suspected to be influenced by the astroglia-neuron interaction. To facilitate the use of our neuron-glia model, a CellML version of it is made publicly available.

The Physiome Model Repository 2.

MOTIVATION: The Physiome Model Repository 2 (PMR2) software was created as part of the IUPS Physiome Project (Hunter and Borg, 2003), and today it serves as the foundation for the CellML model repository. Key advantages brought to the end user by PMR2 include: facilities for model exchange, enhanced collaboration and a detailed change history for each model. AVAILABILITY: PMR2 is available under an open source license at http://www.cellml.org/tools/pmr/; a fully functional instance of this software can be accessed at http://models.physiomeproject.org/.

Calcium homeostasis and signaling in yeast cells and cardiac myocytes.

Calcium ions are the most ubiquitous and versatile signaling molecules in eukaryotic cells. Calcium homeostasis and signaling systems are crucial for both the normal growth of the budding yeast Saccharomyces cerevisiae and the intricate working of the mammalian heart. In this paper, we make a detailed comparison between the calcium homeostasis/signaling networks in yeast cells and those in mammalian cardiac myocytes. This comparison covers not only the components, structure and function of the networks but also includes existing knowledge on the measured and simulated network dynamics using mathematical models. Surprisingly, most of the factors known in the yeast calcium homeostasis/signaling network are conserved and operate similarly in mammalian cells, including cardiac myocytes. Moreover, the budding yeast S. cerevisiae is a simple organism that affords powerful genetic and genomic tools. Thus, exploring and understanding the calcium homeostasis/signaling system in yeast can provide a shortcut to help understand calcium homeostasis/signaling systems in mammalian cardiac myocytes. In turn, this knowledge can be used to help treat relevant human diseases such as pathological cardiac hypertrophy and heart failure.

CellML metadata standards, associated tools and repositories.

The development of standards for encoding mathematical models is an important component of model building and model sharing among scientists interested in understanding multi-scale physiological processes. CellML provides such a standard, particularly for models based on biophysical mechanisms, and a substantial number of models are now available in the CellML Model Repository. However, there is an urgent need to extend the current CellML metadata standard to provide biological and biophysical annotation of the models in order to facilitate model sharing, automated model reduction and connection to biological databases. This paper gives a broad overview of a number of new developments on CellML metadata and provides links to further methodological details available from the CellML website.

Astrocytic mechanisms explaining neural-activity-induced shrinkage of extraneuronal space.

Neuronal stimulation causes approximately 30% shrinkage of the extracellular space (ECS) between neurons and surrounding astrocytes in grey and white matter under experimental conditions. Despite its possible implications for a proper understanding of basic aspects of potassium clearance and astrocyte function, the phenomenon remains unexplained. Here we present a dynamic model that accounts for current experimental data related to the shrinkage phenomenon in wild-type as well as in gene knockout individuals. We find that neuronal release of potassium and uptake of sodium during stimulation, astrocyte uptake of potassium, sodium, and chloride in passive channels, action of the Na/K/ATPase pump, and osmotically driven transport of water through the astrocyte membrane together seem sufficient for generating ECS shrinkage as such. However, when taking into account ECS and astrocyte ion concentrations observed in connection with neuronal stimulation, the actions of the Na(+)/K(+)/Cl(-) (NKCC1) and the Na(+)/HCO(3) (-) (NBC) cotransporters appear to be critical determinants for achieving observed quantitative levels of ECS shrinkage. Considering the current state of knowledge, the model framework appears sufficiently detailed and constrained to guide future key experiments and pave the way for more comprehensive astroglia-neuron interaction models for normal as well as pathophysiological situations.

Simulating in vitro transcriptional response of zinc homeostasis system in Escherichia coli.

BACKGROUND: The zinc homeostasis system in Escherichia coli is one of the most intensively studied prokaryotic zinc homeostasis systems. Its underlying regulatory machine consists of repression on zinc influx through ZnuABC by Zur (Zn2+ uptake regulator) and activation on zinc efflux via ZntA by ZntR (a zinc-responsive regulator). Although these transcriptional regulations seem to be well characterized, and there is an abundance of detailed in vitro experimental data available, as yet there is no mathematical model to help interpret these data. To our knowledge, the work described here is the first attempt to use a mathematical model to simulate these regulatory relations and to help explain the in vitro experimental data. RESULTS: We develop a unified mathematical model consisting of 14 reactions to simulate the in vitro transcriptional response of the zinc homeostasis system in E. coli. Firstly, we simulate the in vitro Zur-DNA interaction by using two of these reactions, which are expressed as 4 ordinary differential equations (ODEs). By imposing the conservation restraints and solving the relevant steady state equations, we find that the simulated sigmoidal curve matches the corresponding experimental data. Secondly, by numerically solving the ODEs for simulating the Zur and ZntR run-off transcription experiments, and depicting the simulated concentrations of zntA and znuC transcripts as a function of free zinc concentration, we find that the simulated curves fit the corresponding in vitro experimental data. Moreover, we also perform simulations, after taking into consideration the competitive effects of ZntR with the zinc buffer, and depict the simulated concentration of zntA transcripts as a function of the total ZntR concentration, both in the presence and absence of Zn(II). The obtained simulation results are in general agreement with the corresponding experimental data. CONCLUSION: Simulation results show that our model can quantitatively reproduce the results of several of the in vitro experiments conducted by Outten CE and her colleagues. Our model provides a detailed insight into the dynamics of the regulatory system and also provides a general framework for simulating in vitro metal-binding and transcription experiments and interpreting the relevant experimental data.

The CellML Model Repository.

SUMMARY: The CellML Model Repository provides free access to over 330 biological models. The vast majority of these models are derived from published, peer-reviewed papers. Model curation is an important and ongoing process to ensure the CellML model is able to accurately reproduce the published results. As the CellML community grows, and more people add their models to the repository, model annotation will become increasingly important to facilitate data searches and information retrieval. AVAILABILITY: The CellML Model Repository is publicly accessible at http://www.cellml.org/models.

Three-colour fluorescence immunohistochemistry reveals the diversity of cells staining for macrophage markers in murine spleen and liver.

Macrophages have traditionally been identified in murine tissues using a small range of markers, typically F4/80, CD68 and CD11b. However many studies have suggested that substantial heterogeneity exists in macrophage populations, and no single marker, nor even pair of markers, can necessarily identify all the populations. Further, many of the key monoclonal antibodies have been raised in the same species, making it difficult to combine them in histochemical studies. Here we have optimised a triple colour immunofluorescent staining protocol, utilising an anti-FITC technique, to allow antibodies to macrophage markers to be used simultaneously. We highlight the substantial heterogeneity of cells in both normal liver and spleen that stain for F4/80, CD68, CD11b, and CD11c. Using diet-induced steatohepatitis as a model of liver inflammation, we show that CD11b is expressed by newly migrating macrophage precursors, but is an unreliable marker for macrophage precursors when used alone because it is also expressed by migrating neutrophils. In healthy livers CD11c expression is a unique feature of a population of cells immediately surrounding the sinusoids. However, during hepatic inflammation CD11c can also be co-expressed by other cells, including both infiltrating cells and F4/80+ cells within the liver parenchyma. While no one marker alone is sufficient to account for all macrophage populations, we confirm that F4/80 marks the majority of the tissue-resident macrophages in both the liver and the spleen, although F4/80- populations that are positive for CD68, CD11b, or CD11c also exist. Distinguishing between tissue macrophages and dendritic cells with these markers remains problematic.

CellML: its future, present and past.

Advances in biotechnology and experimental techniques have lead to the elucidation of vast amounts of biological data. Mathematical models provide a method of analysing this data; however, there are two issues that need to be addressed: (1) the need for standards for defining cell models so they can, for example, be exchanged across the World Wide Web, and also read into simulation software in a consistent format and (2) eliminating the errors which arise with the current method of model publication. CellML has evolved to meet these needs of the modelling community. CellML is a free, open-source, eXtensible markup language based standard for defining mathematical models of cellular function. In this paper we summarise the structure of CellML, its current applications (including biological pathway and electrophysiological models), and its future development--in particular, the development of toolsets and the integration of ontologies.