Improved method for calibration of exchange flows for a physical transport box model of Tampa Bay, FL USA.

We report the results for both sequential and simultaneous calibration of exchange flows between segments of a 10-box, 1-dimensional, well mixed, bifurcated tidal mixing model for Tampa Bay. Calibrations were conducted for three model options having different mathematical expressions for evaporative loss. In approaching this project we asked three questions: does simultaneous calibration or sequential calibration yield better box model performance; which evaporation option best predicts observed salinities; and how well does model performance compare to more complex hydrodynamic models. Sequential calibration followed the classical salt balance and steady state approach. The nonlinear parameter estimator (PEST) was used for simultaneous calibration. The sequential approach proved useful in evaluating the three evaporation options. However, simultaneous calibration proved superior in predicting observed salinities but was ineffective in discerning differences between evaporation options. The simultaneously calibrated model produced residence times that fell within the range of more complex hydrodynamic models of Tampa Bay.

Ramucirumab for the treatment of gastroesophageal cancers.

INTRODUCTION: In 2014, the U.S. Food and Drug Administration (FDA) approved ramucirumab for use in the second line setting of advanced or metastatic, gastric or gastroesophageal adenocarcinoma (GEAC) based on the result of Phase III clinical trials; REGARD and RAINBOW. AREAS COVERED: We briefly review the mechanisms of angiogenesis, anti-angiogenic therapy, and current status of advanced GEAC treatment then highlight the challenges and future prospects of novel molecular targeted agents. EXPERT OPINION: Although both the REGARD and RAINBOW trials met their primary endpoints of significantly prolonged overall survival (OS) and progression-free survival (PFS), the magnitude of the difference is still relatively modest. Given that ramucirumab alone has a marginal effect, a combination of paclitaxel and ramucirumab is strongly preferred as a second line therapy. To maximize the impact of ramucirumab in patients with GEAC, we can leverage the recent pharmacokinetics (PK) data of ramucirumab from the REGARD and RAINBOW trials. In addition, the quest for identifying biomarkers to select patients who are likely to benefit the most should continue. It is our firm belief that taxanes should no longer be added to the frontline regimens in most cases, given the success of the taxane/ramucirumab in the second line setting.

Onset and complications of varicella zoster reactivation in the autologous hematopoietic cell transplant population.

BACKGROUND: Varicella zoster virus (VZV) infections are a common complication in patients receiving autologous or allogeneic hematopoietic cell transplant (HCT). Recent guideline revisions suggest extending VZV prophylaxis to 1 year after autologous HCT. We retrospectively evaluated reactivation at our center, before implementation of extended acyclovir prophylaxis, to determine onset and outcome in the autologous HCT population. METHODS: Inclusion criteria consisted of adult patients who received an autologous HCT with documentation for at least 1 year post transplant. Those excluded from review were patients who received acyclovir prophylaxis for >30 days post transplant or subsequently received an allogeneic transplant within 1 year. For patients in whom reactivation occurred, the severity of infection, the timing of onset, treatment of the reactivation, and any complications were recorded. RESULTS: In the final analysis, 56 patients were assessed. Reactivation of zoster occurred in 16% of recipients with a median onset of 4.5 months post transplant. Complications that were observed include postherpetic neuralgia, severe pain, scarring, and motor weakness. Two patients required hospitalization for treatment, with 1 patient requiring 6 months of rehabilitation for motor weakness following the infection. CONCLUSIONS: Our study revealed a 16% incidence of VZV reactivation in our autologous HCT population. The onset of these occurrences ranged from 2 to 10 months post transplant, with significant VZV-associated complications. We consider VZV reactivation a serious concern in the autologous transplant setting, requiring extended prophylaxis.

Quality assurance of medical ontologies.

OBJECTIVE: To review the literature concerning the quality assurance of medical ontologies. METHODS: scholar.google.com was searched using the search strings (+ontology +"quality assurance") and (+ontology +"evaluation/evaluating"). Relevant publications were selected by manual review. Other work already familiar to the author, or suggested by other researchers contacted by the author, were included. The papers were analysed for common themes. RESULTS: Four broad properties of an ontology were identified that may be quality-assured: philosophical validity, compliance with meta-ontological commitments, 'content correctness', and fitness for purpose. Each published methodology addressed only a subset of these properties. 'Content' may be divided into domain knowledge content, and metadata describing either the provenance of domain knowledge content, or relationships between it and lexical information (e.g. for display and retrieval). 'Correctness' (whether of domain knowledge content or metadata) may also be further subdivided into truth, completeness, parsimony and internal consistency. CONCLUSIONS: Understanding of how to assure the quality of ontologies, or evaluate their fitness for specific purposes, is improving but remains poor. A combination of methodologies is required, but tools to support a comprehensive quality assurance programme remain lacking. Perfect quality of an ontology is not provable and may not be desirable: an ontology compliant with all current philosophical theories, following necessary ontological commitments, and with entirely 'correct' content, may be too complex to be directly usable or useful. The extent to which an ontology's fitness for purpose is predicted or influenced by its other properties remains to be determined. Field studies of ontologies in use, including interrater effects, are required.

Attitudes and access to electronic exchange of information on occupational disease.

BACKGROUND: THOR is a network of work-related disease surveillance schemes dependent on volunteer case reporting by medical specialists. Data collection and dissemination has hitherto been paper-based. AIMS: To elicit the opinion of existing reporters in THOR on electronic exchange of information and to assess the practical capabilities of the same reporters to participate in electronic communication. METHODS: A mail-based questionnaire of randomly selected THOR reporters using closed format questions. RESULTS: The response rate to the questionnaire was 66% (253/383). Almost half (47%) of the responders wanted dissemination of information solely in an electronic form, 35% favoured paper-based reports, while 16% wanted both paper and electronic reports. Two-thirds (66%) would make use of electronic archives of reports and 59% would use this facility to resolve questions by accessing accumulated data. The majority (82%) read e-mail more than once a week and 34% browsed the web as frequently. However, 5% did not have e-mail and 6% never browsed the web. Most responders judged their internet connectivity to be rapid (68%) and convenient (83%), and 91% could receive e-mail attachments. CONCLUSIONS: Most responders have the skills and infrastructure required to engage in electronic information exchange, and are favourably disposed to electronic means of communication. However it is also relevant to note that one-third of responders have a preference for the existing paper-based system.

OpenGALEN: open source medical terminology and tools.

The GALEN programme of research into medical terminology began in 1991. In 1999 OpenGALEN was formed to provide an open source route both for disseminating the results of that programme and as a framework for its future development. Currently available open source resources include a sophisticated ontology development environment and a large open source description logic-based ontology for the medical domain.

Mechanisms of photoinitiated cleavage of DNA by 1,8-naphthalimide derivatives.

Using water-soluble 1,8-naphthalimide derivatives, the mechanisms of photosensitized DNA damage have been elucidated. Specifically, a comparison of rate constants for the photoinduced relaxation of supercoiled to circular DNA, as a function of dissolved halide, oxygen and naphthalimide concentration, has been carried out. The singlet excited states of the naphthalimide derivatives were quenched by chloride, bromide and iodide. In all cases the quenching products were naphthalimide triplet states, produced by induced intersystem crossing within the collision complex. Similarly, the halides were found to quench the triplet excited state of the 1,8-naphthalimide derivatives by an electron transfer mechanism. Bimolecular rate constants were < 10(5) M-1 s-1 for quenching by bromide and chloride. As expected from thermodynamic considerations quenching by iodide was 6.7 x 10(9) and 8.8 x 10(9) M-1 s-1 for the two 1,8-naphthalimide derivatives employed. At sufficiently high ground-state concentration self-quenching of the naphthalimide triplet excited state also occurs. The photosensitized conversion of supercoiled to circular DNA is fastest when self-quenching reactions are favored. The results suggest that, in the case of 1,8-naphthalimide derivatives, radicals derived from quenching of the triplet state by ground-state chromophores are more effective in cleaving DNA than reactive oxygen species or radicals derived from halogen atoms.

Nucleotide oxidation mediated by naphthalimide excited states with covalently attached viologen cosensitizers.

The ground- and excited-state interactions of polymethylene-linked 1,8-naphthalimide-viologen dyads with calf-thymus DNA have been investigated. By virtue of the covalently attached viologen, the compounds represent the first example of linked chromophore/cosensitizer systems in the photooxidation of duplex DNA. The compounds associate strongly with DNA. Analysis of ground-state spectral changes yield binding constants of 0.7-2.5 x 10(6) M-1. Upon 355 nm pulsed irradiation of the compounds in the presence of calf-thymus DNA, reduced viologen is observed within the laser pulse. Photoproducts are not observed on this time scale in the absence of DNA. Since ground-state bleaching of the naphthalimide was not observed, the results suggest that DNA nucleobases are the species being oxidized. The quantum efficiency of radical production increases with the extent of binding to DNA. Under conditions where the compounds are bound predominantly to DNA, the quantum efficiencies were found to range from 0.02 to 0.03. Although small, the values represent a substantial increase in charge-separation yield compared to 1,8-naphthalimide compounds that lack the covalently attached viologen. The mechanism of radical production and effect of number of intervening methylenes are discussed.

Having our cake and eating it too: how the GALEN Intermediate Representation reconciles internal complexity with users' requirements for appropriateness and simplicity.

Clinical terminologies are complex objects, getting more complex as the requirements on them grow, and as more complex technologies are used in their construction. But to the clinical end-user, functionality and utility is important, not inherent complexity--the simpler a clinical terminology can be for the end-user, the better. To reconcile these contradictory requirements, the GALEN Programme has developed an Intermediate Representation that allows the OpenGALEN Clinical Terminology to retain a high degree of internal complexity, whilst allowing it to be efficiently maintained, and easily used. This paper describes the elements of the Intermediate Representation, how it works, and some experience of its use.

GALEN: a third generation terminology tool to support a multipurpose national coding system for surgical procedures.

Generalised architecture for languages, encyclopedia and nomenclatures in medicine (GALEN) has developed a new generation of terminology tools based on a language independent model describing the semantics and allowing computer processing and multiple reuses as well as natural language understanding systems applications to facilitate the sharing and maintaining of consistent medical knowledge. During the European Union 4 Th. framework program project GALEN-IN-USE and later on within two contracts with the national health authorities we applied the modelling and the tools to the development of a new multipurpose coding system for surgical procedures named CCAM in a minority language country, France. On one hand, we contributed to a language independent knowledge repository and multilingual semantic dictionaries for multicultural Europe. On the other hand, we support the traditional process for creating a new coding system in medicine which is very much labour consuming by artificial intelligence tools using a medically oriented recursive ontology and natural language processing. We used an integrated software named CLAW (for classification workbench) to process French professional medical language rubrics produced by the national colleges of surgeons domain experts into intermediate dissections and to the Grail reference ontology model representation. From this language independent concept model representation, on one hand, we generate with the LNAT natural language generator controlled French natural language to support the finalization of the linguistic labels (first generation) in relation with the meanings of the conceptual system structure. On the other hand, the Claw classification manager proves to be very powerful to retrieve the initial domain experts rubrics list with different categories of concepts (second generation) within a semantic structured representation (third generation) bridge to the electronic patient record detailed terminology.

A reference terminology for drugs.

GALEN technology for re-usable terminologies using formal classification is being applied to the creation and maintenance of a reference terminology for drugs. GALEN's techniques are being used to address specific deficiencies of existing drug classifications that make it difficult to create and maintain guidelines to support prescribing in the care of patients with chronic diseases. The reference terminology is in two parts; firstly, a re-usable and automatically-classified 'ontology' is built with GALEN technology; this describes generic drugs, their composition in terms of chemicals and chemical classes, their actions, indications and interactions. Secondly, a 'dictionary' of prescribable proprietary products is integrated with this ontology. The result is a drug resource designed to support both the traditional uses of a drug knowledge base (e.g. prescribing and messaging), and the specialized demands of guideline authoring and execution.

Natural language generation of surgical procedures.

A number of compositional Medical Concept Representation systems are being developed. Although these provide for a detailed conceptual representation of the underlying information, they have to be translated back to natural language for used by end-users and applications. The GALEN programme has been developing one such representation and we report here on a tool developed to generate natural language phrases from the GALEN conceptual representations. This tool can be adapted to different source modelling schemes and to different destination languages or sublanguages of a domain. It is based on a multilingual approach to natural language generation, realised through a clean separation of the domain model from the linguistic model and their link by well defined structures. Specific knowledge structures and operations have been developed for bridging between the modelling 'style' of the conceptual representation and natural language. Using the example of the scheme developed for modelling surgical operative procedures within the GALEN-IN-USE project, we show how the generator is adapted to such a scheme. The basic characteristics of the surgical procedures scheme are presented together with the basic principles of the generation tool. Using worked examples, we discuss the transformation operations which change the initial source representation into a form which can more directly be translated to a given natural language. In particular, the linguistic knowledge which has to be introduced--such as definitions of concepts and relationships is described. We explain the overall generator strategy and how particular transformation operations are triggered by language-dependent and conceptual parameters. Results are shown for generated French phrases corresponding to surgical procedures from the urology domain.

Galen: a third generation terminology tool to support a multipurpose national coding system for surgical procedures.

GALEN has developed a new generation of terminology tools based on a language independent concept reference model using a compositional formalism allowing computer processing and multiple reuses. During the 4th framework program project Galen-In-Use we applied the modelling and the tools to the development of a new multipurpose coding system for surgical procedures (CCAM) in France. On one hand we contributed to a language independent knowledge repository for multicultural Europe. On the other hand we support the traditional process for creating a new coding system in medicine which is very much labour consuming by artificial intelligence tools using a medically oriented recursive ontology and natural language processing. We used an integrated software named CLAW to process French professional medical language rubrics produced by the national colleges of surgeons into intermediate dissections and to the Grail reference ontology model representation. From this language independent concept model representation on one hand we generate controlled French natural language to support the finalization of the linguistic labels in relation with the meanings of the conceptual system structure. On the other hand the classification manager of third generation proves to be very powerful to retrieve the initial professional rubrics with different categories of concepts within a semantic network.

Validating clinical terminology structures: integration and cross-validation of Read Thesaurus and GALEN.

A European pre-standard and an intermediate representation facilitated exchange of two independently authored compositional knowledge bases: one formal and automatically classified, the other manually classified. The exchange highlights different strengths and weaknesses in each approach, and offers a mechanism for partial, mutual quality assurance.

Reconciling users' needs and formal requirements: issues in developing a reusable ontology for medicine.

A common language, or terminology, for representing what clinicians have said and done is an important requirement for individual clinical systems, and it is a pre-requisite for integrating disparate applications in a distributed telematic healthcare environment. Formal representations based on description logics or closely related formalisms are increasingly used for representing medical terminologies. GALEN's experience in using one such formalism raises two major issues, as follows: how to make ontologies based on description logics easy to use and understand for both clinicians and applications developers; what features are required of the ontology and description logic if they are to achieve their aims. Based on our experience we put forward four contentions: two relating to each of these two issues, as follows: that natural language generation is essential to make a description logic based ontology accessible to users; that the description logic based ontology should be treated as an "assembly language" and accessed via "intermediate representations" oriented to users and "perspectives" adapting it to specific applications; that independence and reuse are best supported by partitioning the subsumption hierarchy of elementary concepts into orthogonal taxonomies, each of which forms a pure tree in which the branches at each level are disjoint but nonexhaustive subconcepts of the parent concept; that the expressivity of the description logic must include support for transitive relations despite the computational cost, and that this computational cost is acceptable in practice. The authors argue that these features will be necessary, though by no means sufficient, for the development of any large reusable ontology for medicine.

Natural language generation of surgical procedures.

The GALEN-IN-USE project has developed a compositional scheme for the conceptual representation of surgical operative procedure rubrics. The complex representations which result are translated back to surface language by a tool for multilingual natural language generation. This generator can be adapted to the specific characteristics of the scheme by introducing particular definitions of concepts and relationships. We discuss how the generator uses such definitions to bridge between the modelling 'style' of the GALEN scheme and natural language.

Terminological systems: bridging the generation gap.

A rigorous formal description of the intended behaviour of a compositional terminology, a 'third generation' system, enables powerful semantic processing techniques to assist in the building of a large terminology. Use of an intermediate representation derived from such a formalism, but simplified to resemble a 'second generation' system, enables authors to work in an simpler and more familiar environment, avoiding many of the technical complications of the 'third generation' system.

Rubrics to dissections to GRAIL to classifications.

This paper summarises the process in the GALEN-IN-USE project by which rubrics from traditional medical coding schemes are analysed into an intermediate, relatively informal conceptual representation which is then automatically translated into the GRAIL formalism and its Common Reference Model.

Using the GRAIL language for classification management.

This paper describes a novel approach in classification management where a formal model of medical semantics is being used for manipulations on existing classification systems. The paper addresses the issue of semi-automatically making specialist classifications that are compatible with the source classification. The examples in this paper are from a limited domain. At the time of the presentation results will be shown of the present modelling work within the GALEN-In-Use project. The model will then contain several thousands of medical procedures from four different classification centres.