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Andreas Seyfang

Publications and source records attributed to Andreas Seyfang.

14 recordsLinked to original sources
PubMed2006

Improving medical protocols by formal methods.

OBJECTIVES: During the last decade, evidence-based medicine has given rise to an increasing number of medical practice guidelines and protocols. However, the work done on developing and distributing protocols outweighs the efforts on guaranteeing their quality. Indeed, anomalies like ambiguity and incompleteness are frequent in medical protocols. Recent efforts have tried to address the problem of protocol improvement, but they are not sufficient since they rely on informal processes and notations. Our objective is to improve the quality of medical protocols. APPROACH: The solution we suggest to the problem of quality improvement of protocols consists in the utilisation of formal methods. It requires the definition of an adequate protocol representation language, the development of techniques for the formal analysis of protocols described in that language and, more importantly, the evaluation of the feasibility of the approach based on the formalisation and verification of real-life medical protocols. For the first two aspects we rely on earlier work from the fields of knowledge representation and formal methods. The third aspect, i.e. the evaluation of the use of formal methods in the quality improvement of protocols, constitutes our main objective. The steps with which we have carried out this evaluation are the following: (1) take two real-life reference protocols which cover a wide variety of protocol characteristics; (2) formalise these reference protocols; (3) check the formalisation for the verification of interesting protocol properties; and (4) determine how many errors can be uncovered in this way. RESULTS: Our main results are: a consolidated formal language to model medical practice protocols; two protocols, each both modelled and formalised; a list of properties that medical protocols should satisfy; verification proofs for these protocols and properties; and perspectives of the potentials of this approach. Our results have been evaluated by a panel of medical experts, who judged that the problems we detected in the protocols with the help of formal methods were serious and should be avoided. CONCLUSIONS: We have succeeded in demonstrating the feasibility of formal methods for improving medical protocols.

Artificial Intelligence↗
PubMed2005

'Candidatus Borrelia texasensis', from the American dog tick Dermacentor variabilis.

TXW-1, a Borrelia strain isolated in March 1998 from an adult male Dermacentor variabilis tick feeding on a coyote from Webb county, Texas, USA, was characterized by using randomly amplified polymorphic DNA (RAPD) analysis, RFLP and sequence analysis of flaB and rrs (16S rRNA gene), DNA-DNA hybridization analysis, SDS-PAGE and Western blotting with mAbs. It shows different banding patterns in RFLP analysis of flaB and forms distinct branches in phylogenetic analysis derived from flaB and rrs genes. It differs from other borreliae based on the banding patterns obtained by RAPD analysis. This strain contains a small, 38-kDa endoflagellar protein. DNA-DNA hybridization experiments revealed that the levels of DNA reassociation between TXW-1 and previously described relapsing fever borreliae were 38.64 % (Borrelia turicatae), 38.40 % (Borrelia parkeri), 7.39 % (Borrelia hermsii) and 18.30 % (Borrelia coriaceae). However, the level of DNA relatedness between B. parkeri and B. turicatae was 78.78 %. Sequence analyses of flaB and rrs genes indicate that the similarities of nucleotide sequences among TXW-1 and B. turicatae or B. parkeri are less than that between B. turicatae and B. parkeri, and that the genetic distances among TXW-1 and B. turicatae or B. parkeri are greater than that between B. turicatae and B. parkeri. TXW-1 lacks an ospC gene. Electron microscope observations showed that this spirochaete had different morphological structures compared to previously described relapsing fever borreliae. All the results obtained from the above-mentioned analyses indicate that TXW-1 is different from other described Borrelia species and that it represents a novel species of Borrelia. We have been unable to revive frozen cultures and so can not meet the requirements of the Bacteriological Code to deposit viable type material at two different culture collections. Therefore we use the Candidatus designation; based on these results, the species 'Candidatus Borrelia texasensis' is proposed.

Animals↗
PubMed2004

Automatic control of the inspired oxygen fraction in preterm infants: a randomized crossover trial.

In preterm infants receiving supplemental oxygen, manual control of the inspired oxygen fraction is often time-consuming and inappropriate. We developed a system for automatic oxygen control and hypothesized that this system is more effective than routine manual oxygen control in maintaining target arterial oxygen saturation levels. We performed a randomized controlled crossover clinical trial in 12 preterm infants receiving nasal continuous positive airway pressure and supplemental oxygen. Periods with automatic and routine manual oxygen control were compared with periods of optimal control by a fully dedicated person. The median (range) percentage of time with arterial oxygen saturation levels within target range (87-96%) was 81.7% (39.0-99.8) for routine manual oxygen control, 91.0% (41.4-99.3) for optimal control, and 90.5% (59.0-99.4) for automatic control (ANOVA: p = 0.01). Pairwise post hoc comparisons revealed a statistically significant difference between automatic and routine manual oxygen control (Dunnett's test: p = 0.02). The frequency of manual oxygen adjustments was lowest in automatic control (Friedman's test: p < 0.001). Automatic oxygen control may optimize oxygen administration to preterm infants receiving nasal continuous positive airway pressure and reduce nursing time spent with oxygen control.

Automation↗
PubMed2004

Multiple site-directed mutagenesis of more than 10 sites simultaneously and in a single round.

Site-directed mutagenesis is a powerful tool to explore the structure-function relationship of proteins, but most traditional methods rely on the mutation of only one site at a time and efficiencies drop drastically when more than three sites are targeted simultaneously. Many applications in functional proteomics and genetic engineering, including codon optimization for heterologous expression, generation of cysteine-less proteins, and alanine-scanning mutagenesis, would greatly benefit from a multiple-site mutagenesis method with high efficiency. Here we describe the development of a simple and rapid method for site-directed mutagenesis of more than 10 sites simultaneously with up to 100% efficiency. The method uses two terminal tailed primers with a unique 25-nucleotide tail each that are simultaneously annealed to template DNA together with the set of mutagenic primers in between. Following synthesis of the mutant strand by primer extension and ligation with T4 DNA polymerase and ligase, the unique mutant strand-specific tails of the terminal primers are used as anchors to specifically amplify the mutant strand by high-fidelity polymerase chain reaction. We have employed this novel method to mutate simultaneously all 9 and 11 CUG leucine codons of the Hyg and Neo resistance genes, respectively, to the Candida albicans-friendly UUG leucine codon at 100% efficiency.

Amino Acid Substitution↗
PubMed2004

Substrate specificity of the Leishmania donovani myo-inositol transporter: critical role of inositol C-2, C-3 and C-5 hydroxyl groups.

Inositol is an essential precursor for the formation of glycosyl-phosphatidylinositol (GPI)-anchors found in the majority of surface molecules in trypanosomatids, in addition to its requirement for phoshatidylinositol signal transduction pathways. In Leishmania donovani, high-affinity inositol transport is catalyzed by the active myo-inositol/H+ transporter MIT, which is driven by a proton gradient across the parasite membrane. We have characterized the substrate specificity and pharmacology of L. donovani MIT in vitro and in promastigote cultures. High substrate specificity of myo-inositol transport was shown in competition studies with 14 different monosaccharides and MIT function was unaffected by the structurally similar pentose sugars or hexoses. L-Fucose and D-xylose, both inhibitors of the Na+-dependent inositol transport system in the human host, did not affect MIT transport function in the parasite. Competition studies with eight different inositol isomers revealed that proton bonds between the C-2, C-3 and C-5 hydroxyl groups of myo-inositol and the transporter protein played a critical role for substrate recognition, and the C-3 hydroxyl oxygen appears to act as an electron donor to form an H-bond with a positive charge of the MIT permease. The cytotoxic inositol analogue 3-fluoro-myo-inositol was recognized by MIT with similar affinity as myo-inositol and showed an IC50 value of 42 +/- 8 microM in L. donovani cultures. Finally, substrate affinities of MIT revealed apparent Km values of 84 +/- 8 microM for myo-inositol and 5.4 +/- 0.9 nM for H+, equal pH 8.27 + 0.08, suggesting that the L. donovani myo-inositol/H+ symporter is fully activated at physiological pH in the sandfly midgut or macrophage phagolysosome. We conclude that Leishmania MIT constitutes an attractive target for delivery of cytotoxic inositol analogues and differs significantly from the sodium-coupled myo-inositol transport system of the human host.

Animals↗
PubMed2004

Advanced temporal data abstraction for guideline execution.

Temporal data abstraction bridges the gap between snap shot values delivered by monitoring devices and laboratory tests on one side and high-level medical concepts used in guidelines and by medical professionals on the other side. Within this field, the detection and abstraction of repeated patterns is a complex and important challenge. A repeated pattern is a combination of events or intervals which occur multiple times in a formally describable temporal relation. While there are many approaches to detect patterns in time series without prior definition of target concepts, we describe the application of temporal data abstraction in the context of guideline execution. Here predefined concepts of temporal patterns must be compared with measurement series describing the patient state. We discuss the requirements coming from both high-frequency domains such as intensive care units and low-frequency domains such as diabetes monitoring and show our solution based on a new version of the Asgaard data abstraction unit. It interfaces the dynamically changing patient state to the guideline execution unit and features abstraction modules ranging from simple calculations to statistical measures calculated for sliding time windows.

Artificial Intelligence↗
PubMed2004

Protocure: supporting the development of medical protocols through formal methods.

Medical guidelines and protocols describe the optimal care for a specific group of patients and therefore, when properly applied, improve the quality of patient care. During the last decade, a large number of medical guidelines and protocols have been published. However, the work done on developing and disseminating them far outweighs the efforts on guaranteeing their quality. Indeed, anomalies like ambiguity and incompleteness are frequent in medical guidelines and protocols. An approach grounded on a formal representation, can answer these needs, as we have demonstrated in the Protocure project'. The Protocure II project will aim at integrating formal methods in the life cycle of guidelines.

Clinical Protocols↗
PubMed2004

Tracing the formalization steps of textual guidelines.

This paper presents a new guideline authoring tool, called Guideline Markup Tool (GMT). It proposes two useful features, which are missing in existing tools. First, it facilitates the translation of a free-text guideline into a formal representation, providing special XML macros. Second, it can be used to create links between the original guideline and its formal representation. Therefore, the GMT eases the implementation of clinical guidelines in a formal representation, which can be used in monitoring and therapy planning systems.

Artificial Intelligence↗
PubMed2003

The ERV-9 LTR enhancer is not blocked by the HS5 insulator and synthesizes through the HS5 site non-coding, long RNAs that regulate LTR enhancer function.

A solitary long terminal repeat (LTR) of ERV-9 human endogenous retrovirus is located upstream of the HS5 site in the human beta-globin locus control region and possesses unique enhancer activity in erythroid K562 cells. In cells transfected with plasmid LTR-HS5-epsilonp-GFP, the LTR enhancer activates the GFP reporter gene and is not blocked by the interposed HS5 site, which has been reported to have insulator function. The LTR enhancer initiates synthesis of long RNAs from the LTR promoter through the intervening HS5 site into the epsilon-globin promoter and the GFP gene. Synthesis of the sense, long LTR RNAs is correlated with high level synthesis of GFP mRNA from the epsilon-globin promoter. Mutations of the LTR promoter and/or the epsilon-globin promoter show that (i) the LTR enhancer can autonomously initiate synthesis of LTR RNAs independent of the promoters and (ii) the LTR RNAs are not processed into GFP mRNA or translated into GFP. However, reversing the orientation of the LTR in plasmid (LTR)rev-HS5-epsilonp-GFP, thus reversing the direction of synthesis of LTR RNAs in the antisense direction away from the epsilon-globin promoter and GFP gene drastically reduces the level of GFP mRNA and thus LTR enhancer function. The results suggest that the LTR-assembled transcription machinery in synthesizing non-coding, LTR RNAs can reach the downstream epsilon-globin promoter to activate transcription of the GFP gene.

Base Sequence↗
PubMed2003

High-affinity myo-inositol transport in Candida albicans: substrate specificity and pharmacology.

Inositol is considered a growth factor in yeast cells and it plays an important role in Candida as an essential precursor for phospholipomannan, a glycophosphatidylinositol (GPI)-anchored glycolipid on the cell surface of Candida which is involved in the pathogenicity of this opportunistic fungus and which binds to and stimulates human macrophages. In addition, inositol plays an essential role in the phosphatidylinositol signal transduction pathway, which controls many cell cycle events. Here, high-affinity myo-inositol uptake in Candida albicans has been characterized, with an apparent K(m) value of 240 +/- 15 microM, which appears to be active and energy-dependent as revealed by inhibition with azide and protonophores (FCCP, dinitrophenol). Candida myo-inositol transport was sodium-independent but proton-coupled with an apparent K(m) value of 11.0 +/- 1.1 nM for H(+), equal pH 7.96 +/- 0.05, suggesting that the C. albicans myo-inositol-H(+) transporter is fully activated at physiological pH. C. albicans inositol transport was not affected by cytochalasin B, phloretin or phlorizin, an inhibitor of mammalian sodium-dependent inositol transport. Furthermore, myo-inositol transport showed high substrate specificity for inositol and was not significantly affected by hexose or pentose sugars as competitors, despite their structural similarity. Transport kinetics in the presence of eight different inositol isomers as competitors revealed that proton bonds between the C-2, C-3 and C-4 hydroxyl groups of myo-inositol and the transporter protein play a critical role for substrate recognition and binding. It is concluded that C. albicans myo-inositol-H(+) transport differs kinetically and pharmacologically from the human sodium-dependent myo-inositol transport system and constitutes an attractive target for delivery of cytotoxic inositol analogues in this pathogenic fungus.

Azides↗
PubMed2002

Combining diagnosis and treatment using ASBRU.

Traditionally, diagnosis and treatment have been seen as two distinct tasks. Consequently, most approaches to computer supported health care focus on one of the two-mostly on diagnosis or rather on the interpretation of measurements which is much better understood and formalised. However, in practice diagnosis and treatment overlap and influence each other in many ways. Combinations range from repeatedly going through the diagnosis-treatment loop over a period of time to permanent monitoring of the patients' health condition as it is done in intensive care units. In this article we describe how to model these combinations using the clinical protocol-representation language ASBRU. It implements treatment steps in a hierarchy of skeletal, time-oriented plans. Diagnosis can either be described in a declarative way in the conditions, under which treatment steps are taken or it can be modelled explicitly as plans of their own right. We demonstrate our approach using examples taken from the American Association of Paediatricians' guideline for the treatment of hyperbilirubinemia in the new-born.

Clinical Protocols↗
PubMed2002

Development and evaluation of VIE-PNN, a knowledge-based system for calculating the parenteral nutrition of newborn infants.

Calculating the daily changing composition of parenteral nutrition for small newborn infants is troublesome and time consuming routine work in neonatal intensive care. The task needs expertise and experience and is prone to inherent calculation errors. We designed VIE-PNN (Vienna Expert System for Parenteral Nutrition of Neonates), a knowledge-based system (KBS) in order to reduce daily routine work and calculation errors. VIE-PNN was redesigned several times because the clinicians accepted the system only when it saved time. The most recent version of VIE-PNN uses an Hypertext Markup Language (HTML)-based client-server architecture and is integrated into the intranet of the local patient data management system. Since more than 3 years all parenteral nutrition plans are calculated using VIE-PNN. Evaluating the system's performance and the users contentedness, we compared 50 nutrition plans calculated in parallel using VIE-PNN or a hand-held calculator, retrospectively analyzed more than 5000 nutrition plans stored in VIE-PNNs database and evaluated a user questionnaire. Nutrition plans were calculated in a mean time of 2.4 versus 7.1min using VIE-PNN or the hand-held calculator. Errors and omissions in the nutrition plans were detected in 22% versus 56% and errors in the VIE-PNN's plans occurring only with interactively changed values. Reviews of stored plans show that a mean of 4 out of 16 parameters were interactively changed. VIE-PNN was well accepted. Most important reasons for the successful operation of VIE-PNN in the daily routine work were time savings and robustness of the system.

Artificial Intelligence↗
PubMedDate not supplied

Comparing computer-interpretable guideline models: a case-study approach.

OBJECTIVES: Many groups are developing computer-interpretable clinical guidelines (CIGs) for use during clinical encounters. CIGs use "Task-Network Models" for representation but differ in their approaches to addressing particular modeling challenges. We have studied similarities and differences between CIGs in order to identify issues that must be resolved before a consensus on a set of common components can be developed. DESIGN: We compared six models: Asbru, EON, GLIF, GUIDE, PRODIGY, and PROforma. Collaborators from groups that created these models represented, in their own formalisms, portions of two guidelines: American College of Chest Physicians cough guidelines [correction] and the Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. MEASUREMENTS: We compared the models according to eight components that capture the structure of CIGs. The components enable modelers to encode guidelines as plans that organize decision and action tasks in networks. They also enable the encoded guidelines to be linked with patient data-a key requirement for enabling patient-specific decision support. RESULTS: We found consensus on many components, including plan organization, expression language, conceptual medical record model, medical concept model, and data abstractions. Differences were most apparent in underlying decision models, goal representation, use of scenarios, and structured medical actions. CONCLUSION: We identified guideline components that the CIG community could adopt as standards. Some of the participants are pursuing standardization of these components under the auspices of HL7.

Decision Support Systems, Clinical↗