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Development of a physiologic-based pharmacokinetic model for estimating sulfamethazine concentrations in swine and application to prediction of violative residues in edible tissues.

OBJECTIVE: To develop a flow-limited, physiologic-based pharmacokinetic model for use in estimating concentrations of sulfamethazine after IV administration to swine. SAMPLE POPULATION: 4 published studies provided physiologic values for organ weights, blood flows, clearance, and tissue-to-blood partition coefficients, and 3 published studies provided data on plasma and other tissue compartments for model validation. PROCEDURE: For the parent compound, the model included compartments for blood, adipose, muscle, liver, and kidney tissue with an extra compartment representing the remaining carcass. Compartments for the N-acetyl metabolite included the liver and the remaining body. The model was created and optimized by use of computer software. Sensitivity analysis was completed to evaluate the importance of each constant on the whole model. The model was validated and used to estimate a withhold interval after an IV injection at a dose of 50 mg/kg. The withhold interval was compared to the interval estimated by the Food Animal Residue Avoidance Databank (FARAD). RESULTS: Specific tissue correlations for plasma, adipose, muscle, kidney, and liver tissue compartments were 0.93, 0.86, 0.99, 0.94, and 0.98, respectively. The model typically overpredicted concentrations at early time points but had excellent accuracy at later time points. The withhold interval estimated by use of the model was 120 hours, compared with 100 hours estimated by FARAD. CONCLUSIONS AND CLINICAL RELEVANCE: Use of this model enabled accurate prediction of sulfamethazine pharmacokinetics in swine and has applications for food safety and prediction of drug residues in edible tissues.

Adipose Tissue↗

Fishing for biomarkers: analyzing mass spectrometry data with the new ClinProTools software.

Recently, applications of mass spectrometry in the field of clinical proteomics have gained tremendous visibility in the scientific and clinical community. One major objective is the search for potential biomarkers in complex body fluids like serum, plasma, urine, saliva, or cerebral spinal fluid. For this purpose, efficient visualization of large data sets derived from patient cohorts is crucial to provide clinical experts an interactive impression of the data quality. Additionally, it is necessary to apply statistical analysis and pattern matching algorithms to attain validated signal patterns that may allow for later applications in sample classification. We introduce the new ClinProTools bioinformatics software, which performs all major steps of profiling, screening, and monitoring applications in clinical proteomics. ClinProTools is the data interpretation software of the mass spectrometry-based ClinProt solutions for biomarker analysis. ClinProTools performs data pretreatment, visualization, statistics, pattern determination, pattern evaluation, and classification of spectra. This article will focus on ClinProTool's powerful and intuitive visualization options for clinical proteomics applications.

Algorithms↗

MetaBasis: a web-based database containing metadata on software tools and databases in the field of bioinformatics.

UNLABELLED: We have developed an integrated web-based relational database information system, which offers an extensive search functionality of validated entries containing available bioinformatics computing resources. This system, called MetaBasis, aims to provide the bioinformatics community, and especially newcomers to the field, with easy access to reliable bioinformatics databases and tools. MetaBasis is focused on non-commercial and open-source software tools. AVAILABILITY: http://metabasis.bioacademy.gr/

Computational Biology↗

MINDFIM: a measure of disability in high-functioning traumatic brain injury outpatients.

PRIMARY OBJECTIVE: The study aimed at developing a new valid measure of disability in TBI outpatients. RESEARCH DESIGN AND METHODS: The Rasch model (Winsteps 3.45 software, 2005) was adopted to achieve a linear measure, unidimensional and reliable. The predictive capacity with respect to return to school or job was also tested (logistic regression, STATA 8.0 software, 2004). EXPERIMENTAL INTERVENTIONS: Either tests of Attention, Memory and Verbal Fluency or the FIM were administered to 160 TBI ambulatory outpatients (52 women, age 14-72, 2-117 months after trauma, 111 cases with coma > or = 1 week). Fifty of them (31%) had returned to school or job. MAIN OUTCOMES AND RESULTS: A new scale called MINDFIM could be successfully developed. It includes three cognitive and four FIM motor items (Grooming, Upper Body Dressing, Bathing and Tub/Shower Transfer). The scale raises the ceiling affecting existing instruments. The summated scores are predictive of return to community (74% correct classification). CONCLUSIONS: MINDFIM is valid and useful measure of disability in TBI outpatients.

Activities of Daily Living↗

Regularization of flow streamlines in multislice phase-contrast MR imaging.

Magnetic resonance angiography (MRA) has become an important tool for the clinical evaluation of vascular disease. Flow measurement with phase-contrast (PC) magnetic resonance (MR) imaging provides a powerful method for evaluation of blood velocity information inside vessels. However, image artifacts from complex flow patterns including slow flow, recirculation zone, and pulsatile flow can adversely affect accuracy of results. In this paper, we introduce a new numerical formulation for improving the accuracy of PC velocity fields and corresponding streamlines, based on a physical constraint from fluid dynamics, within a regularization framework. The formulation which makes use of a stream function, automatically enforces continuity constraint of incompressible flow and reconstructs the flow streamlines from PC images. We applied the algorithm to complex MR imaging flow velocities obtained in a flow phantom of an axisymmetric abdominal aortic aneurysm. The algorithm significantly improved streamline results especially inside the recirculation zone, where artifacts are more pronounced. A velocity reconstruction method in primitive variable form is also presented and results are compared with the stream function method. In order to validate flow characteristics derived from PC MR images, we used the FLUENT computational fluid dynamics software package, to simulate flow patterns within the same geometry as our phantom. There was a good agreement between the numerical simulations and recovered PC streamline results. Processed streamlines, in both stream function and primitive variable methods, were more realistic and provided more precise flow patterns than unprocessed PC data. Additionally, the feasibility of the method was demonstrated in the aorta of a normal volunteer.

Algorithms↗

Dermoscopic diagnosis by a trained clinician vs. a clinician with minimal dermoscopy training vs. computer-aided diagnosis of 341 pigmented skin lesions: a comparative study.

BACKGROUND: In the last few years digital dermoscopy has been introduced as an additional tool to improve the clinical diagnosis of pigmented skin lesions. OBJECTIVE: To evaluate the validity of digital dermoscopy by comparing the diagnoses of a dermatologist experienced in dermoscopy (5 years of experience) with those of a clinician with minimal training in this field, and then comparing these results with those obtained using computer-aided diagnoses. METHODS: Three hundred and forty-one pigmented melanocytic and non-melanocytic skin lesions were included. All lesions were surgically excised and histopathologically examined. Digital dermoscopic images of all lesions were framed and analysed using software based on a trained artificial neural network. Cohen's kappa statistic was calculated to assess the validity with regard to the correct diagnoses of melanoma and non-melanoma. RESULTS: Sensitivity was high for the experienced dermatologist and the computer (92%) and lower for the inexperienced clinician (69%). Specificity of the diagnosis by the experienced dermatologist was higher (99%) than that of the inexperienced clinician (94%) and the computer assessment (74%). Notably, computer analysis gave a higher number of false positives (26%) compared with the experienced dermatologist (0.6%) and the inexperienced clinician (5.5%). CONCLUSIONS: Our results indicate that analysis either by a trained dermatologist or an artificial neural network-trained computer can improve the diagnostic accuracy of melanoma compared with that of an inexperienced clinician and that the computer diagnosis might represent a useful tool for the screening of melanoma, particularly at centres not experienced in dermoscopy.

Adolescent↗

[Utilization of expert systems in psychiatry].

Are expert systems liable to be used as consultants in psychiatry? Most expert systems deal with an over-restricted part of psychiatry and cannot be a real help in everyday care. Moreover, most of them are not actually validated (the comparison between the system's and the expert's conclusions in a few cases is not enough). Another problem is that they reflect the uncertainties of nosographic problems. Validation of such systems needs the careful checking of the logical structure of the underlying nosography, the fitness of the structure's knowledge base and the fitness of the inference engine. Moreover, the naïve use of the system by untrained clinicians is the best means of validation since it provides real life proof of the ability of expert systems to make diagnoses in unselected cases where the need for a common diagnostic reference is clear (for example, epidemiologic, psychopharmacological ornosographic research). Some of the best known expert systems in the field of psychiatry are reviewed and another expert system, Adinfer, is presented. Developed since 1982, Adinfer is a forward-tracking level O system (in its simplified version for micro-computers). The knowledge base is a translation of the DSM-III-R into production rules. The program has been included in several software packages and used in many clinical studies, both among psychiatrists and physicians. The program has been validated with 1,141 unselected cases, and with 47 physicians: an 83% agreement rate was found between the system's and the physician's diagnoses, taking into account that the clinicians were asked to give their conclusions according to their usual nosography.(ABSTRACT TRUNCATED AT 250 WORDS)

Artificial Intelligence↗

A realistic 3-D gated cardiac phantom for quality control of gated myocardial perfusion SPET: the Amsterdam gated (AGATE) cardiac phantom.

A realistic 3-D gated cardiac phantom with known left ventricular (LV) volumes and ejection fractions (EFs) was produced to evaluate quantitative measurements obtained from gated myocardial single-photon emission tomography (SPET). The 3-D gated cardiac phantom was designed and constructed to fit into the Data Spectrum anthropomorphic torso phantom. Flexible silicone membranes form the inner and outer walls of the simulated left ventricle. Simulated LV volumes can be varied within the range 45-200 ml. The LV volume curve has a smooth and realistic clinical shape that is produced by a specially shaped cam connected to a piston. A fixed 70-ml stroke volume is applied for EF measurements. An ECG signal is produced at maximum LV filling by a controller unit connected to the pump. This gated cardiac phantom will be referred to as the Amsterdam 3-D gated cardiac phantom, or, in short, the AGATE cardiac phantom. SPET data were acquired with a triple-head SPET system. Data were reconstructed using filtered back-projection following pre-filtering and further processed with the Quantitative Gated SPECT (QGS) software to determine LV volume and EF values. Ungated studies were performed to measure LV volumes ranging from 45 ml to 200 ml. The QGS-determined LV volumes were systematically underestimated. For different LV combinations, the stroke volumes measured were consistent at 60-61 ml for 8-frame studies and 63-65 ml for 16-frame studies. QGS-determined EF values were slightly overestimated between 1.25% EF units for 8-frame studies and 3.25% EF units for 16-frame studies. In conclusion, the AGATE cardiac phantom offers possibilities for quality control, testing and validation of the whole gated cardiac SPET sequence, and testing of different acquisition and processing parameters and software.

Equipment Design↗

New tools for mass isotopomer data evaluation in (13)C flux analysis: mass isotope correction, data consistency checking, and precursor relationships.

13C metabolic flux analysis (MFA) is based on carbon-labeling experiments where a specifically (13)C labeled substrate is fed. The labeled carbon atoms distribute over the metabolic network and the label enrichment of certain metabolic pools is measured by using different methods. Recently, MS methods have been dramatically improved-large and precise datasets are now available. MS data has to be preprocessed and corrected for natural stable mass isotopes. In this article we present (1). a new elegant method to correct MS measurement data for natural stable mass isotopes by infinite dimensional matrix calculus and (2). we statistically analyze and discuss a reconstruction of labeling pattern in metabolic precursors from biosynthesis molecules. Moreover, we establish a new method for consistency checking of MS spectra that can be applied for automatic error recognition in high-throughput flux analysis procedures. Preprocessing the measurement data changes their statistical properties which have to be considered in the subsequent parameter fitting process for (13)C MFA. We show that correcting for stable mass isotopes leads to rather small correlations. On the other hand, a direct reconstruction of a precursor labeling pattern from an aromatic amino acid measurement turns out to be critical. Reasonable results are only obtained if additional, independent information about the labeling of at least one precursor is available. A versatile MatLab tool for the rapid correction and consistency checking of MS spectra is presented. Practical examples for the described methods are also given.

Alanine↗

Automatic initialisation of buffer composition estimation for on-line analysis of unknown buffer solutions.

An automatic initialisation procedure for extracting useful information about buffer composition from a titration experiment is presented in this paper. The initialisation procedure identifies which buffering components are present in the sample from a relatively long list of buffers expected in the system monitored. The procedure determines approximate pKa values of the buffers and evaluates their maximum and minimum concentrations. This information is then used to start an optimisation procedure to fit the model of the buffer components to the titration data and to accurately determine buffer concentrations and pKa values. The procedure has been integrated as a software layer around the buffer capacity optimum model builder (BOMB) that fits a buffer-capacity model to a measured buffer-capacity curve to estimate model properties (pKa values and concentrations). The reliability and robustness of the resulting buffer capacity software (BCS) were tested using a titrimetric analyser simulator (TAS). The BCS was then validated off-line and on-line.

Journal Article↗

Dexterity enhancement with robotic surgery.

BACKGROUND: The aim of this study was to quantify the extent of dexterity enhancement in robotic surgery as compared to laparoscopic surgery. METHODS: Ten surgeons with varying laparoscopic suturing experience were asked to place three sutures on a suture pad. The sutures were placed laparoscopically, robotically with 2-D vision and robotically with 3-D vision. The da Vinci systems Application Programming Interface (API) was used for positional data. A validated motion analysis system was used for data retrieval for the laparoscopic task. Custom software was developed for data analysis. RESULTS: Compared to laparoscopic suturing, when the task was undertaken robotically with 2-D vision there was a 20% reduction in the time taken but this was not significant (p = 0.07). There was a 55% reduction in the path traveled by the right hand (p = 0.01) and a 45% reduction in the path traveled by the left hand (p = 0.008). When the task was undertaken robotically with 3-D vision, there was a 40% reduction in the time taken (p = 0.01). There was a 70% reduction in the path traveled by right hand (p = 0.008) and a 55% reduction by the left hand (p = 0.08). CONCLUSIONS: The presence of wristed instrumentation, tremor abolition, and motion scaling enhance dexterity by nearly 50% as compared to laparoscopic surgery. 3-D vision enhances dexterity by a further 10-15%. In addition, the presence of 3-D vision results in a 93% reduction in skills-based errors.

Clinical Competence↗

ProPose: a docking engine based on a fully configurable protein-ligand interaction model.

Virtual high-throughput screening of molecular databases and in particular high-throughput protein-ligand docking are both common methodologies that identify and enrich hits in the early stages of the drug design process. Current protein-ligand docking algorithms often implement a program-specific model for protein-ligand interaction geometries. However, in order to create a platform for arbitrary queries in molecular databases, a new program is desirable that allows more manual control of the modeling of molecular interactions. For that reason, ProPose, an advanced incremental construction docking engine, is presented here that implements a fast and fully configurable molecular interaction and scoring model. This program uses user-defined, discrete, pharmacophore-like representations of molecular interactions that are transformed on-the-fly into a continuous potential energy surface, allowing for the incorporation of target specific interaction mechanisms into docking protocols in a straightforward manner. A torsion angle library, based on semi-empirical quantum chemistry calculations, is used to provide minimum energy torsion angles for the incremental construction algorithm. Docking results of a diverse set of protein-ligand complexes from the Protein Data Bank demonstrate the feasibility of this new approach. As a result, the seamless integration of pharmacophore-like interaction types into the docking and scoring scheme implemented in ProPose opens new opportunities for efficient, receptor-specific screening protocols. [figure: see text]. ProPose--a fully configurable protein-ligand docking program--transforms pharmacophores into a smooth potential energy surface.

Binding Sites↗

Dose evaluation and measurement of the 188Re liquid-filled balloon in intravascular brachytherapy.

We compared the Monte Carlo evaluation and GafChromic MD-55 film experimental measurement of 188Re liquid-filled balloons in intravascular brachytherapy using two phantoms of 6 mm vascular diameter, a phantom of 4 mm vascular diameter and a phantom of 3 mm vascular diameter. A dose-evaluation interface program was developed and was shown to be capable of quickly providing information such as the necessary 188Re source irradiation time to deliver a prescribed dose.

Blood Vessel Prosthesis↗

SPASM: a 3D-ASM for segmentation of sparse and arbitrarily oriented cardiac MRI data.

A new technique (SPASM) based on a 3D-ASM is presented for automatic segmentation of cardiac MRI image data sets consisting of multiple planes with arbitrary orientations, and with large undersampled regions. Model landmark positions are updated in a two-stage iterative process. First, landmark positions close to intersections with images are updated. Second, the update information is propagated to the regions without image information, such that new locations for the whole set of the model landmarks are obtained. Feature point detection is performed by a fuzzy inference system, based on fuzzy C-means clustering. Model parameters were optimized on a computer cluster and the computational load distributed by grid computing. SPASM was applied to image data sets with an increasing sparsity (from 2 to 11 slices) comprising images with different orientations and stemming from different MRI acquisition protocols. Segmentation outcomes and calculated volumes were compared to manual segmentation on a dense short-axis data configuration in a 3D manner. For all data configurations, (sub-)pixel accuracy was achieved. Performance differences between data configurations were significantly different (p<0.05) for SA data sets with less than 6 slices, but not clinically relevant (volume differences<4 ml). Comparison to results from other 3D model-based methods showed that SPASM performs comparable to or better than these other methods, but SPASM uses considerably less image data. Sensitivity to initial model placement proved to be limited within a range of position perturbations of approximately 20 mm in all directions.

Algorithms↗

Polyethylene wear rate and osteolysis: critical threshold versus continuous dose-response relationship.

We studied the relationship between polyethylene wear and osteolysis in 230 subjects after cemented Charnley total hip arthroplasty in order to examine the validity of the wear rate threshold concept. Polyethylene wear measured using image analysis (EBRA) software was compared in 115 subjects with osteolysis versus 115 control subjects that were individually matched for age, sex, and follow up period. Subjects with osteolysis had almost twice the mean annual wear rate versus the controls. The incidence of osteolysis increased in a linear manner with each quintile increase in wear rate throughout the range 0.01-0.54 mm/year. The odds-ratio for osteolysis approximately doubled with each quintile increase in wear rate above the middle quintile (wear rate 0.08-0.11 mm/year), and decreased at a similar rate with each quintile decrease in wear rate below the middle quintile. Our data suggests that the association of osteolysis with polyethylene wear rate represents a continuous dose-response relationship and does not support the concept of a discrete critical wear rate threshold above which the risk of osteolysis is disproportionately increased.

Aged↗

Dual energy X-ray absorptiometry reference data for Greek population. The impact on diagnosis of using various normal ranges for comparison.

INTRODUCTION: The interpretation of bone mineral density (BMD) measurements and the individual classification of a patient is based on a normal reference range. Unfortunately, not all the manufacturers include in their analysis-software reference values specific for each population. METHODS AND PATIENTS: In our study, using Lunar's DPX-L densitometer, we measured BMD of the lumbar spine and the femur of 4400 healthy women aged (25-80) years and we calculated the corresponding T- and Z-scores. Multiple regression analysis was applied to examine the dependence of BMD on age and weight. Greek data was compared with American and Italian. RESULTS: There was a statistically significant difference between Greek and American mean values of all age groups. The Italian normal range is closer to our data and can be reliably used at least as T-scores are concerned. Still, there is a small discrepancy in Z-scores, which might influence patient management. CONCLUSION: We conclude that Greek reference range should be used for the assessment of osteoporosis of Greek population for better evaluation of bone status and appropriate treatment.

Absorptiometry, Photon↗

Towards absolute activity measurements by ionisation chambers using the PENELOPE Monte-Carlo code.

The Monte-Carlo code PENELOPE for Ionisation Chamber Simulation Method has been applied for the calculation of ionisation-chamber (IC) calibration factors. Measuring only a few radionuclides well selected within the relevant energy range, and determining an adjustable parameter, commonly used radionuclides can be measured without any specific calibration. The simulation revealed a discontinuity in the IC response as a function of photon energy and its dependence on the chemical composition of the radioactive solution.

Calibration↗