Requirements engineering in health care: the example of chemotherapy planning in paediatric oncology

Health care is characterized by highly complex processes of patient care that require unusual amount of communication between different health care professionals of different institutions. Sub-optimal processes can significantly impact on the patient’s health, increase the consumption of services and resources and in severe cases can lead to the patient death. For these reasons, requirements engineering for the development of information technology in health care is a complex process as well: without constant and rigorous evaluation, the impact of new systems on the quality of care is unknown and it is possible that badly designed systems significantly harm patients. To overcome these limitations, we present and discuss an approach to requirements engineering that we applied for the development of applications for chemotherapy planning in paediatric oncology. Chemotherapy planning in paediatric oncology is complex and time-consuming and errors must be avoided by all means. In the multi-hospital/multi-trial-centre environment of paediatric oncology, it is especially difficult and time-consuming to analyse requirements. Our approach combines a grounded theory approach with evolutionary prototyping based on the constant development and refinement of a generic domain model, in this case a domain model for chemotherapy planning in paediatric oncology. The prototypes were introduced in medical centres and final results show that the developed generic domain model is adequate.     

Embryotoxic doses of vitamin A to rabbits result in low plasma but high embryonic concentrations of all-trans-retinoic acid: risk of vitamin A exposure in humans

Retinoid pharmacokinetics were examined in plasma, placenta and embryos of gestational d 12 rabbits following application of an embryotoxic dosing regimen (10 mg retinyl palmitate/kg body wt per day from gestational d 7 to 12). Vehicle-treated or untreated rabbits served as controls. Physiological concentrations of all-trans-retinoic acid (all-trans-RA) and 13-cis-RA in rabbit plasma (5-8.33 nmol/L) were very close to the endogenous levels in human plasma. In addition, we identified endogenous all-trans-RA, 3,4-didehydroretinol and 3,4-didehydroretinoic acid in rabbit embryo. Following the last retinyl palmitate administration, apparent steady-state concentrations of all retinoids were reached in the examined compartments of rabbits. The major polar retinoid in plasma was 9, 13-di-cis-RA, but its embryonic concentrations were only about 6% of those in plasma. In the embryo, retinol and its esters were found at high concentrations; lower amounts of all-trans-4-oxo-RA and the newly identified 14-hydroxy-4, 14-retro-retinol could also be measured. Embryonic concentrations of all-trans-RA were about 100% higher than endogenous levels. The overall exposure of the embryo to this retinoid was, however, substantial. Embryonic area under the concentration time curve values strongly suggest that the embryotoxicity of the applied dosing regimen is mainly due to the action of all-trans-RA. A very remarkable finding of this study is the marginal increase of plasma concentrations of all-trans-RA over their endogenous levels, which is comparable to the human situation after vitamin A intake. This analogy indicates that high vitamin A intake may be associated with a higher risk for teratogenic effects in humans even in the absence of high elevation of plasma all-trans-RA levels.     

Empirical efficiency and volume relationships for HPGe detectors

We have extended the empirical work of Vano et al.[1] relating the slope of the detector efficiency curve to the active volume for Ge detectors. The analysis was carried out using Monte Carlo techniques and covered a wide range of incident energies (200 keV-20 MeV) and active volumes (19.6 cm³–396 cm³). It is shown that the expression of Vano et al.[1] is only valid over the energy range 200 keV-3 MeV for active volumes <50 cm³. The upper bound decreases to 2 MeV for volumes of a few hundred cm³. The usable energy range can, however, be extended to 6 MeV by introducing higher order terms into the polynomial. Above this energy, the shape of the efficiency curve is better described by a non-linear function since linear forms fail simultaneously to fit large active volumes and high energies. We therefore propose a composite function which reduces to the form given in Vano et al. in the low energy/active volume limit. By comparison with the Monte Carlo results, it is estimated that relative efficiencies can be calculated to within 6% over the energy range 200 keV-20 MeV and active volumes 20 cm³–400 cm³. Since the largest errors occur for the smallest volumes, we recommend that for energies <3 MeV a two-fold approach be followed, i.e. using the expression of Vano et al.[1] for active volumes less than 50 cm³ and the proposed non-linear form for larger volumes. For high energy work (E > 3 MeV), we advocate the non-linear form. In this way, average errors can be kept 3%. Finally, we point out that the real power of the expression of Vano et al. lies not in predicting efficiencies, but active volumes.     

Mössbauer effect studies and X-ray diffraction analysis of cobalt ferrite prepared in powder form by thermal decomposition method

Cobalt ferrite (Co_xFe_3?xO₄) is prepared in powder form by thermal decomposition of iron and cobalt salts and is analysed by X-ray diffraction and Mössbauer spectroscopic techniques. The variation of Mössbauer parameters, lattice parameters and crystallite size of the products formed with variation in the composition of Fe and Co ratios are studied. The studies confirm the formation of nano-size cobalt ferrite particles with defect structure and it is found to be maximum for the Fe : Co = 60 : 40 ratio of the initial precursor oxides.     

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Disposition and elimination of meropenem in cerebrospinal fluid of hydrocephalic patients with external ventriculostomy

The broad antibacterial spectrum and the low incidence of seizures in meropenem-treated patients qualifies meropenem for therapy of bacterial meningitis. The present study evaluates concentrations in ventricular cerebrospinal fluid (CSF) in the absence of pronounced meningeal inflammation. Patients with occlusive hydrocephalus caused by cerebrovascular diseases, who had undergone external ventriculostomy (n = 10, age range 48 to 75 years), received 2 g of meropenem intravenously over 30 min. Serum and CSF were drawn repeatedly and analyzed by liquid chromatography-mass spectroscopy. Pharmacokinetics were determined by noncompartmental analysis. Maximum concentrations in serum were 84.7 +/- 23.7 microg/ml. A CSF maximum (CmaxCSF) of 0.63 +/- 0.50 microg/ml (mean +/- standard deviation) was observed 4.1 +/- 2.6 h after the end of the infusion. CmaxCSF and the area under the curve for CSF (AUCCSF) depended on the AUC for serum (AUCS), the CSF-to-serum albumin ratio, and the CSF leukocyte count. Elimination from CSF was considerably slower than from serum (half-life at beta phase [t1/2beta] of 7.36 +/- 2.89 h in CSF versus t1/2beta of 1.69 +/- 0.60 h in serum). The AUCCSF/AUCS ratio for meropenem, as a measure of overall CSF penetration, was 0.047 +/- 0.022. The AUCCSF/AUCS ratio for meropenem was similar to that for other beta-lactam antibiotics with a low binding to serum proteins. The concentration maxima of meropenem in ventricular CSF observed in this study are high enough to kill fully susceptible pathogens. They may not be sufficient to kill bacteria with a reduced sensitivity to carbapenems, although clinical success has been reported for patients with meningitis caused by penicillin-resistant pneumococci and Pseudomonas aeruginosa.     

Computability of Countable Subshifts in One Dimension

We investigate the computability of countable subshifts in one dimension, and their members. Subshifts of Cantor?CBendixson rank two contain only eventually periodic elements. Any rank two subshift in 2^? is decidable. Subshifts of rank three may contain members of arbitrary Turing degree. In contrast, effectively closed ( $\Pi^{0}_{1}$ ) subshifts of rank three contain only computable elements, but $\Pi^{0}_{1}$ subshifts of rank four may contain members of arbitrary $\Delta^{0}_{2}$ degree. There is no subshift of rank ??+1.     

Preparation of grids for simulations of groundwater flow in fractured porous media

This work presents an extension of grid generation techniques for finite-volume discretizations of density-driven flow in fractured porous media, in which fractures are considered as low-dimensional manifolds and are resolved by sides of grid elements. The proposed technique introduces additional degrees of freedom for the unknowns assigned to the fractures and thus allows to reconstruct jumps of the solution over a fracture. Through the concept of degenerated elements, the proposed technique can be used for arbitrary junctions of fractures but is sufficiently simple regarding the implementation and allows for the application of conventional numerical solvers. Numerical experiments presented at the end of the paper demonstrate the applicability of this technique in two and three dimensions for complicated fracture networks.