Benchmarking therapeutic drug monitoring software: A review of available computer tools

Therapeutic drug monitoring (TDM) aims to optimize treatments by individualizing dosage regimens based on the measurement of blood concentrations. Dosage individualization to maintain concentrations within a target range requires pharmacokinetic and clinical capabilities. Bayesian calculations currently represent the gold standard TDM approach but require computation assistance. In recent decades computer programs have been developed to assist clinicians in this assignment. The aim of this survey was to assess and compare computer tools designed to support TDM clinical activities. The literature and the Internet were searched to identify software. All programs were tested on personal computers. Each program was scored against a standardized grid covering pharmacokinetic relevance, user friendliness, computing aspects, interfacing and storage. A weighting factor was applied to each criterion of the grid to account for its relative importance. To assess the robustness of the software, six representative clinical vignettes were processed through each of them. Altogether, 12 software tools were identified, tested and ranked, representing a comprehensive review of the available software. Numbers of drugs handled by the software vary widely (from two to 180), and eight programs offer users the possibility of adding new drug models based on population pharmacokinetic analyses. Bayesian computation to predict dosage adaptation from blood concentration (a posteriori adjustment) is performed by ten tools, while nine are also able to propose a priori dosage regimens, based only on individual patient covariates such as age, sex and bodyweight. Among those applying Bayesian calculation, MM-USC*PACK© uses the non-parametric approach. The top two programs emerging from this benchmark were MwPharm© and TCIWorks. Most other programs evaluated had good potential while being less sophisticated or less user friendly. Programs vary in complexity and might not fit all healthcare settings. Each software tool must therefore be regarded with respect to the individual needs of hospitals or clinicians. Programs should be easy and fast for routine activities, including for non-experienced users. Computer-assisted TDM is gaining growing interest and should further improve, especially in terms of information system interfacing, user friendliness, data storage capability and report generation.

Determination of displacement, stress- and strain-distribution in the human heart: a FE-model on the basis of MR imaging.

The determination of characteristic cardiac parameters, such as displacement, stress and strain distribution are essential for an understanding of the mechanics of the heart. The calculation of these parameters has been limited until recently by the use of idealised mathematical representations of biventricular geometries and by applying simple material laws. On the basis of 20 short axis heart slices and in consideration of linear and nonlinear material behaviour we have developed a FE model with about 100,000 degrees of freedom. Marching Cubes and Phong's incremental shading technique were used to visualise the three dimensional geometry. In a quasistatic FE analysis continuous distribution of regional stress and strain corresponding to the endsystolic state were calculated. Substantial regional variation of the Von Mises stress and the total strain energy were observed at all levels of the heart model. The results of both the linear elastic model and the model with a nonlinear material description (Mooney-Rivlin) were compared. While the stress distribution and peak stress values were found to be comparable, the displacement vectors obtained with the nonlinear model were generally higher in comparison with the linear elastic case indicating the need to include nonlinear effects.

Device-specific weighted T-score for two quantitative ultrasounds: operational propositions for the management of osteoporosis for 65 years and older women in Switzerland.

The World Health Organization (WHO) criteria for the diagnosis of osteoporosis are mainly applicable for dual X-ray absorptiometry (DXA) measurements at the spine and hip levels. There is a growing demand for cheaper devices, free of ionizing radiation such as promising quantitative ultrasound (QUS). In common with many other countries, QUS measurements are increasingly used in Switzerland without adequate clinical guidelines. The T-score approach developed for DXA cannot be applied to QUS, although well-conducted prospective studies have shown that ultrasound could be a valuable predictor of fracture risk. As a consequence, an expert committee named the Swiss Quality Assurance Project (SQAP, for which the main mission is the establishment of quality assurance procedures for DXA and QUS in Switzerland) was mandated by the Swiss Association Against Osteoporosis (ASCO) in 2000 to propose operational clinical recommendations for the use of QUS in the management of osteoporosis for two QUS devices sold in Switzerland. Device-specific weighted "T-score" based on the risk of osteoporotic hip fractures as well as on the prediction of DXA osteoporosis at the hip, according to the WHO definition of osteoporosis, were calculated for the Achilles (Lunar, General Electric, Madison, Wis.) and Sahara (Hologic, Waltham, Mass.) ultrasound devices. Several studies (totaling a few thousand subjects) were used to calculate age-adjusted odd ratios (OR) and area under the receiver operating curve (AUC) for the prediction of osteoporotic fracture (taking into account a weighting score depending on the design of the study involved in the calculation). The ORs were 2.4 (1.9-3.2) and AUC 0.72 (0.66-0.77), respectively, for the Achilles, and 2.3 (1.7-3.1) and 0.75 (0.68-0.82), respectively, for the Sahara device. To translate risk estimates into thresholds for clinical application, 90% sensitivity was used to define low fracture and low osteoporosis risk, and a specificity of 80% was used to define subjects as being at high risk of fracture or having osteoporosis at the hip. From the combination of the fracture model with the hip DXA osteoporotic model, we found a T-score threshold of -1.2 and -2.5 for the stiffness (Achilles) determining, respectively, the low- and high-risk subjects. Similarly, we found a T-score at -1.0 and -2.2 for the QUI index (Sahara). Then a screening strategy combining QUS, DXA, and clinical factors for the identification of women needing treatment was proposed. The application of this approach will help to minimize the inappropriate use of QUS from which the whole field currently suffers.

A potential vector of Schistosoma mansoni in Uruguay

Susceptibily experiments were carried out with a Biomphalaria straminea-like planorbid snail (Biomphalaria aff. straminea, species inquirenda) from Espinillar, near Salto (Uruguay), in the area of the Salto Grande reservoir, exposed individually to 5 miracidia of Schistosoma mansoni (SJ2 and BH2 strains). Of 130 snails exposed to the SJ2 strain, originally infective to Biomphalaria tenagophila, 30 became infected (23%). The prepatent (precercaria) period ranged from 35 to 65 days. The cercarial output was irregular, following no definite pattern, varying from 138 to 76,075 per snail (daily average 4.3 to 447.5 and ending up with death. Three specimens that died, without having shed cercarie, on days 69 (2) and 80 after exposure to miracidia, had developing secondary sporocysts in their tissues, justifying the prospect of a longer precercarial period in these cases. In a control group of 120 B. teangophila, exposed to the SJ2 strain, 40 became infected, showing an infection rate (33.3%) not significantly different from that of the Espinillar snail (X [raised to the power of] 2 = 3.26). No cercarie were produced by any of the Espinilar snails exposed to miracidia of the BH2 strain, originally infective to Biomphalaria glabrata. Four specimens showed each a primary sporocyst in one tentacle, which disappeared between 15 and 25 days post-exposure, and two others died with immature, very slender sporocysts in their tissues on days 36 and 54. In a control group of 100 B. glabrata exposed to BH2 miracidia, 94 shed cercariae (94%) and 6 remained negative. Calculation of Frandsen's (1979a, b) TCP/100 index shows that "Espinillar Biomphalaria-SJ2 S. mansoni" is a vector-parasite "compatible" combination. Seeing that tenagophila-borne schistosomiasis is prevalent in Rio de Janeiro and São Paulo states and has recently spread sothwards to Santa Catarina state, and the range of B. tenagophila overlaps taht of the Espinillar Biomphalaria, the possibility of schistosomiais establishing itself in Uruguay, although not imminent, is not to be disregarded.

Evaluation of a summary score of cognitive performance for use in trials in perioperative and critical care.

Background/Aims: Cognitive dysfunction after medical treatment is increasingly being recognized. Studies on this topic require repeated cognitive testing within a short time. However, with repeated testing, practice effects must be expected. We quantified practice effects in a demographically corrected summary score of a neuropsychological test battery repeatedly administered to healthy elderly volunteers. Methods: The Consortium to Establish a Registry for Alzheimer's Disease (CERAD) Neuropsychological Assessment Battery (for which a demographically corrected summary score was developed), phonemic fluency tests, and trail-making tests were administered in healthy volunteers aged 65 years or older on days 0, 7, and 90. This battery allows calculation of a demographically adjusted continuous summary score. Results: Significant practice effects were observed in the CERAD total score and in the word list (learning and recall) subtest. Based on these volunteer data, we developed a threshold for diagnosis of postoperative cognitive dysfunction (POCD) with the CERAD total score. Conclusion: Practice effects with repeated administration of neuropsychological tests must be accounted for in the interpretation of such tests. Ignoring practice effects may lead to an underestimation of POCD. The usefulness of the proposed demographically adjusted continuous score for cognitive function will have to be tested prospectively in patients.

Estimates of radiation-absorbed dose to kidneys in patients treated with 90Y-ibritumomab tiuxetan.

The aim of the present study was to retrospectively estimate the absorbed dose to kidneys in 17 patients treated in clinical practice with 90Y-ibritumomab tiuxetan for non-Hodgkin's lymphoma, using appropriate dosimetric approaches available. METHODS: The single-view effective point source method, including background subtraction, is used for planar quantification of renal activity. Since the high uptake in the liver affects the activity estimate in the right kidney, the dose to the left kidney serves as a surrogate for the dose to both kidneys. Calculation of absorbed dose is based on the Medical Internal Radiation Dose methodology with adjustment for patient kidney mass. RESULTS: The median dose to kidneys, based on the left kidney only, is 2.1 mGy/MBq (range, 0.92-4.4), whereas a value of 2.5 mGy/MBq (range, 1.5-4.7) is obtained, considering the activity in both kidneys. CONCLUSIONS: Irrespective of the method, doses to kidneys obtained in the present study were about 10 times higher than the median dose of 0.22 mGy/MBq (range, 0.00-0.95) were originally reported from the study leading to Food and Drug Administration approval. Our results are in good agreement with kidney-dose estimates recently reported from high-dose myeloablative therapy with 90Y-ibritumomab tiuxetan.

A morphological, isoenzymatic and behavioural study of ten populations of Anopheles(Nyssorhynchus) albitarsis Lynch-Arribalzaga, 1878 (Diptera: culicidae) including from the type-locality - Baradero, Argentina

Anopheles (Nyssorhynchus) albitarsis Lynch-Arribalzaga, 1878 shows morphological and behavioural variations which results in it being sometimes considered as a major malaria vector and at other times as playing no important role in epidemiology. With the aim of clarifying the taxonomy of the species, comparative morphological and isoenzymatic studies were made in populations from the type-locality, Baradero, Argentina and from 9 different localities inBrazil. Morphological studies consisted of the observation of eggs in scanning electron microscopy, of complete chaetotaxy of larvae and pupae and of the detailed drawing of male and female adults. Only Guajara-Mirim and Rio Branco populations, described previously as Anopheles deaneorum sp.n., showed morphological differences. Isoenzymes were studied using 4th instar larvae homogenate and agarosegel electrophoresis. Eleven enzymatic loci were analyzed. By calculation of Nei's Genetic Distance (D), the populations could be separated into 5 groups: i)Baradero, ii)Marajo, iii)Boa Vista, iv)Angra, Itaguai and Paraipaba and v)Guajara-Mirim and Rio Branco. These groups belong to 2 major clusters called I and II, separated by D = 0.345. In the I cluster are groups i, ii and iii and in II clusteriv and v. In I, D=0.246 separates i and ii from iii, while i is separated by D =0.181 from ii. In II, D = 0.223 between iv and v. Only the population of group vcould be distinguished morphologically from the others, leading to the description of an independent species An. deaneorum.

Tractable valuations under uncertainty

I put forward a concise and intuitive formula for the calculation of the valuation for a good in the presence of the expectation that further, related, goods will soon become available. This valuation is tractable in the sense that it does not require the explicit resolution of the consumerís life-time problem.

Estudi exploratori per a la reconstrucció de temperatures de l'aigua i de l'aire en la conca central del llac Baikal (Sibèria) en els últims 40000 anys

Aquest estudi consisteix en un anàlisi exploratori que té per objectiu principal la realització d’una reconstrucció de la temperatura de l’aigua i l’aire del llac Baikal durant els últims 40.000 anys. El treball s’ha dut a terme mitjançant l’ús de les proxys de reconstrucció de la temperatura y la utilització dels mètodes TEX86, MAAT, i la d’aportació de matèria orgànica d’origen terrestre, el BIT, aplicant-les a la mostra VER93-2 st GC-24, extreta pel Baikal Drilling Project a la conca central, amb l’objectiu de fer una aportació de dades paleoclimàtiques per tal d’aconseguir una millora en les interpretacions de futurs esdeveniments climàtics, i d’identificar esdeveniments climàtics sobtats, tals com els Heinrich events i els Youngers Dryas. Abans de la realització de l’anàlisi de les mostres s’ha dut a terme una extrapolació de l’edat en el testimoni, degut a que l’edat del core BDP VER93-2.st.GC-24 havia estat extrapolada fins a 277,5 cm de profunditat i en el present estudi s’ha ampliat l’anàlisi fins als 460 cm. de profunditat. Un cop obtinguts els resultats s’ha realitzat un càlcul de precisió i reproductibilitat per tal de conèixer una estimació quantitativa de la variabilitat de les dades obtingudes en les diferents proxys, en el qual ha estat demostrat una baixa variabilitat de les dades, exceptuant la variabilitat del TEX86 i la precisió del MAAT. Per a la localització dels diferents esdeveniments climàtics donats durant l’Holocè i el Plistocè s’han realitzat anàlisis gràfics dels propis resultats, juntament i en comparació dels resultats realitzats per Escala et al. (r.n.p [resultats no publicats]) en la conca sud, i de l’estudi publicat per Prokopenko et al., en el que s’analitza la presència de diatomees i matèria orgànica l’Atlàntic Nord. Els resultats integrats d’Escala et al.,(r.n.p) i els d’aquest estudi coincideixen en la datació dels diferents esdeveniments, amb alguna variació hipotèticament produïda per l’extrapolació d’edat realitzada en el present estudi i la gran aportació de matèria orgànica en el lloc d’extracció del testimoni per part del riu Selenga. Aquests resultats mostren una possible relació entre els esdeveniments climàtics i la variació de la temperatura de l’aigua.

Deadlock avoidance with virtual channels

High Performance Computing is a rapidly evolving area of computer science which attends to solve complicated computational problems with the combination of computational nodes connected through high speed networks. This work concentrates on the networks problems that appear in such networks and specially focuses on the Deadlock problem that can decrease the efficiency of the communication or even destroy the balance and paralyze the network. Goal of this work is the Deadlock avoidance with the use of virtual channels, in the switches of the network where the problem appears. The deadlock avoidance assures that will not be loss of data inside network, having as result the increased latency of the served packets, due to the extra calculation that the switches have to make to apply the policy.

Balanç de carbó atmosfèric: raó entre les emissions de metà de les vaques i el segrest forestal de CO2

Treball de recerca realitzat per un alumne d'ensenyament secundari i guardonat amb un Premi CIRIT per fomentar l'esperit científic del Jovent l'any 2009. L’objectiu d’aquest treball és determinar la capacitat de segrest de CO2 d’un bosc dels Pirineus, per tal de reduir el seu efecte hivernacle, en relació a l’impacte climàtic que tindrien les emissions de metà de les vaques. La metodologia s’ha basat en estimar la producció de fusta a partir d’inventaris forestals d’un bosc del Pallars Sobirà, i calcular-ne el segrest de CO2. Per altra banda, s’ha estimat bibliogràficament les emissions de metà d’una vaca. A partir de factors de conversió s’ha estimat la superfície de bosc que compensaria l’efecte hivernacle de les emissions de metà d’una vaca durant un any. El valor obtingut és de 0,727 hectàrees de bosc per vaca i any. Amb aquest valor s’ha estimat la superfície de bosc necessària per compensar les emissions de metà de la població de vaques de Catalunya. Aquests resultats són aproximats, donades les diferències en el creixement dels boscos de Catalunya. Aquest estudi dóna una dada comprensible que posa de manifest el concepte de balanç de carboni i els diferents elements que el formen.